Mixed Topics

You only are free when you realize you belong no place – you belong every place – no place at all. The price is high. The reward is great. ~ Maya Angelou

At 8 o’clock, every weekday morning, for years and years now, two friends appear in my kitchen for coffee, and so one identity I carry includes being part of the “coffee ladies.” While this is one of the smaller and more intimate groups to which I belong, I am also a member (“distinguished,” no less) of a slightly larger group: the American Psychiatric Association, and being part of both groups is meaningful to me in more ways than I can describe.

When I think back over the years, I – like most people – have belonged to many people and places, either officially or unofficially. It is these connections that define us, fill our time, give us meaning and purpose, and anchor us. We belong to our families and friends, but we also belong to our professional and community groups, our institutions – whether they are hospitals, schools, religious centers, country clubs, or charitable organizations – as well as interest and advocacy groups. And finally, we belong to our coworkers and to our patients, and they to us, especially if we see the same people over time. Being a psychiatrist can be a solitary career, and it can take a little effort to be a part of larger worlds, especially for those who find solace in more individual activities.

As I’ve gotten older, I’ve noticed that I belong to fewer of these groups. I’m no longer a little league or field hockey mom, nor a member of the neighborhood babysitting co-op, and I’ve exhausted the gamut of council and leadership positions in my APA district branch. I’ve joined organizations only to pay the membership fee, and then never gone to their meetings or events. The pandemic has accounted for some of this: I still belong to my book club, but I often read the book and don’t go to the Zoom meetings as I miss the real-life aspect of getting together. Being boxed on a screen is not the same as the one-on-one conversations before the formal book discussion. And while I still carry a host of identities, I imagine it is not unusual to belong to fewer organizations as time passes. It’s not all bad, there is something good to be said for living life at a less frenetic pace as fewer entities lay claim to my time.

In psychiatry, our patients span the range of human experience: Some are very engaged with their worlds, while others struggle to make even the most basic of connections. Their lives may seem disconnected – empty, even – and I find myself encouraging people to reach out, to find activities that will ease their loneliness and integrate a feeling of belonging in a way that adds meaning and purpose. For some people, this may be as simple as asking a friend to have lunch, but even that can be an overwhelming obstacle for someone who is depressed, or for someone who has no friends.

Patients may counter my suggestions with a host of reasons as to why they can’t connect. Perhaps their friend is too busy with work or his family, the lunch would cost too much, there’s no transportation, or no restaurant that could meet their dietary needs. Or perhaps they are just too fearful of being rejected.

Psychiatric disorders, by their nature, can be very isolating. Depressed and anxious people often find it a struggle just to get through their days, adding new people and activities is not something that brings joy. For people suffering with psychosis, their internal realities are often all-consuming and there may be no room for accommodating others. And finally, what I hear over and over, is that people are afraid of what others might think of them, and this fear is paralyzing. I try to suggest that we never really know or control what others think of us, but obviously, this does not reassure most patients as they are also bewildered by their irrational fear. To go to an event unaccompanied, or even to a party to which they have been invited, is a hurdle they won’t (or can’t) attempt.

The pandemic, with its initial months of shutdown, and then with years of fear of illness, has created new ways of connecting. Our “Zoom” world can be very convenient – in many ways it has opened up aspects of learning and connection for people who are short on time,or struggle with transportation. In the comfort of our living rooms, in pajamas and slippers, we can take classes, join clubs, attend Alcoholics Anonymous meetings, go to conferences or religious services, and be part of any number of organizations without flying or searching for parking. I love that, with 1 hour and a single click, I can now attend my department’s weekly Grand Rounds. But for many who struggle with using technology, or who don’t feel the same benefits from online encounters, the pandemic has been an isolating and lonely time.

It should not be assumed that isolation has been a negative experience for everyone. For many who struggle with interpersonal relationships, for children who are bullied or teased at school or who feel self-conscious sitting alone at lunch, there may not be the presumed “fear of missing out.” As one adult patient told me: “You know, I do ‘alone’ well.” For some, it has been a relief to be relieved of the pressure to socialize, attend parties, or pursue online dating – a process I think of as “people-shopping” which looks so different from the old days of organic interactions that led to romantic interactions over time. Many have found relief without the pressures of social interactions.

Community, connection, and belonging are not inconsequential things, however. They are part of what adds to life’s richness, and they are associated with good health and longevity. The Harvard Study of Adult Development, begun in 1938, has been tracking two groups of Boston teenagers – and now their wives and children – for 84 years. Tracking one group of Harvard students and another group of teens from poorer areas in Boston, the project is now on its 4th director.

George Vaillant, MD, author of “Aging Well: Surprising Guideposts to a Happier Life from the Landmark Harvard Study of Adult Development” (New York: Little, Brown Spark, 2002) was the program’s director from 1972 to 2004. “When the study began, nobody cared about empathy or attachment. But the key to healthy aging is relationships, relationships, relationships,” Dr. Vaillant said in an interview in the Harvard Gazette.

Susan Pinker is a social psychologist and author of “The Village Effect: How Face-to-Face Contact Can Make Us Healthier and Happier” (Toronto: Random House Canada, 2014). In her 2017 TED talk, she notes that in all developed countries, women live 6-8 years longer than men, and are half as likely to die at any age. She is underwhelmed by digital relationships, and says that real life relationships affect our physiological states differently and in more beneficial ways. “Building your village and sustaining it is a matter of life and death,” she states at the end of her TED talk.

I spoke with Ms. Pinker about her thoughts on how our personal villages change over time. She was quick to tell me that she is not against digital communities. “I’m not a Luddite. As a writer, I probably spend as much time facing a screen as anyone else. But it’s important to remember that digital communities can amplify existing relationships, and don’t replace in-person social contact. A lot of people have drunk the Kool-Aid about virtual experiences, even though they are not the same as real life interactions.

“Loneliness takes on a U-shaped function across adulthood,” she explained with regard to how age impacts our social connections. “People are lonely when they first leave home or when they finish college and go out into the world. Then they settle into new situations; they can make friends at work, through their children, in their neighborhood, or by belonging to organizations. As people settle into their adult lives, there are increased opportunities to connect in person. But loneliness increases again in late middle age.” She explained that everyone loses people as their children move away, friends move, and couples may divorce or a spouse dies.

“Attrition of our social face-to-face networks is an ugly feature of aging,” Ms. Pinker said. “Some people are good at replacing the vacant spots; they sense that it is important to invest in different relationships as you age. It’s like a garden that you need to tend by replacing the perennials that die off in the winter.” The United States, she pointed out, has a culture that is particularly difficult for people in their later years.

My world is a little quieter than it once was, but collecting and holding on to people is important to me. The organizations and affiliations change over time, as does the brand of coffee. So I try to inspire some of my more isolated patients to prioritize their relationships, to let go of their grudges, to tolerate the discomfort of moving from their places of comfort to the temporary discomfort of reaching out in the service of achieving a less solitary, more purposeful, and healthier life. When it doesn’t come naturally, it can be hard work.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

You only are free when you realize you belong no place – you belong every place – no place at all. The price is high. The reward is great. ~ Maya Angelou

At 8 o’clock, every weekday morning, for years and years now, two friends appear in my kitchen for coffee, and so one identity I carry includes being part of the “coffee ladies.” While this is one of the smaller and more intimate groups to which I belong, I am also a member (“distinguished,” no less) of a slightly larger group: the American Psychiatric Association, and being part of both groups is meaningful to me in more ways than I can describe.

When I think back over the years, I – like most people – have belonged to many people and places, either officially or unofficially. It is these connections that define us, fill our time, give us meaning and purpose, and anchor us. We belong to our families and friends, but we also belong to our professional and community groups, our institutions – whether they are hospitals, schools, religious centers, country clubs, or charitable organizations – as well as interest and advocacy groups. And finally, we belong to our coworkers and to our patients, and they to us, especially if we see the same people over time. Being a psychiatrist can be a solitary career, and it can take a little effort to be a part of larger worlds, especially for those who find solace in more individual activities.

As I’ve gotten older, I’ve noticed that I belong to fewer of these groups. I’m no longer a little league or field hockey mom, nor a member of the neighborhood babysitting co-op, and I’ve exhausted the gamut of council and leadership positions in my APA district branch. I’ve joined organizations only to pay the membership fee, and then never gone to their meetings or events. The pandemic has accounted for some of this: I still belong to my book club, but I often read the book and don’t go to the Zoom meetings as I miss the real-life aspect of getting together. Being boxed on a screen is not the same as the one-on-one conversations before the formal book discussion. And while I still carry a host of identities, I imagine it is not unusual to belong to fewer organizations as time passes. It’s not all bad, there is something good to be said for living life at a less frenetic pace as fewer entities lay claim to my time.

In psychiatry, our patients span the range of human experience: Some are very engaged with their worlds, while others struggle to make even the most basic of connections. Their lives may seem disconnected – empty, even – and I find myself encouraging people to reach out, to find activities that will ease their loneliness and integrate a feeling of belonging in a way that adds meaning and purpose. For some people, this may be as simple as asking a friend to have lunch, but even that can be an overwhelming obstacle for someone who is depressed, or for someone who has no friends.

Patients may counter my suggestions with a host of reasons as to why they can’t connect. Perhaps their friend is too busy with work or his family, the lunch would cost too much, there’s no transportation, or no restaurant that could meet their dietary needs. Or perhaps they are just too fearful of being rejected.

Psychiatric disorders, by their nature, can be very isolating. Depressed and anxious people often find it a struggle just to get through their days, adding new people and activities is not something that brings joy. For people suffering with psychosis, their internal realities are often all-consuming and there may be no room for accommodating others. And finally, what I hear over and over, is that people are afraid of what others might think of them, and this fear is paralyzing. I try to suggest that we never really know or control what others think of us, but obviously, this does not reassure most patients as they are also bewildered by their irrational fear. To go to an event unaccompanied, or even to a party to which they have been invited, is a hurdle they won’t (or can’t) attempt.

The pandemic, with its initial months of shutdown, and then with years of fear of illness, has created new ways of connecting. Our “Zoom” world can be very convenient – in many ways it has opened up aspects of learning and connection for people who are short on time,or struggle with transportation. In the comfort of our living rooms, in pajamas and slippers, we can take classes, join clubs, attend Alcoholics Anonymous meetings, go to conferences or religious services, and be part of any number of organizations without flying or searching for parking. I love that, with 1 hour and a single click, I can now attend my department’s weekly Grand Rounds. But for many who struggle with using technology, or who don’t feel the same benefits from online encounters, the pandemic has been an isolating and lonely time.

It should not be assumed that isolation has been a negative experience for everyone. For many who struggle with interpersonal relationships, for children who are bullied or teased at school or who feel self-conscious sitting alone at lunch, there may not be the presumed “fear of missing out.” As one adult patient told me: “You know, I do ‘alone’ well.” For some, it has been a relief to be relieved of the pressure to socialize, attend parties, or pursue online dating – a process I think of as “people-shopping” which looks so different from the old days of organic interactions that led to romantic interactions over time. Many have found relief without the pressures of social interactions.

Community, connection, and belonging are not inconsequential things, however. They are part of what adds to life’s richness, and they are associated with good health and longevity. The Harvard Study of Adult Development, begun in 1938, has been tracking two groups of Boston teenagers – and now their wives and children – for 84 years. Tracking one group of Harvard students and another group of teens from poorer areas in Boston, the project is now on its 4th director.

George Vaillant, MD, author of “Aging Well: Surprising Guideposts to a Happier Life from the Landmark Harvard Study of Adult Development” (New York: Little, Brown Spark, 2002) was the program’s director from 1972 to 2004. “When the study began, nobody cared about empathy or attachment. But the key to healthy aging is relationships, relationships, relationships,” Dr. Vaillant said in an interview in the Harvard Gazette.

Susan Pinker is a social psychologist and author of “The Village Effect: How Face-to-Face Contact Can Make Us Healthier and Happier” (Toronto: Random House Canada, 2014). In her 2017 TED talk, she notes that in all developed countries, women live 6-8 years longer than men, and are half as likely to die at any age. She is underwhelmed by digital relationships, and says that real life relationships affect our physiological states differently and in more beneficial ways. “Building your village and sustaining it is a matter of life and death,” she states at the end of her TED talk.

I spoke with Ms. Pinker about her thoughts on how our personal villages change over time. She was quick to tell me that she is not against digital communities. “I’m not a Luddite. As a writer, I probably spend as much time facing a screen as anyone else. But it’s important to remember that digital communities can amplify existing relationships, and don’t replace in-person social contact. A lot of people have drunk the Kool-Aid about virtual experiences, even though they are not the same as real life interactions.

“Loneliness takes on a U-shaped function across adulthood,” she explained with regard to how age impacts our social connections. “People are lonely when they first leave home or when they finish college and go out into the world. Then they settle into new situations; they can make friends at work, through their children, in their neighborhood, or by belonging to organizations. As people settle into their adult lives, there are increased opportunities to connect in person. But loneliness increases again in late middle age.” She explained that everyone loses people as their children move away, friends move, and couples may divorce or a spouse dies.

“Attrition of our social face-to-face networks is an ugly feature of aging,” Ms. Pinker said. “Some people are good at replacing the vacant spots; they sense that it is important to invest in different relationships as you age. It’s like a garden that you need to tend by replacing the perennials that die off in the winter.” The United States, she pointed out, has a culture that is particularly difficult for people in their later years.

My world is a little quieter than it once was, but collecting and holding on to people is important to me. The organizations and affiliations change over time, as does the brand of coffee. So I try to inspire some of my more isolated patients to prioritize their relationships, to let go of their grudges, to tolerate the discomfort of moving from their places of comfort to the temporary discomfort of reaching out in the service of achieving a less solitary, more purposeful, and healthier life. When it doesn’t come naturally, it can be hard work.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

You only are free when you realize you belong no place – you belong every place – no place at all. The price is high. The reward is great. ~ Maya Angelou

At 8 o’clock, every weekday morning, for years and years now, two friends appear in my kitchen for coffee, and so one identity I carry includes being part of the “coffee ladies.” While this is one of the smaller and more intimate groups to which I belong, I am also a member (“distinguished,” no less) of a slightly larger group: the American Psychiatric Association, and being part of both groups is meaningful to me in more ways than I can describe.

When I think back over the years, I – like most people – have belonged to many people and places, either officially or unofficially. It is these connections that define us, fill our time, give us meaning and purpose, and anchor us. We belong to our families and friends, but we also belong to our professional and community groups, our institutions – whether they are hospitals, schools, religious centers, country clubs, or charitable organizations – as well as interest and advocacy groups. And finally, we belong to our coworkers and to our patients, and they to us, especially if we see the same people over time. Being a psychiatrist can be a solitary career, and it can take a little effort to be a part of larger worlds, especially for those who find solace in more individual activities.

As I’ve gotten older, I’ve noticed that I belong to fewer of these groups. I’m no longer a little league or field hockey mom, nor a member of the neighborhood babysitting co-op, and I’ve exhausted the gamut of council and leadership positions in my APA district branch. I’ve joined organizations only to pay the membership fee, and then never gone to their meetings or events. The pandemic has accounted for some of this: I still belong to my book club, but I often read the book and don’t go to the Zoom meetings as I miss the real-life aspect of getting together. Being boxed on a screen is not the same as the one-on-one conversations before the formal book discussion. And while I still carry a host of identities, I imagine it is not unusual to belong to fewer organizations as time passes. It’s not all bad, there is something good to be said for living life at a less frenetic pace as fewer entities lay claim to my time.

In psychiatry, our patients span the range of human experience: Some are very engaged with their worlds, while others struggle to make even the most basic of connections. Their lives may seem disconnected – empty, even – and I find myself encouraging people to reach out, to find activities that will ease their loneliness and integrate a feeling of belonging in a way that adds meaning and purpose. For some people, this may be as simple as asking a friend to have lunch, but even that can be an overwhelming obstacle for someone who is depressed, or for someone who has no friends.

Patients may counter my suggestions with a host of reasons as to why they can’t connect. Perhaps their friend is too busy with work or his family, the lunch would cost too much, there’s no transportation, or no restaurant that could meet their dietary needs. Or perhaps they are just too fearful of being rejected.

Psychiatric disorders, by their nature, can be very isolating. Depressed and anxious people often find it a struggle just to get through their days, adding new people and activities is not something that brings joy. For people suffering with psychosis, their internal realities are often all-consuming and there may be no room for accommodating others. And finally, what I hear over and over, is that people are afraid of what others might think of them, and this fear is paralyzing. I try to suggest that we never really know or control what others think of us, but obviously, this does not reassure most patients as they are also bewildered by their irrational fear. To go to an event unaccompanied, or even to a party to which they have been invited, is a hurdle they won’t (or can’t) attempt.

The pandemic, with its initial months of shutdown, and then with years of fear of illness, has created new ways of connecting. Our “Zoom” world can be very convenient – in many ways it has opened up aspects of learning and connection for people who are short on time,or struggle with transportation. In the comfort of our living rooms, in pajamas and slippers, we can take classes, join clubs, attend Alcoholics Anonymous meetings, go to conferences or religious services, and be part of any number of organizations without flying or searching for parking. I love that, with 1 hour and a single click, I can now attend my department’s weekly Grand Rounds. But for many who struggle with using technology, or who don’t feel the same benefits from online encounters, the pandemic has been an isolating and lonely time.

It should not be assumed that isolation has been a negative experience for everyone. For many who struggle with interpersonal relationships, for children who are bullied or teased at school or who feel self-conscious sitting alone at lunch, there may not be the presumed “fear of missing out.” As one adult patient told me: “You know, I do ‘alone’ well.” For some, it has been a relief to be relieved of the pressure to socialize, attend parties, or pursue online dating – a process I think of as “people-shopping” which looks so different from the old days of organic interactions that led to romantic interactions over time. Many have found relief without the pressures of social interactions.

Community, connection, and belonging are not inconsequential things, however. They are part of what adds to life’s richness, and they are associated with good health and longevity. The Harvard Study of Adult Development, begun in 1938, has been tracking two groups of Boston teenagers – and now their wives and children – for 84 years. Tracking one group of Harvard students and another group of teens from poorer areas in Boston, the project is now on its 4th director.

George Vaillant, MD, author of “Aging Well: Surprising Guideposts to a Happier Life from the Landmark Harvard Study of Adult Development” (New York: Little, Brown Spark, 2002) was the program’s director from 1972 to 2004. “When the study began, nobody cared about empathy or attachment. But the key to healthy aging is relationships, relationships, relationships,” Dr. Vaillant said in an interview in the Harvard Gazette.

Susan Pinker is a social psychologist and author of “The Village Effect: How Face-to-Face Contact Can Make Us Healthier and Happier” (Toronto: Random House Canada, 2014). In her 2017 TED talk, she notes that in all developed countries, women live 6-8 years longer than men, and are half as likely to die at any age. She is underwhelmed by digital relationships, and says that real life relationships affect our physiological states differently and in more beneficial ways. “Building your village and sustaining it is a matter of life and death,” she states at the end of her TED talk.

I spoke with Ms. Pinker about her thoughts on how our personal villages change over time. She was quick to tell me that she is not against digital communities. “I’m not a Luddite. As a writer, I probably spend as much time facing a screen as anyone else. But it’s important to remember that digital communities can amplify existing relationships, and don’t replace in-person social contact. A lot of people have drunk the Kool-Aid about virtual experiences, even though they are not the same as real life interactions.

“Loneliness takes on a U-shaped function across adulthood,” she explained with regard to how age impacts our social connections. “People are lonely when they first leave home or when they finish college and go out into the world. Then they settle into new situations; they can make friends at work, through their children, in their neighborhood, or by belonging to organizations. As people settle into their adult lives, there are increased opportunities to connect in person. But loneliness increases again in late middle age.” She explained that everyone loses people as their children move away, friends move, and couples may divorce or a spouse dies.

“Attrition of our social face-to-face networks is an ugly feature of aging,” Ms. Pinker said. “Some people are good at replacing the vacant spots; they sense that it is important to invest in different relationships as you age. It’s like a garden that you need to tend by replacing the perennials that die off in the winter.” The United States, she pointed out, has a culture that is particularly difficult for people in their later years.

My world is a little quieter than it once was, but collecting and holding on to people is important to me. The organizations and affiliations change over time, as does the brand of coffee. So I try to inspire some of my more isolated patients to prioritize their relationships, to let go of their grudges, to tolerate the discomfort of moving from their places of comfort to the temporary discomfort of reaching out in the service of achieving a less solitary, more purposeful, and healthier life. When it doesn’t come naturally, it can be hard work.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Emergencies happen anywhere, anytime – and sometimes physicians find themselves in situations where they are the only ones who can help. “Is There a Doctor in the House?” is a new series telling these stories.

When the plane crashed, I was asleep. I had arrived the evening before with my wife and three sons at a house on Kezar Lake on the Maine–New Hampshire border. We were going to spend a week there with my wife’s four brothers and their families. I was woken by people screaming my name. I jumped out of bed and ran downstairs. My kids had been watching a float plane circling and gliding along the lake. It had crashed into the water and flipped upside down. My oldest brother-in-law jumped into his ski boat and we sped out to the scene.

All we can see are the plane’s pontoons. The rest is underwater. A woman has already surfaced, screaming. I dive in.

I find the woman’s husband and 3-year-old son struggling to get free from the plane through the smashed windshield. They manage to get to the surface. The pilot is dead, impaled through the chest by the left wing strut.

The big problem: A little girl, whom I would learn later is named Lauren, remained trapped. The water is murky but I can see her, a 5- or 6-year-old girl with this long hair, strapped in upside down and unconscious.

The mom and I dive down over and over, pulling and ripping at the door. We cannot get it open. Finally, I’m able to bend the door open enough where I can reach in, but I can’t undo the seatbelt. In my mind, I’m debating, should I try and go through the front windshield? I’m getting really tired, I can tell there’s fuel in the water, and I don’t want to drown in the plane. So I pop up to the surface and yell, “Does anyone have a knife?”

My brother-in-law shoots back to shore in the boat, screaming, “Get a knife!” My niece gets in the boat with one. I’m standing on the pontoon, and my niece is in the front of the boat calling, “Uncle Todd! Uncle Todd!” and she throws the knife. It goes way over my head. I can’t even jump for it, it’s so high.

I have to get the knife. So, I dive into the water to try and find it. Somehow, the black knife has landed on the white wing, 4 or 5 feet under the water. Pure luck. It could have sunk down a hundred feet into the lake. I grab the knife and hand it to the mom, Beth. She’s able to cut the seatbelt, and we both pull Lauren to the surface.

I lay her out on the pontoon. She has no pulse and her pupils are fixed and dilated. Her mom is yelling, “She’s dead, isn’t she?” I start CPR. My skin and eyes are burning from the airplane fuel in the water. I get her breathing, and her heart comes back very quickly. Lauren starts to vomit and I’m trying to keep her airway clear. She’s breathing spontaneously and she has a pulse, so I decide it’s time to move her to shore.

We pull the boat up to the dock and Lauren’s now having anoxic seizures. Her brain has been without oxygen, and now she’s getting perfused again. We get her to shore and lay her on the lawn. I’m still doing mouth-to-mouth, but she’s seizing like crazy, and I don’t have any way to control that. Beth is crying and wants to hold her daughter gently while I’m working.

Someone had called 911, and finally this dude shows up with an ambulance, and it’s like something out of World War II. All he has is an oxygen tank, but the mask is old and cracked. It’s too big for Lauren, but it sort of fits me, so I’m sucking in oxygen and blowing it into the girl’s mouth. I’m doing whatever I can, but I don’t have an IV to start. I have no fluids. I got nothing.

As it happens, I’d done my emergency medicine training at Maine Medical Center, so I tell someone to call them and get a Life Flight chopper. We have to drive somewhere where the chopper can land, so we take the ambulance to the parking lot of the closest store called the Wicked Good Store. That’s a common thing in Maine. Everything is “wicked good.”

The whole town is there by that point. The chopper arrives. The ambulance doors pop open and a woman says, “Todd?” And I say, “Heather?”

Heather is an emergency flight nurse whom I’d trained with many years ago. There’s immediate trust. She has all the right equipment. We put in breathing tubes and IVs. We stop Lauren from seizing. The kid is soon stable.

There is only one extra seat in the chopper, so I tell Beth to go. They take off.

Suddenly, I begin to doubt my decision. Lauren had been underwater for 15 minutes at minimum. I know how long that is. Did I do the right thing? Did I resuscitate a brain-dead child? I didn’t think about it at the time, but if that patient had come to me in the emergency department, I’m honestly not sure what I would have done.

So, I go home. And I don’t get a call. The FAA and sheriff arrive to take statements from us. I don’t hear from anyone.

The next day I start calling. No one will tell me anything, so I finally get to one of the pediatric ICU attendings who had trained me. He says Lauren literally woke up and said, “I have to go pee.” And that was it. She was 100% normal. I couldn’t believe it.

Here’s a theory: In kids, there’s something called the glottic reflex. I think her glottic reflex went off as soon as she hit the water, which basically closed her airway. So when she passed out, she could never get enough water in her lungs and still had enough air in there to keep her alive. Later, I got a call from her uncle. He could barely get the words out because he was in tears. He said Lauren was doing beautifully.  

Three days later, I drove to Lauren’s house with my wife and kids. I had her read to me. I watched her play on the jungle gym for motor function. All sorts of stuff. She was totally normal.

Beth told us that the night before the accident, her mother had given the women in her family what she called a “miracle bracelet,” a bracelet that is supposed to give you one miracle in your life. Beth said she had the bracelet on her wrist the day of the accident, and now it’s gone. “Saving Lauren’s life was my miracle,” she said.

Funny thing: For 20 years, I ran all the EMS, police, fire, ambulance, in Boulder, Colo., where I live. I wrote all the protocols, and I would never advise any of my paramedics to dive into jet fuel to save someone. That was risky. But at the time, it was totally automatic. I think it taught me not to give up in certain situations, because you really don’t know.

Dr. Dorfman is an emergency medicine physician in Boulder, Colo., and medical director at Cedalion Health.
 

A version of this article first appeared on Medscape.com.

Emergencies happen anywhere, anytime – and sometimes physicians find themselves in situations where they are the only ones who can help. “Is There a Doctor in the House?” is a new series telling these stories.

When the plane crashed, I was asleep. I had arrived the evening before with my wife and three sons at a house on Kezar Lake on the Maine–New Hampshire border. We were going to spend a week there with my wife’s four brothers and their families. I was woken by people screaming my name. I jumped out of bed and ran downstairs. My kids had been watching a float plane circling and gliding along the lake. It had crashed into the water and flipped upside down. My oldest brother-in-law jumped into his ski boat and we sped out to the scene.

All we can see are the plane’s pontoons. The rest is underwater. A woman has already surfaced, screaming. I dive in.

I find the woman’s husband and 3-year-old son struggling to get free from the plane through the smashed windshield. They manage to get to the surface. The pilot is dead, impaled through the chest by the left wing strut.

The big problem: A little girl, whom I would learn later is named Lauren, remained trapped. The water is murky but I can see her, a 5- or 6-year-old girl with this long hair, strapped in upside down and unconscious.

The mom and I dive down over and over, pulling and ripping at the door. We cannot get it open. Finally, I’m able to bend the door open enough where I can reach in, but I can’t undo the seatbelt. In my mind, I’m debating, should I try and go through the front windshield? I’m getting really tired, I can tell there’s fuel in the water, and I don’t want to drown in the plane. So I pop up to the surface and yell, “Does anyone have a knife?”

My brother-in-law shoots back to shore in the boat, screaming, “Get a knife!” My niece gets in the boat with one. I’m standing on the pontoon, and my niece is in the front of the boat calling, “Uncle Todd! Uncle Todd!” and she throws the knife. It goes way over my head. I can’t even jump for it, it’s so high.

I have to get the knife. So, I dive into the water to try and find it. Somehow, the black knife has landed on the white wing, 4 or 5 feet under the water. Pure luck. It could have sunk down a hundred feet into the lake. I grab the knife and hand it to the mom, Beth. She’s able to cut the seatbelt, and we both pull Lauren to the surface.

I lay her out on the pontoon. She has no pulse and her pupils are fixed and dilated. Her mom is yelling, “She’s dead, isn’t she?” I start CPR. My skin and eyes are burning from the airplane fuel in the water. I get her breathing, and her heart comes back very quickly. Lauren starts to vomit and I’m trying to keep her airway clear. She’s breathing spontaneously and she has a pulse, so I decide it’s time to move her to shore.

We pull the boat up to the dock and Lauren’s now having anoxic seizures. Her brain has been without oxygen, and now she’s getting perfused again. We get her to shore and lay her on the lawn. I’m still doing mouth-to-mouth, but she’s seizing like crazy, and I don’t have any way to control that. Beth is crying and wants to hold her daughter gently while I’m working.

Someone had called 911, and finally this dude shows up with an ambulance, and it’s like something out of World War II. All he has is an oxygen tank, but the mask is old and cracked. It’s too big for Lauren, but it sort of fits me, so I’m sucking in oxygen and blowing it into the girl’s mouth. I’m doing whatever I can, but I don’t have an IV to start. I have no fluids. I got nothing.

As it happens, I’d done my emergency medicine training at Maine Medical Center, so I tell someone to call them and get a Life Flight chopper. We have to drive somewhere where the chopper can land, so we take the ambulance to the parking lot of the closest store called the Wicked Good Store. That’s a common thing in Maine. Everything is “wicked good.”

The whole town is there by that point. The chopper arrives. The ambulance doors pop open and a woman says, “Todd?” And I say, “Heather?”

Heather is an emergency flight nurse whom I’d trained with many years ago. There’s immediate trust. She has all the right equipment. We put in breathing tubes and IVs. We stop Lauren from seizing. The kid is soon stable.

There is only one extra seat in the chopper, so I tell Beth to go. They take off.

Suddenly, I begin to doubt my decision. Lauren had been underwater for 15 minutes at minimum. I know how long that is. Did I do the right thing? Did I resuscitate a brain-dead child? I didn’t think about it at the time, but if that patient had come to me in the emergency department, I’m honestly not sure what I would have done.

So, I go home. And I don’t get a call. The FAA and sheriff arrive to take statements from us. I don’t hear from anyone.

The next day I start calling. No one will tell me anything, so I finally get to one of the pediatric ICU attendings who had trained me. He says Lauren literally woke up and said, “I have to go pee.” And that was it. She was 100% normal. I couldn’t believe it.

Here’s a theory: In kids, there’s something called the glottic reflex. I think her glottic reflex went off as soon as she hit the water, which basically closed her airway. So when she passed out, she could never get enough water in her lungs and still had enough air in there to keep her alive. Later, I got a call from her uncle. He could barely get the words out because he was in tears. He said Lauren was doing beautifully.  

Three days later, I drove to Lauren’s house with my wife and kids. I had her read to me. I watched her play on the jungle gym for motor function. All sorts of stuff. She was totally normal.

Beth told us that the night before the accident, her mother had given the women in her family what she called a “miracle bracelet,” a bracelet that is supposed to give you one miracle in your life. Beth said she had the bracelet on her wrist the day of the accident, and now it’s gone. “Saving Lauren’s life was my miracle,” she said.

Funny thing: For 20 years, I ran all the EMS, police, fire, ambulance, in Boulder, Colo., where I live. I wrote all the protocols, and I would never advise any of my paramedics to dive into jet fuel to save someone. That was risky. But at the time, it was totally automatic. I think it taught me not to give up in certain situations, because you really don’t know.

Dr. Dorfman is an emergency medicine physician in Boulder, Colo., and medical director at Cedalion Health.
 

A version of this article first appeared on Medscape.com.

Emergencies happen anywhere, anytime – and sometimes physicians find themselves in situations where they are the only ones who can help. “Is There a Doctor in the House?” is a new series telling these stories.

When the plane crashed, I was asleep. I had arrived the evening before with my wife and three sons at a house on Kezar Lake on the Maine–New Hampshire border. We were going to spend a week there with my wife’s four brothers and their families. I was woken by people screaming my name. I jumped out of bed and ran downstairs. My kids had been watching a float plane circling and gliding along the lake. It had crashed into the water and flipped upside down. My oldest brother-in-law jumped into his ski boat and we sped out to the scene.

All we can see are the plane’s pontoons. The rest is underwater. A woman has already surfaced, screaming. I dive in.

I find the woman’s husband and 3-year-old son struggling to get free from the plane through the smashed windshield. They manage to get to the surface. The pilot is dead, impaled through the chest by the left wing strut.

The big problem: A little girl, whom I would learn later is named Lauren, remained trapped. The water is murky but I can see her, a 5- or 6-year-old girl with this long hair, strapped in upside down and unconscious.

The mom and I dive down over and over, pulling and ripping at the door. We cannot get it open. Finally, I’m able to bend the door open enough where I can reach in, but I can’t undo the seatbelt. In my mind, I’m debating, should I try and go through the front windshield? I’m getting really tired, I can tell there’s fuel in the water, and I don’t want to drown in the plane. So I pop up to the surface and yell, “Does anyone have a knife?”

My brother-in-law shoots back to shore in the boat, screaming, “Get a knife!” My niece gets in the boat with one. I’m standing on the pontoon, and my niece is in the front of the boat calling, “Uncle Todd! Uncle Todd!” and she throws the knife. It goes way over my head. I can’t even jump for it, it’s so high.

I have to get the knife. So, I dive into the water to try and find it. Somehow, the black knife has landed on the white wing, 4 or 5 feet under the water. Pure luck. It could have sunk down a hundred feet into the lake. I grab the knife and hand it to the mom, Beth. She’s able to cut the seatbelt, and we both pull Lauren to the surface.

I lay her out on the pontoon. She has no pulse and her pupils are fixed and dilated. Her mom is yelling, “She’s dead, isn’t she?” I start CPR. My skin and eyes are burning from the airplane fuel in the water. I get her breathing, and her heart comes back very quickly. Lauren starts to vomit and I’m trying to keep her airway clear. She’s breathing spontaneously and she has a pulse, so I decide it’s time to move her to shore.

We pull the boat up to the dock and Lauren’s now having anoxic seizures. Her brain has been without oxygen, and now she’s getting perfused again. We get her to shore and lay her on the lawn. I’m still doing mouth-to-mouth, but she’s seizing like crazy, and I don’t have any way to control that. Beth is crying and wants to hold her daughter gently while I’m working.

Someone had called 911, and finally this dude shows up with an ambulance, and it’s like something out of World War II. All he has is an oxygen tank, but the mask is old and cracked. It’s too big for Lauren, but it sort of fits me, so I’m sucking in oxygen and blowing it into the girl’s mouth. I’m doing whatever I can, but I don’t have an IV to start. I have no fluids. I got nothing.

As it happens, I’d done my emergency medicine training at Maine Medical Center, so I tell someone to call them and get a Life Flight chopper. We have to drive somewhere where the chopper can land, so we take the ambulance to the parking lot of the closest store called the Wicked Good Store. That’s a common thing in Maine. Everything is “wicked good.”

The whole town is there by that point. The chopper arrives. The ambulance doors pop open and a woman says, “Todd?” And I say, “Heather?”

Heather is an emergency flight nurse whom I’d trained with many years ago. There’s immediate trust. She has all the right equipment. We put in breathing tubes and IVs. We stop Lauren from seizing. The kid is soon stable.

There is only one extra seat in the chopper, so I tell Beth to go. They take off.

Suddenly, I begin to doubt my decision. Lauren had been underwater for 15 minutes at minimum. I know how long that is. Did I do the right thing? Did I resuscitate a brain-dead child? I didn’t think about it at the time, but if that patient had come to me in the emergency department, I’m honestly not sure what I would have done.

So, I go home. And I don’t get a call. The FAA and sheriff arrive to take statements from us. I don’t hear from anyone.

The next day I start calling. No one will tell me anything, so I finally get to one of the pediatric ICU attendings who had trained me. He says Lauren literally woke up and said, “I have to go pee.” And that was it. She was 100% normal. I couldn’t believe it.

Here’s a theory: In kids, there’s something called the glottic reflex. I think her glottic reflex went off as soon as she hit the water, which basically closed her airway. So when she passed out, she could never get enough water in her lungs and still had enough air in there to keep her alive. Later, I got a call from her uncle. He could barely get the words out because he was in tears. He said Lauren was doing beautifully.  

Three days later, I drove to Lauren’s house with my wife and kids. I had her read to me. I watched her play on the jungle gym for motor function. All sorts of stuff. She was totally normal.

Beth told us that the night before the accident, her mother had given the women in her family what she called a “miracle bracelet,” a bracelet that is supposed to give you one miracle in your life. Beth said she had the bracelet on her wrist the day of the accident, and now it’s gone. “Saving Lauren’s life was my miracle,” she said.

Funny thing: For 20 years, I ran all the EMS, police, fire, ambulance, in Boulder, Colo., where I live. I wrote all the protocols, and I would never advise any of my paramedics to dive into jet fuel to save someone. That was risky. But at the time, it was totally automatic. I think it taught me not to give up in certain situations, because you really don’t know.

Dr. Dorfman is an emergency medicine physician in Boulder, Colo., and medical director at Cedalion Health.
 

A version of this article first appeared on Medscape.com.

What’s the opposite of an antibiotic?

Everyone knows that LOTME loves a good dichotomy: yin/yang, good/evil, heads/tails, particle/wave, peanut butter/jelly. They’re all great. We’re also big fans of microbiomes, particularly the gut microbiome. But what if we could combine the two? A healthy and nutritious story about the gut microbiome, with a dash of added dichotomy for flavor. Is such a thing even possible? Let’s find out.

Nastya Dulhiier/Unsplash

First, we need an antibiotic, a drug designed to fight bacterial infections. If you’ve got strep throat, otitis media, or bubonic plague, there’s a good chance you will receive an antibiotic. That antibiotic will kill the bad bacteria that are making you sick, but it will also kill a lot of the good bacteria that inhabit your gut microbiome, which results in side effects like bloating and diarrhea.

It comes down to diversity, explained Elisa Marroquin, PhD, of Texas Christian University (Go Horned Frogs!): “In a human community, we need people that have different professions because we don’t all know how to do every single job. And so the same happens with bacteria. We need lots of different gut bacteria that know how to do different things.”

She and her colleagues reviewed 29 studies published over the last 7 years and found a way to preserve the diversity of a human gut microbiome that’s dealing with an antibiotic. Their solution? Prescribe a probiotic.

The way to fight the effects of stopping a bacterial infection is to provide food for what are, basically, other bacterial infections. Antibiotic/probiotic is a prescription for dichotomy, and it means we managed to combine gut microbiomes with a dichotomy. And you didn’t think we could do it.
 

The earphone of hearing aids

It’s estimated that up to 75% of people who need hearing aids don’t wear them. Why? Well, there’s the social stigma about not wanting to appear too old, and then there’s the cost factor.

Antoni Shkraba/Pexels

Is there a cheaper, less stigmatizing option to amplify hearing? The answer, according to otolaryngologist Yen-fu Cheng, MD, of Taipei Veterans General Hospital and associates, is wireless earphones. AirPods, if you want to be brand specific.

Airpods can be on the more expensive side – running about $129 for AirPods 2 and $249 for AirPods Pro – but when compared with premium hearing aids ($10,000), or even basic aids (about $1,500), the Apple products come off inexpensive after all.

The team tested the premium and basic hearing aids against the AirPods 2 and the AirPod Pro using Apple’s Live Listen feature, which helps amplify sound through the company’s wireless earphones and iPhones and was initially designed to assist people with normal hearing in situations such as birdwatching.

The AirPods Pro worked just as well as the basic hearing aid but not quite as well as the premium hearing aid in a quiet setting, while the AirPods 2 performed the worst. When tested in a noisy setting, the AirPods Pro was pretty comparable to the premium hearing aid, as long as the noise came from a lateral direction. Neither of the AirPod models did as well as the hearing aids with head-on noises.

Wireless earbuds may not be the perfect solution from a clinical standpoint, but they’re a good start for people who don’t have access to hearing aids, Dr. Cheng noted.

So who says headphones damage your hearing? They might actually help.
 

Now I lay me down to sleep, I pray the computer my soul to keep

Radiation is the boring hazard of space travel. No one dies in a space horror movie because they’ve been slowly exposed to too much cosmic radiation. It’s always “thrown out the airlock” this and “eaten by a xenomorph” that.

Michael Chiara/Unsplash

Radiation, however, is not something that can be ignored, but it turns out that a potential solution is another science fiction staple: artificial hibernation. Generally in sci-fi, hibernation is a plot convenience to get people from point A to point B in a ship that doesn’t break the laws of physics. Here on Earth, though, it is well known that animals naturally entering a state of torpor during hibernation gain significant resistance to radiation.

The problem, of course, is that humans don’t hibernate, and no matter how hard people who work 100-hour weeks for Elon Musk try, sleeping for months on end is simply something we can’t do. However, a new study shows that it’s possible to induce this torpor state in animals that don’t naturally hibernate. By injecting rats with adenosine 5’-monophosphate monohydrate and keeping them in a room held at 16° C, an international team of scientists successfully induced a synthetic torpor state.

That’s not all they did: The scientists also exposed the hibernating rats to a large dose of radiation approximating that found in deep space. Which isn’t something we’d like to explain to our significant other when we got home from work. “So how was your day?” “Oh, I irradiated a bunch of sleeping rats. … Don’t worry they’re fine!” Which they were. Thanks to the hypoxic and hypothermic state, the tissue was spared damage from the high-energy ion radiation.

Obviously, there’s a big difference between a rat and a human and a lot of work to be done, but the study does show that artificial hibernation is possible. Perhaps one day we’ll be able to fall asleep and wake up light-years away under an alien sky, and we won’t be horrifically mutated or riddled with cancer. If, however, you find yourself in hibernation on your way to Jupiter (or Saturn) to investigate a mysterious black monolith, we suggest sleeping with one eye open and gripping your pillow tight.

What’s the opposite of an antibiotic?

Everyone knows that LOTME loves a good dichotomy: yin/yang, good/evil, heads/tails, particle/wave, peanut butter/jelly. They’re all great. We’re also big fans of microbiomes, particularly the gut microbiome. But what if we could combine the two? A healthy and nutritious story about the gut microbiome, with a dash of added dichotomy for flavor. Is such a thing even possible? Let’s find out.

Nastya Dulhiier/Unsplash

First, we need an antibiotic, a drug designed to fight bacterial infections. If you’ve got strep throat, otitis media, or bubonic plague, there’s a good chance you will receive an antibiotic. That antibiotic will kill the bad bacteria that are making you sick, but it will also kill a lot of the good bacteria that inhabit your gut microbiome, which results in side effects like bloating and diarrhea.

It comes down to diversity, explained Elisa Marroquin, PhD, of Texas Christian University (Go Horned Frogs!): “In a human community, we need people that have different professions because we don’t all know how to do every single job. And so the same happens with bacteria. We need lots of different gut bacteria that know how to do different things.”

She and her colleagues reviewed 29 studies published over the last 7 years and found a way to preserve the diversity of a human gut microbiome that’s dealing with an antibiotic. Their solution? Prescribe a probiotic.

The way to fight the effects of stopping a bacterial infection is to provide food for what are, basically, other bacterial infections. Antibiotic/probiotic is a prescription for dichotomy, and it means we managed to combine gut microbiomes with a dichotomy. And you didn’t think we could do it.
 

The earphone of hearing aids

It’s estimated that up to 75% of people who need hearing aids don’t wear them. Why? Well, there’s the social stigma about not wanting to appear too old, and then there’s the cost factor.

Antoni Shkraba/Pexels

Is there a cheaper, less stigmatizing option to amplify hearing? The answer, according to otolaryngologist Yen-fu Cheng, MD, of Taipei Veterans General Hospital and associates, is wireless earphones. AirPods, if you want to be brand specific.

Airpods can be on the more expensive side – running about $129 for AirPods 2 and $249 for AirPods Pro – but when compared with premium hearing aids ($10,000), or even basic aids (about $1,500), the Apple products come off inexpensive after all.

The team tested the premium and basic hearing aids against the AirPods 2 and the AirPod Pro using Apple’s Live Listen feature, which helps amplify sound through the company’s wireless earphones and iPhones and was initially designed to assist people with normal hearing in situations such as birdwatching.

The AirPods Pro worked just as well as the basic hearing aid but not quite as well as the premium hearing aid in a quiet setting, while the AirPods 2 performed the worst. When tested in a noisy setting, the AirPods Pro was pretty comparable to the premium hearing aid, as long as the noise came from a lateral direction. Neither of the AirPod models did as well as the hearing aids with head-on noises.

Wireless earbuds may not be the perfect solution from a clinical standpoint, but they’re a good start for people who don’t have access to hearing aids, Dr. Cheng noted.

So who says headphones damage your hearing? They might actually help.
 

Now I lay me down to sleep, I pray the computer my soul to keep

Radiation is the boring hazard of space travel. No one dies in a space horror movie because they’ve been slowly exposed to too much cosmic radiation. It’s always “thrown out the airlock” this and “eaten by a xenomorph” that.

Michael Chiara/Unsplash

Radiation, however, is not something that can be ignored, but it turns out that a potential solution is another science fiction staple: artificial hibernation. Generally in sci-fi, hibernation is a plot convenience to get people from point A to point B in a ship that doesn’t break the laws of physics. Here on Earth, though, it is well known that animals naturally entering a state of torpor during hibernation gain significant resistance to radiation.

The problem, of course, is that humans don’t hibernate, and no matter how hard people who work 100-hour weeks for Elon Musk try, sleeping for months on end is simply something we can’t do. However, a new study shows that it’s possible to induce this torpor state in animals that don’t naturally hibernate. By injecting rats with adenosine 5’-monophosphate monohydrate and keeping them in a room held at 16° C, an international team of scientists successfully induced a synthetic torpor state.

That’s not all they did: The scientists also exposed the hibernating rats to a large dose of radiation approximating that found in deep space. Which isn’t something we’d like to explain to our significant other when we got home from work. “So how was your day?” “Oh, I irradiated a bunch of sleeping rats. … Don’t worry they’re fine!” Which they were. Thanks to the hypoxic and hypothermic state, the tissue was spared damage from the high-energy ion radiation.

Obviously, there’s a big difference between a rat and a human and a lot of work to be done, but the study does show that artificial hibernation is possible. Perhaps one day we’ll be able to fall asleep and wake up light-years away under an alien sky, and we won’t be horrifically mutated or riddled with cancer. If, however, you find yourself in hibernation on your way to Jupiter (or Saturn) to investigate a mysterious black monolith, we suggest sleeping with one eye open and gripping your pillow tight.

What’s the opposite of an antibiotic?

Everyone knows that LOTME loves a good dichotomy: yin/yang, good/evil, heads/tails, particle/wave, peanut butter/jelly. They’re all great. We’re also big fans of microbiomes, particularly the gut microbiome. But what if we could combine the two? A healthy and nutritious story about the gut microbiome, with a dash of added dichotomy for flavor. Is such a thing even possible? Let’s find out.

Nastya Dulhiier/Unsplash

First, we need an antibiotic, a drug designed to fight bacterial infections. If you’ve got strep throat, otitis media, or bubonic plague, there’s a good chance you will receive an antibiotic. That antibiotic will kill the bad bacteria that are making you sick, but it will also kill a lot of the good bacteria that inhabit your gut microbiome, which results in side effects like bloating and diarrhea.

It comes down to diversity, explained Elisa Marroquin, PhD, of Texas Christian University (Go Horned Frogs!): “In a human community, we need people that have different professions because we don’t all know how to do every single job. And so the same happens with bacteria. We need lots of different gut bacteria that know how to do different things.”

She and her colleagues reviewed 29 studies published over the last 7 years and found a way to preserve the diversity of a human gut microbiome that’s dealing with an antibiotic. Their solution? Prescribe a probiotic.

The way to fight the effects of stopping a bacterial infection is to provide food for what are, basically, other bacterial infections. Antibiotic/probiotic is a prescription for dichotomy, and it means we managed to combine gut microbiomes with a dichotomy. And you didn’t think we could do it.
 

The earphone of hearing aids

It’s estimated that up to 75% of people who need hearing aids don’t wear them. Why? Well, there’s the social stigma about not wanting to appear too old, and then there’s the cost factor.

Antoni Shkraba/Pexels

Is there a cheaper, less stigmatizing option to amplify hearing? The answer, according to otolaryngologist Yen-fu Cheng, MD, of Taipei Veterans General Hospital and associates, is wireless earphones. AirPods, if you want to be brand specific.

Airpods can be on the more expensive side – running about $129 for AirPods 2 and $249 for AirPods Pro – but when compared with premium hearing aids ($10,000), or even basic aids (about $1,500), the Apple products come off inexpensive after all.

The team tested the premium and basic hearing aids against the AirPods 2 and the AirPod Pro using Apple’s Live Listen feature, which helps amplify sound through the company’s wireless earphones and iPhones and was initially designed to assist people with normal hearing in situations such as birdwatching.

The AirPods Pro worked just as well as the basic hearing aid but not quite as well as the premium hearing aid in a quiet setting, while the AirPods 2 performed the worst. When tested in a noisy setting, the AirPods Pro was pretty comparable to the premium hearing aid, as long as the noise came from a lateral direction. Neither of the AirPod models did as well as the hearing aids with head-on noises.

Wireless earbuds may not be the perfect solution from a clinical standpoint, but they’re a good start for people who don’t have access to hearing aids, Dr. Cheng noted.

So who says headphones damage your hearing? They might actually help.
 

Now I lay me down to sleep, I pray the computer my soul to keep

Radiation is the boring hazard of space travel. No one dies in a space horror movie because they’ve been slowly exposed to too much cosmic radiation. It’s always “thrown out the airlock” this and “eaten by a xenomorph” that.

Michael Chiara/Unsplash

Radiation, however, is not something that can be ignored, but it turns out that a potential solution is another science fiction staple: artificial hibernation. Generally in sci-fi, hibernation is a plot convenience to get people from point A to point B in a ship that doesn’t break the laws of physics. Here on Earth, though, it is well known that animals naturally entering a state of torpor during hibernation gain significant resistance to radiation.

The problem, of course, is that humans don’t hibernate, and no matter how hard people who work 100-hour weeks for Elon Musk try, sleeping for months on end is simply something we can’t do. However, a new study shows that it’s possible to induce this torpor state in animals that don’t naturally hibernate. By injecting rats with adenosine 5’-monophosphate monohydrate and keeping them in a room held at 16° C, an international team of scientists successfully induced a synthetic torpor state.

That’s not all they did: The scientists also exposed the hibernating rats to a large dose of radiation approximating that found in deep space. Which isn’t something we’d like to explain to our significant other when we got home from work. “So how was your day?” “Oh, I irradiated a bunch of sleeping rats. … Don’t worry they’re fine!” Which they were. Thanks to the hypoxic and hypothermic state, the tissue was spared damage from the high-energy ion radiation.

Obviously, there’s a big difference between a rat and a human and a lot of work to be done, but the study does show that artificial hibernation is possible. Perhaps one day we’ll be able to fall asleep and wake up light-years away under an alien sky, and we won’t be horrifically mutated or riddled with cancer. If, however, you find yourself in hibernation on your way to Jupiter (or Saturn) to investigate a mysterious black monolith, we suggest sleeping with one eye open and gripping your pillow tight.

Numerous species of fungi exist in cancer cells and differ by tumor type, according to findings from a large study of multiple sample types across 35 different cancers.

The investigators characterized the cancer mycobiome within 17,401 tissue, blood, and plasma samples from four international cohorts, revealing new information about fungi distribution, association with immune cells, and potential prognostic value.

Fungi were detected in all cancer types studied and were often intracellular, reported Lian Narunsky-Haziza, PhD, of Weizmann Institute of Science, Rehovot, Israel, and colleagues.

Additionally, multiple fungal-bacterial-immune ecologies were detected across tumors, and intratumoral fungi stratified clinical outcomes, including immunotherapy response, they noted. Also, cell-free fungal DNA diagnosed healthy and cancer patients in early-stage disease.

The findings, published online in the journal Cell, have potential implications for cancer detection, diagnosis, and treatment, the researchers suggested.

The existence of fungi in most human cancers “is both a surprise and to be expected,” study coauthor Rob Knight, PhD, a professor at the University of California, San Diego, stated in a press release. “It is surprising because we don’t know how fungi could get into tumors throughout the body. But it is also expected, because it fits the pattern of healthy microbiomes throughout the body, including the gut, mouth, and skin, where bacteria and fungi interact as part of a complex community.”

Exploration of the associations between cancer and microbes are nothing new, but cancer-associated fungi have rarely been examined, the authors noted.

The findings from this pan-cancer analysis, which suggested “prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers,” complement current “understanding of the interaction between cancer cells and the bacteria that exist in tumors alongside fungi, bacteria that have been shown to affect cancer growth, metastasis, and response to therapy,” they explained.

Of note, the study revealed multiple correlations between the presence of specific fungi in tumors and conditions related to treatment. For example, patients with breast cancer whose tumors contained Malassezia globosa – a fungus found naturally on the skin – had a much lower survival rate than those whose tumors did not contain the fungus. Furthermore, specific fungi were more prevalent in breast tumors from older vs. younger patients, in lung tumors of smokers vs. nonsmokers, and in melanoma tumors that responded to immunotherapy vs. those that did not respond.

These findings suggest that fungal activity is “a new and emerging hallmark of cancer,” stated study coleader Ravid Straussman, PhD, of the Weizmann molecular cell biology department. “These findings should drive us to better explore the potential effects of tumor fungi and to re-examine almost everything we know about cancer through a ‘microbiome lens.’ ”

Unique relationships observed between fungi and bacteria – for example, tumors that contain Aspergillus fungi tended to have specific bacteria in them, whereas tumors that contain Malassezia fungi tended to have other bacteria in them – may have implications for treatment, as they correlated with both tumor immunity and patient survival, according to the authors.

“This study sheds new light on the complex biological environment within tumors, and future research will reveal how fungi affect cancerous growth,” said coauthor Yitzhak Pilpel, PhD, a principal investigator at the Weizmann molecular genetics department. “The fact that fungi can be found not only in cancer cells but also in immune cells implies that, in the future, we’ll probably find that fungi have some effect not only on the cancer cells but also on immune cells and their activity.”

A further finding related to the presence of fungal and bacterial DNA in human blood further suggests that measuring microbial DNA in the blood could lead to early detection of cancer, the authors noted.

Dr. Straussman’s research is supported by the Swiss Society Institute for Cancer Prevention Research, the Fabricant-Morse Families Research Fund for Humanity, the Dr. Chantal d’Adesky Scheinberg Research Fund, and the Dr. Dvora and Haim Teitelbaum Endowment Fund.
 

A version of this article first appeared on Medscape.com.

Numerous species of fungi exist in cancer cells and differ by tumor type, according to findings from a large study of multiple sample types across 35 different cancers.

The investigators characterized the cancer mycobiome within 17,401 tissue, blood, and plasma samples from four international cohorts, revealing new information about fungi distribution, association with immune cells, and potential prognostic value.

Fungi were detected in all cancer types studied and were often intracellular, reported Lian Narunsky-Haziza, PhD, of Weizmann Institute of Science, Rehovot, Israel, and colleagues.

Additionally, multiple fungal-bacterial-immune ecologies were detected across tumors, and intratumoral fungi stratified clinical outcomes, including immunotherapy response, they noted. Also, cell-free fungal DNA diagnosed healthy and cancer patients in early-stage disease.

The findings, published online in the journal Cell, have potential implications for cancer detection, diagnosis, and treatment, the researchers suggested.

The existence of fungi in most human cancers “is both a surprise and to be expected,” study coauthor Rob Knight, PhD, a professor at the University of California, San Diego, stated in a press release. “It is surprising because we don’t know how fungi could get into tumors throughout the body. But it is also expected, because it fits the pattern of healthy microbiomes throughout the body, including the gut, mouth, and skin, where bacteria and fungi interact as part of a complex community.”

Exploration of the associations between cancer and microbes are nothing new, but cancer-associated fungi have rarely been examined, the authors noted.

The findings from this pan-cancer analysis, which suggested “prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers,” complement current “understanding of the interaction between cancer cells and the bacteria that exist in tumors alongside fungi, bacteria that have been shown to affect cancer growth, metastasis, and response to therapy,” they explained.

Of note, the study revealed multiple correlations between the presence of specific fungi in tumors and conditions related to treatment. For example, patients with breast cancer whose tumors contained Malassezia globosa – a fungus found naturally on the skin – had a much lower survival rate than those whose tumors did not contain the fungus. Furthermore, specific fungi were more prevalent in breast tumors from older vs. younger patients, in lung tumors of smokers vs. nonsmokers, and in melanoma tumors that responded to immunotherapy vs. those that did not respond.

These findings suggest that fungal activity is “a new and emerging hallmark of cancer,” stated study coleader Ravid Straussman, PhD, of the Weizmann molecular cell biology department. “These findings should drive us to better explore the potential effects of tumor fungi and to re-examine almost everything we know about cancer through a ‘microbiome lens.’ ”

Unique relationships observed between fungi and bacteria – for example, tumors that contain Aspergillus fungi tended to have specific bacteria in them, whereas tumors that contain Malassezia fungi tended to have other bacteria in them – may have implications for treatment, as they correlated with both tumor immunity and patient survival, according to the authors.

“This study sheds new light on the complex biological environment within tumors, and future research will reveal how fungi affect cancerous growth,” said coauthor Yitzhak Pilpel, PhD, a principal investigator at the Weizmann molecular genetics department. “The fact that fungi can be found not only in cancer cells but also in immune cells implies that, in the future, we’ll probably find that fungi have some effect not only on the cancer cells but also on immune cells and their activity.”

A further finding related to the presence of fungal and bacterial DNA in human blood further suggests that measuring microbial DNA in the blood could lead to early detection of cancer, the authors noted.

Dr. Straussman’s research is supported by the Swiss Society Institute for Cancer Prevention Research, the Fabricant-Morse Families Research Fund for Humanity, the Dr. Chantal d’Adesky Scheinberg Research Fund, and the Dr. Dvora and Haim Teitelbaum Endowment Fund.
 

A version of this article first appeared on Medscape.com.

Numerous species of fungi exist in cancer cells and differ by tumor type, according to findings from a large study of multiple sample types across 35 different cancers.

The investigators characterized the cancer mycobiome within 17,401 tissue, blood, and plasma samples from four international cohorts, revealing new information about fungi distribution, association with immune cells, and potential prognostic value.

Fungi were detected in all cancer types studied and were often intracellular, reported Lian Narunsky-Haziza, PhD, of Weizmann Institute of Science, Rehovot, Israel, and colleagues.

Additionally, multiple fungal-bacterial-immune ecologies were detected across tumors, and intratumoral fungi stratified clinical outcomes, including immunotherapy response, they noted. Also, cell-free fungal DNA diagnosed healthy and cancer patients in early-stage disease.

The findings, published online in the journal Cell, have potential implications for cancer detection, diagnosis, and treatment, the researchers suggested.

The existence of fungi in most human cancers “is both a surprise and to be expected,” study coauthor Rob Knight, PhD, a professor at the University of California, San Diego, stated in a press release. “It is surprising because we don’t know how fungi could get into tumors throughout the body. But it is also expected, because it fits the pattern of healthy microbiomes throughout the body, including the gut, mouth, and skin, where bacteria and fungi interact as part of a complex community.”

Exploration of the associations between cancer and microbes are nothing new, but cancer-associated fungi have rarely been examined, the authors noted.

The findings from this pan-cancer analysis, which suggested “prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers,” complement current “understanding of the interaction between cancer cells and the bacteria that exist in tumors alongside fungi, bacteria that have been shown to affect cancer growth, metastasis, and response to therapy,” they explained.

Of note, the study revealed multiple correlations between the presence of specific fungi in tumors and conditions related to treatment. For example, patients with breast cancer whose tumors contained Malassezia globosa – a fungus found naturally on the skin – had a much lower survival rate than those whose tumors did not contain the fungus. Furthermore, specific fungi were more prevalent in breast tumors from older vs. younger patients, in lung tumors of smokers vs. nonsmokers, and in melanoma tumors that responded to immunotherapy vs. those that did not respond.

These findings suggest that fungal activity is “a new and emerging hallmark of cancer,” stated study coleader Ravid Straussman, PhD, of the Weizmann molecular cell biology department. “These findings should drive us to better explore the potential effects of tumor fungi and to re-examine almost everything we know about cancer through a ‘microbiome lens.’ ”

Unique relationships observed between fungi and bacteria – for example, tumors that contain Aspergillus fungi tended to have specific bacteria in them, whereas tumors that contain Malassezia fungi tended to have other bacteria in them – may have implications for treatment, as they correlated with both tumor immunity and patient survival, according to the authors.

“This study sheds new light on the complex biological environment within tumors, and future research will reveal how fungi affect cancerous growth,” said coauthor Yitzhak Pilpel, PhD, a principal investigator at the Weizmann molecular genetics department. “The fact that fungi can be found not only in cancer cells but also in immune cells implies that, in the future, we’ll probably find that fungi have some effect not only on the cancer cells but also on immune cells and their activity.”

A further finding related to the presence of fungal and bacterial DNA in human blood further suggests that measuring microbial DNA in the blood could lead to early detection of cancer, the authors noted.

Dr. Straussman’s research is supported by the Swiss Society Institute for Cancer Prevention Research, the Fabricant-Morse Families Research Fund for Humanity, the Dr. Chantal d’Adesky Scheinberg Research Fund, and the Dr. Dvora and Haim Teitelbaum Endowment Fund.
 

A version of this article first appeared on Medscape.com.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

Boston dietitian Katarina Mollo, MEd, RDN, LDN, has virtually no memory of life without celiac disease (CD). Diagnosed at age 4, Dr. Mollo has been on a gluten-free diet for 41 years, which she says has kept her healthy and may also be why she hasn’t developed other autoimmune diseases. It’s also played a part in her thinking about screening patients with CD.

“I think [physicians] should definitely be screening people with celiac disease for autoimmune disorders, especially if they see things like anemia or if a child has dropped on the growth chart and has nutrient deficiencies,” said Dr. Mollo, whose daughter also has the disease. “I would recommend that they see someone who specializes in celiac disease so they can get monitored and have regular follow-up checks for nutrient deficiencies and other autoimmune disorders.”

Dr. Mollo’s views on screening are echoed by many CD specialists and physicians, who cite multiple studies that have found that people with the disease face higher risks for diabetes, thyroid conditions, arthritis, and other autoimmune disorders.

Gastroenterologist Alessio Fasano, MD, with Massachusetts General Hospital, Boston, said there has been a “shift in the paradigm in thinking” about cross-screening for CD and autoimmune disorders. As result, he believes the answer to the question of whether to routinely do so is a no-brainer.

“The bottom line is, if you have CD, it [should be] routine that during your annual follow-ups you check for the possibility of the onset of other autoimmune disease. And people with other autoimmune diseases, like type 1 diabetes, should also be screened for CD because of the comorbidity,” said Dr. Fasano, professor of pediatrics and gastroenterology at Harvard Medical School and professor of nutrition at the Harvard School of Public Health, both in Boston. “This is what we call good clinical practice.”
 

Screening, despite lack of consensus guidelines

Other CD specialists differ on the need for universal cross-screening but agree that, at least in some cases, people with one autoimmune disorder should be tested for others.

Jolanda Denham, MD, a pediatric gastroenterologist affiliated with Nemours Children’s Hospital in Orlando, routinely recommends that her patients with CD be screened for certain autoimmune disorders – such as type 1 diabetes and autoimmune thyroid and liver diseases – even though medical organizations have not developed clear consensus or standard guidelines on cross-screening.

“There currently is no evidence to support the screening of celiac patients for all autoimmune and rheumatologic disorders,” she said. “It is true that celiac disease is an autoimmune disorder, and as such, there is a definite increased risk of these disorders in patients with celiac disease and vice versa.”

Echoing Dr. Denham, New York–based gastroenterologist Benjamin Lebwohl, MD, president of the Society for the Study of Celiac Disease, urges physicians to look beyond consensus guidelines and to err on the side of caution and make the best decisions for their patients on a case-by-case basis.

“Given the increased risk of certain autoimmune conditions in people with celiac disease, it behooves physicians to have a low threshold to evaluate for these conditions if any suggestive symptoms are present,” said Dr. Lebwohl, director of clinical research at the Celiac Disease Center at Columbia University, New York.

“Whether to screen for these conditions among people who are entirely without symptoms is less certain, and there is no consensus on that. But it is reasonable and common to include some basic tests with annual blood work, such as thyroid function and a liver profile, since both autoimmune thyroid disease and autoimmune liver disease can be silent early on and the patient would potentially benefit from identification and treatment of these conditions,” he said.

The American Diabetes Association and the International Society of Pediatric and Adolescent Diabetes do recommend that people with diabetes be screened for CD years after diagnosis, noted Robert Rapaport, MD, a pediatric endocrinologist, with Kravis Children’s Hospital, New York. But in a study published in 2021, he and colleagues found that this wasn’t occurring, which prompted them to recommend yearly screening.

“There is a consensus that in children with type 1 diabetes, we screen them for other autoimmune disorders, specifically for thyroid disease and celiac disease,” said Dr. Rapaport, who is also Emma Elizabeth Sullivan Professor of Pediatric Endocrinology and Diabetes at Icahn School of Medicine at Mount Sinai, New York. “But there is no consensus going the other way – for patients with celiac disease, what other autoimmune conditions they should be screened for.”

This hasn’t kept some doctors from extending cross-screening efforts to their patients.

“At our center, we screen ... for thyroid disease and autoimmune liver disease as part of routine healthcare maintenance for our celiac disease patients. We discuss symptoms of diabetes and send screening with [hemoglobin] A1c for anyone who has symptoms,” said Lui Edwin, MD, a pediatric gastroenterologist with Children’s Hospital Colorado, Aurora, and director of the Colorado Center for Celiac Disease, who delivered a lecture on CD-autoimmune screening at the International Celiac Disease Symposium in October.

“It is definitely worth screening for celiac disease in [those with] other autoimmune disorders,” Dr. Edwin added.

“The symptoms can be very heterogeneous. Diagnosing and treating celiac disease can make a huge impact with respect to symptoms, quality of life, and preventing disease-related complications,” he said.
 

Mounting evidence linking CD to autoimmune disorders

Many studies have linked CD to a variety of other autoimmune disorders. The association could be due to common genetic factors or because CD might lead to such conditions. Researchers have found that people diagnosed with CD later in life are more likely to develop other autoimmune disorders.

Going gluten free has preventive advantages

In a landmark 2012 study, researchers with the Celiac Disease Center at Columbia University stopped short of recommending routine screening for the general public or asymptomatic individuals in high-prevalence groups. But they concluded that more screening of symptomatic individuals – and close relatives – would speed treatment for those with more than one autoimmune disorder.

They also noted that some studies have found that a gluten-free diet might help prevent the development of other autoimmune disorders.

Marisa Gallant Stahl, MD, a gastroenterologist with Children’s Hospital Colorado, agreed that it is important that physicians keep gluten-free diets in mind when determining which patients to cross-screen.

“The literature is mixed, but some studies suggest that treating celiac disease with a gluten-free diet actually augments the treatment and control of other autoimmune disorders [and] adherence to a gluten-free diet does reduce the risk of cancer associated with celiac disease,” she said.

Dr. Denham agreed. “Strict adherence to a gluten-free diet definitely protects against the development of enteropathy-associated T-cell lymphoma but may be protective against non-Hodgkin’s lymphoma and adenocarcinoma of the small intestine as well. All three are associated with long-term nonadherence to a gluten-free diet.”

She also noted that a gluten-free diet may help people with CD manage other autoimmune disorders, which can be complicated by CD.

“Good control of celiac disease will help prevent complications that can worsen symptoms and outcomes of concomitant autoimmune and rheumatologic disorders,” she said.
 

Other factors to consider

Dr. Fasano added that autoimmune disorders can be complicated by CD in cases in which oral medications or healthful foods are not properly absorbed in the intestines.

“For example, with Hashimoto’s disease, if you have hormone replacement with oral treatments and your intestines are not 100% functional because you have inflammation, then you may have a problem [with] the absorption of medications like levothyroxine,” he said.

“It’s the same story with diabetes. You don’t take insulin by mouth, but glucose [control] strongly depends on several factors, mostly what comes from the diet, and if it’s erratic, that can be a problem. ... So, the treatment of autoimmune diseases can be influenced by celiac disease,” he said.

In addition, Dr. Fasano and others believe that people with CD and other autoimmune disorders should be managed by a team of experts who can personalize the care on the basis of specific needs of the individual patient. These should include specialists, dietitians, mental health counselors, and family social workers.

“It has to be a multidisciplinary approach to maintain the good health of an individual,” Dr. Fasano said. “Celiac disease is the quintessential example in which the primary care physician needs to be the quarterback of the team, the patient is active in his or her health, and [specialists] not only deliver personalized care but also preventive intervention, particularly the prevention of comorbidities.”

Financial disclosures for those quoted in this article were not available at the time of publication.

A version of this article first appeared on Medscape.com.

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) morbidity and mortality continues to be controversial, particularly for older adults. Recently published, robust randomized controlled trials have revealed less cardiovascular benefit from aspirin for primary prevention compared with previous trials; additionally, an increased risk of major bleeding events has been notably more prevalent in older adults.^1-5 These trials have suggested that preventative aspirin use in older adults confers less benefit than other therapies for decreasing atherosclerotic CVD (ASCVD) risk, including blood pressure (BP) control, cholesterol management, and tobacco cessation.^1,6

A recent meta-analysis indicated a composite cardiovascular risk reduction in patients aged 53 to 74 years taking aspirin vs no aspirin; however, this benefit was offset with an even greater increased risk of major bleeding.⁷ This trend was consistent regardless of stratification by 10-year ASCVD risk or presence of diabetes mellitus (DM) diagnosis.^7,8 Additionally, the recently published Aspirin in Reducing Events in the Elderly (ASPREE) trial studied the impacts of aspirin use in healthy adults aged ≥ 70 years and aged ≥ 65 years among Black and Hispanic adults.⁴ The study concluded that the risk of major bleeding with aspirin use was even higher vs the potential cardiovascular benefit in older adults.⁴

With this emerging evidence, guidelines have been updated to represent the need for risk vs benefit considerations regarding aspirin use for primary prevention in older adults.^1,9,10 The most recent guideline update from the American College of Cardiology and American Heart Association (ACC/AHA) recommends against the routine use of aspirin in patients aged > 70 years or those with bleeding risk factors.¹ The guideline recommends considering aspirin use for patients ages 40 to 70 years only after a patient-specific risk vs benefit discussion.¹ Furthermore, the 2020 American Diabetes Association guideline recommends considering aspirin use for primary prevention in adults with DM between ages 50 and 70 only after a risk vs benefit discussion of patient-specific bleeding risk factors and ASCVD risk-enhancing factors.¹⁰

Despite the demonstrated risks for bleeding with the routine use of aspirin, studies indicate that aspirin continues to be used commonly among older adults, often when unnecessary. In the 2017 National Health Interview Survey, about 23% of adults aged > 40 years in the United States without CVD used aspirin daily, and 23% of these did so without recommendation from a health care professional.¹¹ Furthermore, nearly half of adults ages ≥ 70 years and nearly one-quarter of adults with a history of peptic ulcer disease used aspirin daily.¹¹ Although the most recent guidelines from the ACC/AHA do not recommend a 10-year ASCVD risk threshold for therapy, one study illustrated that 12% of older adult patients were inappropriately prescribed aspirin for primary prevention despite a 10-year ASCVD risk of < 6%.^1,12 These studies highlight the large proportion of individuals, particularly older adults, who may be inappropriately taking aspirin for primary prevention.

Deprescribing Program

Deprescribing potentially inappropriate medications (PIMs) is particularly important in the older adult population, as these individuals experience a high risk of adverse effects (AEs), polypharmacy, cognitive decline, and falls related to medication use.^6,13-17 Evidence suggests that mortality outcomes are improved with the implementation of targeted deprescribing efforts based on patient-specific factors.¹⁸ Additionally, deprescribing unnecessary medications may improve adherence to other essential medications and reduce financial burdens.¹⁹ Pharmacists play a crucial role among health care professionals in the implementation of deprescribing practices, and studies have shown that physicians are highly accepting of pharmacists’ deprescribing recommendations.^13,20-22

Despite the evidence for the benefits of deprescribing, limited data are available regarding the impact and feasibility of a targeted aspirin deprescribing approach by nonphysician practitioners.²³ The objective of this study was to implement and evaluate the success of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting.

This aspirin deprescribing protocol was developed by ambulatory care clinical pharmacist or clinical pharmacist practitioners (CPPs), at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. Within the US Department of Veterans Affairs (VA) health care system, CPPs work under a broad scope of practice with the ability to independently prescribe and monitor medications. The protocol was reviewed by physician stakeholders in both primary care and cardiology and a list was generated, including patients from 2 primary care panels aged ≥ 70 years with aspirin on their medication list, either as a prescription or over-the-counter medication, using the VA Information System Technology and Architecture. A CPP or supervised pharmacy intern identified patients from this list who were appropriate for risk/benefit discussions regarding the discontinuation of aspirin. Patients were excluded from the intervention if they had a history of clinical ASCVD, including myocardial infarction (MI), stable or unstable angina, coronary artery disease (CAD), coronary or other arterial revascularization, cerebrovascular accident (CVA), transient ischemic accident (TIA), or peripheral artery disease (PAD), or another documented indication for aspirin use, including pain, flushing (with niacin use), venous thromboembolism prophylaxis, valvular heart disease, or acute or recurrent pericarditis.

After identifying eligible patients, a CPP or pharmacy intern contacted patients by telephone, following a script to guide conversation. All patients were screened for potential appropriate aspirin indications, particularly any history of MI, CAD, CVA, TIA, PAD, or other clinical ASCVD. The patient was asked about their rationale for taking aspirin and patient-specific ASCVD risk-enhancing factors and bleeding risk factors and educated them on lifestyle modalities to reduce ASCVD risk, using the script as a guide. ASCVD risk-enhancing factors included family history of premature MI, inability to achieve BP goal, DM with the inability to achieve blood glucose or hemoglobin A_1c goal, tobacco use, or inadequate statin therapy. Bleeding risk factors included a history of gastrointestinal bleed or peptic ulcer disease, concurrent use of medications that increase bleeding risk, chronic kidney disease, or thrombocytopenia.

Through shared decision making with careful consideration of these factors, we reached a conclusion with each patient to either continue or to deprescribe aspirin. Each discussion was documented in the electronic health record (EHR) using a standard documentation template (eAppendix, available at doi:10.12788/fp.0320). The patient’s medication list also was updated to reflect changes in aspirin use. For patients who declined deprescribing, the CPP or pharmacy intern asked the patient for their primary reason for preferring to continue aspirin, which was subsequently categorized as one of the following: no prior concerns with bleeding, concerns about a future cardiovascular event, wishing to discuss further with their primary care practitioner (PCP), or identifying an appropriate use for aspirin not evident through record review. For the patients who wished to further discuss the issue with their PCP before deprescribing, the patient’s PCP was notified of this preference by a record alert to the note documenting the encounter, and the patient was also encouraged to follow up about this issue. A voicemail was left if the patient did not answer requesting a call back, and a second attempt was made within 2 weeks.

Data Collected

We collected data to assess the proportion of patients for whom aspirin for primary prevention was discontinued. For patients who declined deprescribing, we documented the rationale for continuing aspirin. Additionally, the feasibility of implementation was assessed, including pharmacist time spent on each record review and intervention. Descriptive statistics were generated to evaluate baseline characteristics and intervention outcomes. The time to completion of these tasks was summarized with descriptive statistics.

We reviewed 459 patient records, and 110 were determined eligible for risk/benefit discussions.

Results of the time-study analysis for each intervention indicated that a pharmacy intern or pharmacist spent about 2 minutes reviewing the record of each patient to determine eligibility for risk/benefit discussions. The 110 patients identified as eligible were 24% of the 459 records reviewed. An average (range) of 12 (6-20) minutes was spent on the telephone call plus documentation for each patient contacted. Additionally, we estimated that CPPs and pharmacy interns spent an approximate combined 12 hours in the development and review of materials for this program, including the protocol, script, and documentation templates. This also included about 1 hour to identify appropriate parameters for, and generate, the eligible patient list.

Discussion

The implementation of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting led to the discontinuation of inappropriate aspirin use in nearly half of older adults contacted. Furthermore, opportunities were identified to update medication lists to reflect previously self-discontinued aspirin for older adults. Just over one-quarter of those contacted declined to discontinue or reduce their aspirin dose. It is hypothesized that with these targeted deprescribing interventions, overall risk reduction for bleeding and polypharmacy will be observed for older adults.¹

In addition to deprescribing aspirin, CPPs used shared decision making to initiate risk/benefit discussions and to educate on targeted lifestyle modifications to lower ASCVD risk. While not all patients agreed to discontinue aspirin, all were provided education that may empower them to engage in future discussions with PCPs regarding appropriate aspirin use. Previous pharmacist-led deprescribing initiatives for proton pump inhibitors and other PIMs have indicated that a large percentage of patients who opt to further discuss a deprescribing concern with their PCPs ultimately resulted in deprescribing outcomes.^24,25 Additionally, a recent trial examining pharmacist-led deprescribing of 4 common PIMs in older adults compared the impact of pharmacists leading educational interventions directly to patients with pharmacists making deprescribing recommendations to physicians. Deprescribing was more successful when patients were involved in the decision-making process.²⁶

Limitations

Although this quality improvement initiative resulted in the deprescribing of inappropriate aspirin for many older adults, a limitation is the small sample size within a single institution. The population of male veterans also may limit generalizability to nonmale and nonveteran older adults. As the protocol was initiated within a limited number of primary care teams initially, future implementation into additional primary care teams will increase the number of older adults impacted by risk/benefit discussions regarding aspirin use. This work may not be generalizable to other health care systems. Many patients within the VA receive both their primary and specialty care within the system, which facilitates communication and collaboration between primary and specialty practitioners. The protocol may require workflow adjustments for patients receiving care within multiple systems. Additionally, although the deprescribing protocol was created in collaboration with physicians, CPPs within the VA work under a broad scope of practice that includes independent medication prescribing, deprescribing, and monitoring. This may be a consideration when implementing similar protocols at other sites, as collaborative practice agreements may need to be in place.

Future Directions

The time required to complete these interventions was generally feasible, though this intervention would require some workflow alteration to be incorporated routinely into a CPP’s schedule. The telephone calls were completed as isolated interventions and were not incorporated into existing scheduled primary care appointments. In the future, the aspirin deprescribing protocol could be incorporated into existing pharmacist-led primary care appointments. Based on the outcomes of this study, CPPs are leading an initiative to develop an aspirin deprescribing clinical reminder tool, which may be quickly inserted into a progress note within the EHR and may be incorporated into any primary care visit led by a CPP or PCP.

Conclusions

This study demonstrates that a pharmacist-led aspirin deprescribing protocol in the ambulatory care pharmacy setting was successful in the discontinuation of unnecessary aspirin use in older adults. The protocol also provided opportunities for education on ASCVD risk reduction in all older adults reached. These findings highlight the role of pharmacists in deprescribing PIMs for older adults and identifying opportunities to further streamline risk/benefit discussions on aspirin deprescribing potential within primary care visits.

The use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) morbidity and mortality continues to be controversial, particularly for older adults. Recently published, robust randomized controlled trials have revealed less cardiovascular benefit from aspirin for primary prevention compared with previous trials; additionally, an increased risk of major bleeding events has been notably more prevalent in older adults.^1-5 These trials have suggested that preventative aspirin use in older adults confers less benefit than other therapies for decreasing atherosclerotic CVD (ASCVD) risk, including blood pressure (BP) control, cholesterol management, and tobacco cessation.^1,6

A recent meta-analysis indicated a composite cardiovascular risk reduction in patients aged 53 to 74 years taking aspirin vs no aspirin; however, this benefit was offset with an even greater increased risk of major bleeding.⁷ This trend was consistent regardless of stratification by 10-year ASCVD risk or presence of diabetes mellitus (DM) diagnosis.^7,8 Additionally, the recently published Aspirin in Reducing Events in the Elderly (ASPREE) trial studied the impacts of aspirin use in healthy adults aged ≥ 70 years and aged ≥ 65 years among Black and Hispanic adults.⁴ The study concluded that the risk of major bleeding with aspirin use was even higher vs the potential cardiovascular benefit in older adults.⁴

With this emerging evidence, guidelines have been updated to represent the need for risk vs benefit considerations regarding aspirin use for primary prevention in older adults.^1,9,10 The most recent guideline update from the American College of Cardiology and American Heart Association (ACC/AHA) recommends against the routine use of aspirin in patients aged > 70 years or those with bleeding risk factors.¹ The guideline recommends considering aspirin use for patients ages 40 to 70 years only after a patient-specific risk vs benefit discussion.¹ Furthermore, the 2020 American Diabetes Association guideline recommends considering aspirin use for primary prevention in adults with DM between ages 50 and 70 only after a risk vs benefit discussion of patient-specific bleeding risk factors and ASCVD risk-enhancing factors.¹⁰

Despite the demonstrated risks for bleeding with the routine use of aspirin, studies indicate that aspirin continues to be used commonly among older adults, often when unnecessary. In the 2017 National Health Interview Survey, about 23% of adults aged > 40 years in the United States without CVD used aspirin daily, and 23% of these did so without recommendation from a health care professional.¹¹ Furthermore, nearly half of adults ages ≥ 70 years and nearly one-quarter of adults with a history of peptic ulcer disease used aspirin daily.¹¹ Although the most recent guidelines from the ACC/AHA do not recommend a 10-year ASCVD risk threshold for therapy, one study illustrated that 12% of older adult patients were inappropriately prescribed aspirin for primary prevention despite a 10-year ASCVD risk of < 6%.^1,12 These studies highlight the large proportion of individuals, particularly older adults, who may be inappropriately taking aspirin for primary prevention.

Deprescribing Program

Deprescribing potentially inappropriate medications (PIMs) is particularly important in the older adult population, as these individuals experience a high risk of adverse effects (AEs), polypharmacy, cognitive decline, and falls related to medication use.^6,13-17 Evidence suggests that mortality outcomes are improved with the implementation of targeted deprescribing efforts based on patient-specific factors.¹⁸ Additionally, deprescribing unnecessary medications may improve adherence to other essential medications and reduce financial burdens.¹⁹ Pharmacists play a crucial role among health care professionals in the implementation of deprescribing practices, and studies have shown that physicians are highly accepting of pharmacists’ deprescribing recommendations.^13,20-22

Despite the evidence for the benefits of deprescribing, limited data are available regarding the impact and feasibility of a targeted aspirin deprescribing approach by nonphysician practitioners.²³ The objective of this study was to implement and evaluate the success of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting.

This aspirin deprescribing protocol was developed by ambulatory care clinical pharmacist or clinical pharmacist practitioners (CPPs), at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. Within the US Department of Veterans Affairs (VA) health care system, CPPs work under a broad scope of practice with the ability to independently prescribe and monitor medications. The protocol was reviewed by physician stakeholders in both primary care and cardiology and a list was generated, including patients from 2 primary care panels aged ≥ 70 years with aspirin on their medication list, either as a prescription or over-the-counter medication, using the VA Information System Technology and Architecture. A CPP or supervised pharmacy intern identified patients from this list who were appropriate for risk/benefit discussions regarding the discontinuation of aspirin. Patients were excluded from the intervention if they had a history of clinical ASCVD, including myocardial infarction (MI), stable or unstable angina, coronary artery disease (CAD), coronary or other arterial revascularization, cerebrovascular accident (CVA), transient ischemic accident (TIA), or peripheral artery disease (PAD), or another documented indication for aspirin use, including pain, flushing (with niacin use), venous thromboembolism prophylaxis, valvular heart disease, or acute or recurrent pericarditis.

After identifying eligible patients, a CPP or pharmacy intern contacted patients by telephone, following a script to guide conversation. All patients were screened for potential appropriate aspirin indications, particularly any history of MI, CAD, CVA, TIA, PAD, or other clinical ASCVD. The patient was asked about their rationale for taking aspirin and patient-specific ASCVD risk-enhancing factors and bleeding risk factors and educated them on lifestyle modalities to reduce ASCVD risk, using the script as a guide. ASCVD risk-enhancing factors included family history of premature MI, inability to achieve BP goal, DM with the inability to achieve blood glucose or hemoglobin A_1c goal, tobacco use, or inadequate statin therapy. Bleeding risk factors included a history of gastrointestinal bleed or peptic ulcer disease, concurrent use of medications that increase bleeding risk, chronic kidney disease, or thrombocytopenia.

Through shared decision making with careful consideration of these factors, we reached a conclusion with each patient to either continue or to deprescribe aspirin. Each discussion was documented in the electronic health record (EHR) using a standard documentation template (eAppendix, available at doi:10.12788/fp.0320). The patient’s medication list also was updated to reflect changes in aspirin use. For patients who declined deprescribing, the CPP or pharmacy intern asked the patient for their primary reason for preferring to continue aspirin, which was subsequently categorized as one of the following: no prior concerns with bleeding, concerns about a future cardiovascular event, wishing to discuss further with their primary care practitioner (PCP), or identifying an appropriate use for aspirin not evident through record review. For the patients who wished to further discuss the issue with their PCP before deprescribing, the patient’s PCP was notified of this preference by a record alert to the note documenting the encounter, and the patient was also encouraged to follow up about this issue. A voicemail was left if the patient did not answer requesting a call back, and a second attempt was made within 2 weeks.

Data Collected

We collected data to assess the proportion of patients for whom aspirin for primary prevention was discontinued. For patients who declined deprescribing, we documented the rationale for continuing aspirin. Additionally, the feasibility of implementation was assessed, including pharmacist time spent on each record review and intervention. Descriptive statistics were generated to evaluate baseline characteristics and intervention outcomes. The time to completion of these tasks was summarized with descriptive statistics.

We reviewed 459 patient records, and 110 were determined eligible for risk/benefit discussions.

Results of the time-study analysis for each intervention indicated that a pharmacy intern or pharmacist spent about 2 minutes reviewing the record of each patient to determine eligibility for risk/benefit discussions. The 110 patients identified as eligible were 24% of the 459 records reviewed. An average (range) of 12 (6-20) minutes was spent on the telephone call plus documentation for each patient contacted. Additionally, we estimated that CPPs and pharmacy interns spent an approximate combined 12 hours in the development and review of materials for this program, including the protocol, script, and documentation templates. This also included about 1 hour to identify appropriate parameters for, and generate, the eligible patient list.

Discussion

The implementation of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting led to the discontinuation of inappropriate aspirin use in nearly half of older adults contacted. Furthermore, opportunities were identified to update medication lists to reflect previously self-discontinued aspirin for older adults. Just over one-quarter of those contacted declined to discontinue or reduce their aspirin dose. It is hypothesized that with these targeted deprescribing interventions, overall risk reduction for bleeding and polypharmacy will be observed for older adults.¹

In addition to deprescribing aspirin, CPPs used shared decision making to initiate risk/benefit discussions and to educate on targeted lifestyle modifications to lower ASCVD risk. While not all patients agreed to discontinue aspirin, all were provided education that may empower them to engage in future discussions with PCPs regarding appropriate aspirin use. Previous pharmacist-led deprescribing initiatives for proton pump inhibitors and other PIMs have indicated that a large percentage of patients who opt to further discuss a deprescribing concern with their PCPs ultimately resulted in deprescribing outcomes.^24,25 Additionally, a recent trial examining pharmacist-led deprescribing of 4 common PIMs in older adults compared the impact of pharmacists leading educational interventions directly to patients with pharmacists making deprescribing recommendations to physicians. Deprescribing was more successful when patients were involved in the decision-making process.²⁶

Limitations

Although this quality improvement initiative resulted in the deprescribing of inappropriate aspirin for many older adults, a limitation is the small sample size within a single institution. The population of male veterans also may limit generalizability to nonmale and nonveteran older adults. As the protocol was initiated within a limited number of primary care teams initially, future implementation into additional primary care teams will increase the number of older adults impacted by risk/benefit discussions regarding aspirin use. This work may not be generalizable to other health care systems. Many patients within the VA receive both their primary and specialty care within the system, which facilitates communication and collaboration between primary and specialty practitioners. The protocol may require workflow adjustments for patients receiving care within multiple systems. Additionally, although the deprescribing protocol was created in collaboration with physicians, CPPs within the VA work under a broad scope of practice that includes independent medication prescribing, deprescribing, and monitoring. This may be a consideration when implementing similar protocols at other sites, as collaborative practice agreements may need to be in place.

Future Directions

The time required to complete these interventions was generally feasible, though this intervention would require some workflow alteration to be incorporated routinely into a CPP’s schedule. The telephone calls were completed as isolated interventions and were not incorporated into existing scheduled primary care appointments. In the future, the aspirin deprescribing protocol could be incorporated into existing pharmacist-led primary care appointments. Based on the outcomes of this study, CPPs are leading an initiative to develop an aspirin deprescribing clinical reminder tool, which may be quickly inserted into a progress note within the EHR and may be incorporated into any primary care visit led by a CPP or PCP.

Conclusions

This study demonstrates that a pharmacist-led aspirin deprescribing protocol in the ambulatory care pharmacy setting was successful in the discontinuation of unnecessary aspirin use in older adults. The protocol also provided opportunities for education on ASCVD risk reduction in all older adults reached. These findings highlight the role of pharmacists in deprescribing PIMs for older adults and identifying opportunities to further streamline risk/benefit discussions on aspirin deprescribing potential within primary care visits.

The use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) morbidity and mortality continues to be controversial, particularly for older adults. Recently published, robust randomized controlled trials have revealed less cardiovascular benefit from aspirin for primary prevention compared with previous trials; additionally, an increased risk of major bleeding events has been notably more prevalent in older adults.^1-5 These trials have suggested that preventative aspirin use in older adults confers less benefit than other therapies for decreasing atherosclerotic CVD (ASCVD) risk, including blood pressure (BP) control, cholesterol management, and tobacco cessation.^1,6

A recent meta-analysis indicated a composite cardiovascular risk reduction in patients aged 53 to 74 years taking aspirin vs no aspirin; however, this benefit was offset with an even greater increased risk of major bleeding.⁷ This trend was consistent regardless of stratification by 10-year ASCVD risk or presence of diabetes mellitus (DM) diagnosis.^7,8 Additionally, the recently published Aspirin in Reducing Events in the Elderly (ASPREE) trial studied the impacts of aspirin use in healthy adults aged ≥ 70 years and aged ≥ 65 years among Black and Hispanic adults.⁴ The study concluded that the risk of major bleeding with aspirin use was even higher vs the potential cardiovascular benefit in older adults.⁴

With this emerging evidence, guidelines have been updated to represent the need for risk vs benefit considerations regarding aspirin use for primary prevention in older adults.^1,9,10 The most recent guideline update from the American College of Cardiology and American Heart Association (ACC/AHA) recommends against the routine use of aspirin in patients aged > 70 years or those with bleeding risk factors.¹ The guideline recommends considering aspirin use for patients ages 40 to 70 years only after a patient-specific risk vs benefit discussion.¹ Furthermore, the 2020 American Diabetes Association guideline recommends considering aspirin use for primary prevention in adults with DM between ages 50 and 70 only after a risk vs benefit discussion of patient-specific bleeding risk factors and ASCVD risk-enhancing factors.¹⁰

Despite the demonstrated risks for bleeding with the routine use of aspirin, studies indicate that aspirin continues to be used commonly among older adults, often when unnecessary. In the 2017 National Health Interview Survey, about 23% of adults aged > 40 years in the United States without CVD used aspirin daily, and 23% of these did so without recommendation from a health care professional.¹¹ Furthermore, nearly half of adults ages ≥ 70 years and nearly one-quarter of adults with a history of peptic ulcer disease used aspirin daily.¹¹ Although the most recent guidelines from the ACC/AHA do not recommend a 10-year ASCVD risk threshold for therapy, one study illustrated that 12% of older adult patients were inappropriately prescribed aspirin for primary prevention despite a 10-year ASCVD risk of < 6%.^1,12 These studies highlight the large proportion of individuals, particularly older adults, who may be inappropriately taking aspirin for primary prevention.

Deprescribing Program

Deprescribing potentially inappropriate medications (PIMs) is particularly important in the older adult population, as these individuals experience a high risk of adverse effects (AEs), polypharmacy, cognitive decline, and falls related to medication use.^6,13-17 Evidence suggests that mortality outcomes are improved with the implementation of targeted deprescribing efforts based on patient-specific factors.¹⁸ Additionally, deprescribing unnecessary medications may improve adherence to other essential medications and reduce financial burdens.¹⁹ Pharmacists play a crucial role among health care professionals in the implementation of deprescribing practices, and studies have shown that physicians are highly accepting of pharmacists’ deprescribing recommendations.^13,20-22

Despite the evidence for the benefits of deprescribing, limited data are available regarding the impact and feasibility of a targeted aspirin deprescribing approach by nonphysician practitioners.²³ The objective of this study was to implement and evaluate the success of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting.

This aspirin deprescribing protocol was developed by ambulatory care clinical pharmacist or clinical pharmacist practitioners (CPPs), at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. Within the US Department of Veterans Affairs (VA) health care system, CPPs work under a broad scope of practice with the ability to independently prescribe and monitor medications. The protocol was reviewed by physician stakeholders in both primary care and cardiology and a list was generated, including patients from 2 primary care panels aged ≥ 70 years with aspirin on their medication list, either as a prescription or over-the-counter medication, using the VA Information System Technology and Architecture. A CPP or supervised pharmacy intern identified patients from this list who were appropriate for risk/benefit discussions regarding the discontinuation of aspirin. Patients were excluded from the intervention if they had a history of clinical ASCVD, including myocardial infarction (MI), stable or unstable angina, coronary artery disease (CAD), coronary or other arterial revascularization, cerebrovascular accident (CVA), transient ischemic accident (TIA), or peripheral artery disease (PAD), or another documented indication for aspirin use, including pain, flushing (with niacin use), venous thromboembolism prophylaxis, valvular heart disease, or acute or recurrent pericarditis.

After identifying eligible patients, a CPP or pharmacy intern contacted patients by telephone, following a script to guide conversation. All patients were screened for potential appropriate aspirin indications, particularly any history of MI, CAD, CVA, TIA, PAD, or other clinical ASCVD. The patient was asked about their rationale for taking aspirin and patient-specific ASCVD risk-enhancing factors and bleeding risk factors and educated them on lifestyle modalities to reduce ASCVD risk, using the script as a guide. ASCVD risk-enhancing factors included family history of premature MI, inability to achieve BP goal, DM with the inability to achieve blood glucose or hemoglobin A_1c goal, tobacco use, or inadequate statin therapy. Bleeding risk factors included a history of gastrointestinal bleed or peptic ulcer disease, concurrent use of medications that increase bleeding risk, chronic kidney disease, or thrombocytopenia.

Through shared decision making with careful consideration of these factors, we reached a conclusion with each patient to either continue or to deprescribe aspirin. Each discussion was documented in the electronic health record (EHR) using a standard documentation template (eAppendix, available at doi:10.12788/fp.0320). The patient’s medication list also was updated to reflect changes in aspirin use. For patients who declined deprescribing, the CPP or pharmacy intern asked the patient for their primary reason for preferring to continue aspirin, which was subsequently categorized as one of the following: no prior concerns with bleeding, concerns about a future cardiovascular event, wishing to discuss further with their primary care practitioner (PCP), or identifying an appropriate use for aspirin not evident through record review. For the patients who wished to further discuss the issue with their PCP before deprescribing, the patient’s PCP was notified of this preference by a record alert to the note documenting the encounter, and the patient was also encouraged to follow up about this issue. A voicemail was left if the patient did not answer requesting a call back, and a second attempt was made within 2 weeks.

Data Collected

We collected data to assess the proportion of patients for whom aspirin for primary prevention was discontinued. For patients who declined deprescribing, we documented the rationale for continuing aspirin. Additionally, the feasibility of implementation was assessed, including pharmacist time spent on each record review and intervention. Descriptive statistics were generated to evaluate baseline characteristics and intervention outcomes. The time to completion of these tasks was summarized with descriptive statistics.

We reviewed 459 patient records, and 110 were determined eligible for risk/benefit discussions.

Results of the time-study analysis for each intervention indicated that a pharmacy intern or pharmacist spent about 2 minutes reviewing the record of each patient to determine eligibility for risk/benefit discussions. The 110 patients identified as eligible were 24% of the 459 records reviewed. An average (range) of 12 (6-20) minutes was spent on the telephone call plus documentation for each patient contacted. Additionally, we estimated that CPPs and pharmacy interns spent an approximate combined 12 hours in the development and review of materials for this program, including the protocol, script, and documentation templates. This also included about 1 hour to identify appropriate parameters for, and generate, the eligible patient list.

Discussion

The implementation of a pharmacist-driven aspirin deprescribing protocol for older adults in a primary care setting led to the discontinuation of inappropriate aspirin use in nearly half of older adults contacted. Furthermore, opportunities were identified to update medication lists to reflect previously self-discontinued aspirin for older adults. Just over one-quarter of those contacted declined to discontinue or reduce their aspirin dose. It is hypothesized that with these targeted deprescribing interventions, overall risk reduction for bleeding and polypharmacy will be observed for older adults.¹

In addition to deprescribing aspirin, CPPs used shared decision making to initiate risk/benefit discussions and to educate on targeted lifestyle modifications to lower ASCVD risk. While not all patients agreed to discontinue aspirin, all were provided education that may empower them to engage in future discussions with PCPs regarding appropriate aspirin use. Previous pharmacist-led deprescribing initiatives for proton pump inhibitors and other PIMs have indicated that a large percentage of patients who opt to further discuss a deprescribing concern with their PCPs ultimately resulted in deprescribing outcomes.^24,25 Additionally, a recent trial examining pharmacist-led deprescribing of 4 common PIMs in older adults compared the impact of pharmacists leading educational interventions directly to patients with pharmacists making deprescribing recommendations to physicians. Deprescribing was more successful when patients were involved in the decision-making process.²⁶

Limitations

Although this quality improvement initiative resulted in the deprescribing of inappropriate aspirin for many older adults, a limitation is the small sample size within a single institution. The population of male veterans also may limit generalizability to nonmale and nonveteran older adults. As the protocol was initiated within a limited number of primary care teams initially, future implementation into additional primary care teams will increase the number of older adults impacted by risk/benefit discussions regarding aspirin use. This work may not be generalizable to other health care systems. Many patients within the VA receive both their primary and specialty care within the system, which facilitates communication and collaboration between primary and specialty practitioners. The protocol may require workflow adjustments for patients receiving care within multiple systems. Additionally, although the deprescribing protocol was created in collaboration with physicians, CPPs within the VA work under a broad scope of practice that includes independent medication prescribing, deprescribing, and monitoring. This may be a consideration when implementing similar protocols at other sites, as collaborative practice agreements may need to be in place.

Future Directions

The time required to complete these interventions was generally feasible, though this intervention would require some workflow alteration to be incorporated routinely into a CPP’s schedule. The telephone calls were completed as isolated interventions and were not incorporated into existing scheduled primary care appointments. In the future, the aspirin deprescribing protocol could be incorporated into existing pharmacist-led primary care appointments. Based on the outcomes of this study, CPPs are leading an initiative to develop an aspirin deprescribing clinical reminder tool, which may be quickly inserted into a progress note within the EHR and may be incorporated into any primary care visit led by a CPP or PCP.

Conclusions

This study demonstrates that a pharmacist-led aspirin deprescribing protocol in the ambulatory care pharmacy setting was successful in the discontinuation of unnecessary aspirin use in older adults. The protocol also provided opportunities for education on ASCVD risk reduction in all older adults reached. These findings highlight the role of pharmacists in deprescribing PIMs for older adults and identifying opportunities to further streamline risk/benefit discussions on aspirin deprescribing potential within primary care visits.

In 2019, diabetes mellitus (DM) was the seventh leading cause of death in the United States, and currently, about 11% of the American population has a DM diagnosis.¹ Most have a diagnosis of type 2 diabetes (T2DM), which has a strong genetic predisposition, and the risk of developing T2DM increases with age, obesity, and lack of physical activity.^1,2 Nearly one-quarter of veterans have a diagnosis of DM, and DM is the leading cause of comorbidities, such as blindness, end-stage renal disease, and amputation for patients receiving care from the Veterans Health Administration (VHA).² The elevated incidence of DM in the veteran population is attributed to a variety of factors, including exposure to herbicides, such as Agent Orange, advanced age, increased risk of obesity, and limited access to high-quality food.³

After diagnosis, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) emphasize the appropriate use of lifestyle management and pharmacologic therapy for DM care. The use of pharmacologic agents (oral medications, insulin, or noninsulin injectables) is often determined by efficacy, cost, potential adverse effects (AEs), and patient factors and comorbidities.^4,5

The initial recommendation for pharmacologic treatment for T2DM differs slightly between expert guidelines. The ADA and AACE/ACE recommend any of the following as initial monotherapy, listed in order to represent a hierarchy of usage: metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 (SGLT-2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors, with the first 3 agents carrying the strongest recommendations.^4,5 For patients with established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure, it is recommended to start a long-acting GLP-1 RA or SGLT-2 inhibitor. For patients with T2DM and hemoglobin A_1c (HbA_1c) between 7.5% and 9.0% at diagnosis, the AACE/ACE recommend initiation of dual therapy using metformin alongside another first-line agent and recommend the addition of another antidiabetic agent if glycemic goals are not met after regular follow-up. AACE/ACE recommend the consideration of insulin therapy in symptomatic patients with HbA_1c > 9.0%.⁵ In contrast, the ADA recommends metformin as first-line therapy for all patients with T2DM and recommends dual therapy using metformin and another preferred agent (selection based on comorbidities) when HbA_1c is 1.5% to 2% above target. The ADA recommends the consideration of insulin with HbA_1c > 10% or with evidence of ongoing catabolism or symptoms of hyperglycemia.⁴ There are several reasons why insulin may be initiated prior to GLP-1 RAs, including profound hyperglycemia at time of diagnosis or implementation of insulin agents prior to commercial availability of GLP-1 RA.

GLP-1 RAs are analogs of the hormone incretin, which increases glucose-dependent insulin secretion, decreases postprandial glucagon secretion, increases satiety, and slows gastric emptying.^6,7 When used in combination with noninsulin agents, GLP-1 RAs have demonstrated HbA_1c reductions of 0.5% to 1.5%.⁸ The use of GLP-1 RAs with basal insulin also has been studied extensively.^6,8-10 When the combination of GLP-1 RAs and basal insulin was compared with basal/bolus insulin regimens, the use of the GLP-1 RAs resulted in lower HbA_1c levels and lower incidence of hypoglycemia.^6,9 Data have demonstrated the complementary mechanisms of using basal insulin and GLP 1 RAs in decreasing HbA_1c levels, insulin requirements, and weight compared with using basal insulin monotherapy and basal/bolus combinations.^6,9-13 Moreover, 3 GLP-1 RA medications currently on the market (liraglutide, dulaglutide, and semaglutide) have displayed cardiovascular and renal benefits, further supporting the use of these medications.^2,5

Despite these benefits, GLP-1 RAs may have bothersome AEs and are associated with a high cost.⁶ In addition, some studies have found that as the length of therapy increases, the positive effects of these agents may diminish.^9,11 In one study, which looked at the impact of the addition of exenatide to patients taking basal or basal/bolus insulin regimens, mean changes in weight were −2.4 kg at 0 to 6 months, −4.3 kg at 6 to 12 months, −6.2 kg at 12 to 18 months, and −5.5 kg at 18 to 27 months. After 18 months, an increase in weight was observed, but the increase remained lower than baseline.¹¹ Another study, conducted over 12 months, found no significant decrease in weight or total daily dose (TDD) of insulin when exenatide or liraglutide were added to various insulin regimens (basal or basal/bolus).¹³ To date, minimal published data exist regarding the addition of newer GLP-1 RAs and the long-term use of these agents beyond 12 months in patients taking basal/bolus insulin regimens. The primary goal of this study was to evaluate the effect of adding GLP-1 RAs to basal/bolus insulin regimens over a 24-month period.

Methods

This study was a retrospective, electronic health record review of all patients on basal and bolus insulin regimens who received additional therapy with a GLP-1 RA at Veteran Health Indiana in Indianapolis from September 1, 2015, to June 30, 2019. Patients meeting inclusion criteria served as their own control. The primary outcome was change in HbA_1c at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and TDD of insulin at 3, 6, 12, 18, and 24 months after the initiation of the GLP-1 RAs and incidence of patient-reported or laboratory-confirmed hypoglycemia and other AEs.

Patients were included if they were aged ≥ 18 years with a diagnosis of T2DM, had concomitant prescriptions for both a basal insulin (glargine, detemir, or NPH) and a bolus insulin (aspart, lispro, or regular) before receiving add-on therapy with a GLP-1 RA (exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide, or semaglutide) from September 1, 2015, to June 30, 2019, and had baseline and subsequent HbA_1c measurements available in the electronic health record. Patients were excluded if they had a diagnosis of type 1 DM (T1DM), were followed by an outside clinician for DM care, or if the GLP-1 RA was discontinued before subsequent HbA_1c measurement. The study protocol was approved by the Research and Development Office of Veteran Health Indiana, and the project was deemed exempt from review by the Indiana University Institutional Review Board due to the retrospective nature of the study.

Data analysis was performed using Excel. Change from baseline for each interval was computed, and 1 sample t tests (2-tailed) compared change from baseline to no change. Due to the disparity in the number of patients with data available at each of the time intervals, a mean plot was presented for each group of patients within each interval, allowing mean changes in individual groups to be observed over time.

Results

One hundred twenty-three subjects met inclusion criteria; 16 patients were excluded due to GLP-1 RA discontinuation before follow-up measurement of HbA_1c; 14 were excluded due to patients being managed by a clinician outside of the facility; 1 patient was excluded for lack of documentation regarding baseline and subsequent insulin doses. Ninety-two patient charts were reviewed. Participants had a mean age of 64 years, 95% were male, and 89% were White. Mean baseline HbA_1c was 9.2%, mean body mass index was 38.9, and the mean TDD of insulin was 184 units.

Since some patients switched between GLP-1 RAs throughout the study and there was variation in timing of laboratory and clinic follow-up,

Discussion

Adding a GLP-1 RA to basal/bolus insulin regimens was associated with a statistically significant decrease in HbA_1c at each time point through 18 months. The greatest improvement in glycemic control from baseline was seen at 3 months, with improvements in HbA_1c diminishing at each subsequent period. The study also demonstrated a significant decrease in weight at each time point through 18 months. The greatest decrease in weight was observed at both 6 and 12 months. Statistically significant decreases in TDD were observed at 3, 6, and 12 months. Insulin changes after 12 months were not found to be statistically significant.

Few studies have previously evaluated the use of GLP-1 RAs in patients with T2DM who are already taking basal/bolus insulin regimens. Gyorffy and colleagues reported significant improvements in glycemic control at 3 and 6 months in a sample of 54 patients taking basal/bolus insulin when liraglutide or exenatide was added, although statistical significance was not found at the final 12-month time point.¹³ That study also found a significant decrease in weight at 6 months; however there was not a significant reduction in weight at both 3 and 12 months of GLP-1 RA therapy. There was not a significant decrease in TDD at any of the collected time points. Nonetheless, Gyorffy and colleagues concluded that reduction in TDD leveled off after 12 months, which is consistent with this study’s findings. The small size of the study may have limited the ability to detect statistical significance; however, this study was conducted in a population that was racially diverse and included a higher proportion of women, though average age was similar.¹³

Yoon and colleagues reported weight loss through 18 months, then saw weight increase, though weights did remain lower than baseline. The study also showed no significant change in TDD of insulin after 12 months of concomitant exenatide and insulin therapy.¹¹ Although these results mirror the outcomes observed in this study, Yoon and colleagues did not differentiate results between basal and basal/bolus insulin groups.¹¹ Seino and colleagues observed no significant change in weight after 36 weeks of GLP-1 RA therapy in Japanese patients when used with basal and basal/bolus insulin regimens. Despite the consideration that the population in the study was not overweight (mean body mass index was 25.6), the results of these studies support the idea that effects of GLP-1 RAs on weight and TDD may diminish over time.¹⁴

Within the VHA, GLP-1 RAs are nonformulary medications. Patients must meet certain criteria in order to be approved for these agents, which may include diagnosis of CVD, renal disease, or failure to reach glycemic control with the use of oral agents or insulin. Therefore, participants of this study represent a particular subset of VHA patients, many of whom may have been selected for consideration due to long-standing or uncontrolled T2DM and failure of previous therapies. The baseline demographics support this idea, given poor glycemic control at baseline and high insulin requirements. Once approved for GLP-1 RA therapy, semaglutide is currently the preferred agent within the VHA, with other agents available for select considerations. It should be noted that albiglutide, which was the primary agent selected for some of the patients included in this study, was removed from the market in 2017 for economic considerations.¹⁵ In the case for these patients, a conversion to a formulary-preferred GLP-1 RA was made.

Most of the patients included in this study (70%) were maintained on metformin from baseline throughout the study period. Fifty-seven percent of patients were taking TDD of insulin > 150 units. Considering the significant cost of concentrated insulins, the addition of GLP-1 RAs to standard insulin may prove to be beneficial from a cost standpoint. Additional research in this area may be warranted to establish more data regarding this potential benefit of GLP-1 RAs as add-on therapy.

Many adverse drug reactions were reported at different periods; however, most of these were associated with the gastrointestinal system, which is consistent with current literature, drug labeling, and the mechanism of action.¹⁶ Hypoglycemia occurred in about one-third of the participants; however, it should be noted that alone, GLP-1 RAs are not associated with a high risk of hypoglycemia. Previous studies have found that GLP-1 RA monotherapy is associated with hypoglycemia in 1.6% to 12.6% of patients.^17,18 More likely, the combination of basal/bolus insulin and the GLP-1 RA’s effect on increasing insulin sensitivity through weight loss, improving glucose-dependent insulin secretion, or by decreasing appetite and therefore decreasing carbohydrate intake contributed to the hypoglycemia prevalence.

Limitations and Strengths

Limitations of this study include a small patient population and a gradual reduction in available data as time periods progressed, making even smaller sample sizes for subsequent time periods. A majority of participants were older, males and White race. This could have limited the determination of statistical significance and applicability of the results to other patient populations. Another potential limitation was the retrospective nature of the study design, which may have limited reporting of hypoglycemia and other AEs based on the documentation of the clinician.

Strengths included the study duration and the diversity of GLP-1 RAs used by participants, as the impact of many of these agents has not yet been assessed in the literature. In addition, the retrospective nature of the study allows for a more realistic representation of patient adherence, education, and motivation, which are likely different from those of patients included in prospective clinical trials.

There are no clear guidelines dictating the optimal duration of concomitant GLP-1 RA and insulin therapy; however, our study suggests that there may be continued benefits past short-term use. Also our study suggests that patients with T2DM treated with basal/bolus insulin regimens may glean additional benefit from adding GLP-1 RAs; however, further randomized, controlled studies are warranted, particularly in poorly controlled patients requiring even more aggressive treatment regimens, such as concentrated insulins.

Conclusions

In our study, adding GLP-1 RA to basal/bolus insulin was associated with a significant decrease in HbA_1c from baseline through 18 months. An overall decrease in weight and TDD of insulin was observed through 24 months, but the change in weight was not significant past 18 months, and the change in insulin requirement was not significant past 12 months. Hypoglycemia was observed in almost one-third of patients, and gastrointestinal symptoms were the most common AE observed as a result of adding GLP-1 RAs. More studies are needed to better evaluate the durability and cost benefit of GLP-1 RAs, especially in patients with high insulin requirements.

Acknowledgments

This material is the result of work supported with resources and facilities at Veteran Health Indiana in Indianapolis. Study data were collected and managed using REDCap electronic data capture tools hosted at Veteran Health Indiana. The authors also acknowledge George Eckert for his assistance with data analysis.

In 2019, diabetes mellitus (DM) was the seventh leading cause of death in the United States, and currently, about 11% of the American population has a DM diagnosis.¹ Most have a diagnosis of type 2 diabetes (T2DM), which has a strong genetic predisposition, and the risk of developing T2DM increases with age, obesity, and lack of physical activity.^1,2 Nearly one-quarter of veterans have a diagnosis of DM, and DM is the leading cause of comorbidities, such as blindness, end-stage renal disease, and amputation for patients receiving care from the Veterans Health Administration (VHA).² The elevated incidence of DM in the veteran population is attributed to a variety of factors, including exposure to herbicides, such as Agent Orange, advanced age, increased risk of obesity, and limited access to high-quality food.³

After diagnosis, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) emphasize the appropriate use of lifestyle management and pharmacologic therapy for DM care. The use of pharmacologic agents (oral medications, insulin, or noninsulin injectables) is often determined by efficacy, cost, potential adverse effects (AEs), and patient factors and comorbidities.^4,5

The initial recommendation for pharmacologic treatment for T2DM differs slightly between expert guidelines. The ADA and AACE/ACE recommend any of the following as initial monotherapy, listed in order to represent a hierarchy of usage: metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 (SGLT-2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors, with the first 3 agents carrying the strongest recommendations.^4,5 For patients with established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure, it is recommended to start a long-acting GLP-1 RA or SGLT-2 inhibitor. For patients with T2DM and hemoglobin A_1c (HbA_1c) between 7.5% and 9.0% at diagnosis, the AACE/ACE recommend initiation of dual therapy using metformin alongside another first-line agent and recommend the addition of another antidiabetic agent if glycemic goals are not met after regular follow-up. AACE/ACE recommend the consideration of insulin therapy in symptomatic patients with HbA_1c > 9.0%.⁵ In contrast, the ADA recommends metformin as first-line therapy for all patients with T2DM and recommends dual therapy using metformin and another preferred agent (selection based on comorbidities) when HbA_1c is 1.5% to 2% above target. The ADA recommends the consideration of insulin with HbA_1c > 10% or with evidence of ongoing catabolism or symptoms of hyperglycemia.⁴ There are several reasons why insulin may be initiated prior to GLP-1 RAs, including profound hyperglycemia at time of diagnosis or implementation of insulin agents prior to commercial availability of GLP-1 RA.

GLP-1 RAs are analogs of the hormone incretin, which increases glucose-dependent insulin secretion, decreases postprandial glucagon secretion, increases satiety, and slows gastric emptying.^6,7 When used in combination with noninsulin agents, GLP-1 RAs have demonstrated HbA_1c reductions of 0.5% to 1.5%.⁸ The use of GLP-1 RAs with basal insulin also has been studied extensively.^6,8-10 When the combination of GLP-1 RAs and basal insulin was compared with basal/bolus insulin regimens, the use of the GLP-1 RAs resulted in lower HbA_1c levels and lower incidence of hypoglycemia.^6,9 Data have demonstrated the complementary mechanisms of using basal insulin and GLP 1 RAs in decreasing HbA_1c levels, insulin requirements, and weight compared with using basal insulin monotherapy and basal/bolus combinations.^6,9-13 Moreover, 3 GLP-1 RA medications currently on the market (liraglutide, dulaglutide, and semaglutide) have displayed cardiovascular and renal benefits, further supporting the use of these medications.^2,5

Despite these benefits, GLP-1 RAs may have bothersome AEs and are associated with a high cost.⁶ In addition, some studies have found that as the length of therapy increases, the positive effects of these agents may diminish.^9,11 In one study, which looked at the impact of the addition of exenatide to patients taking basal or basal/bolus insulin regimens, mean changes in weight were −2.4 kg at 0 to 6 months, −4.3 kg at 6 to 12 months, −6.2 kg at 12 to 18 months, and −5.5 kg at 18 to 27 months. After 18 months, an increase in weight was observed, but the increase remained lower than baseline.¹¹ Another study, conducted over 12 months, found no significant decrease in weight or total daily dose (TDD) of insulin when exenatide or liraglutide were added to various insulin regimens (basal or basal/bolus).¹³ To date, minimal published data exist regarding the addition of newer GLP-1 RAs and the long-term use of these agents beyond 12 months in patients taking basal/bolus insulin regimens. The primary goal of this study was to evaluate the effect of adding GLP-1 RAs to basal/bolus insulin regimens over a 24-month period.

Methods

This study was a retrospective, electronic health record review of all patients on basal and bolus insulin regimens who received additional therapy with a GLP-1 RA at Veteran Health Indiana in Indianapolis from September 1, 2015, to June 30, 2019. Patients meeting inclusion criteria served as their own control. The primary outcome was change in HbA_1c at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and TDD of insulin at 3, 6, 12, 18, and 24 months after the initiation of the GLP-1 RAs and incidence of patient-reported or laboratory-confirmed hypoglycemia and other AEs.

Patients were included if they were aged ≥ 18 years with a diagnosis of T2DM, had concomitant prescriptions for both a basal insulin (glargine, detemir, or NPH) and a bolus insulin (aspart, lispro, or regular) before receiving add-on therapy with a GLP-1 RA (exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide, or semaglutide) from September 1, 2015, to June 30, 2019, and had baseline and subsequent HbA_1c measurements available in the electronic health record. Patients were excluded if they had a diagnosis of type 1 DM (T1DM), were followed by an outside clinician for DM care, or if the GLP-1 RA was discontinued before subsequent HbA_1c measurement. The study protocol was approved by the Research and Development Office of Veteran Health Indiana, and the project was deemed exempt from review by the Indiana University Institutional Review Board due to the retrospective nature of the study.

Data analysis was performed using Excel. Change from baseline for each interval was computed, and 1 sample t tests (2-tailed) compared change from baseline to no change. Due to the disparity in the number of patients with data available at each of the time intervals, a mean plot was presented for each group of patients within each interval, allowing mean changes in individual groups to be observed over time.

Results

One hundred twenty-three subjects met inclusion criteria; 16 patients were excluded due to GLP-1 RA discontinuation before follow-up measurement of HbA_1c; 14 were excluded due to patients being managed by a clinician outside of the facility; 1 patient was excluded for lack of documentation regarding baseline and subsequent insulin doses. Ninety-two patient charts were reviewed. Participants had a mean age of 64 years, 95% were male, and 89% were White. Mean baseline HbA_1c was 9.2%, mean body mass index was 38.9, and the mean TDD of insulin was 184 units.

Since some patients switched between GLP-1 RAs throughout the study and there was variation in timing of laboratory and clinic follow-up,

Discussion

Adding a GLP-1 RA to basal/bolus insulin regimens was associated with a statistically significant decrease in HbA_1c at each time point through 18 months. The greatest improvement in glycemic control from baseline was seen at 3 months, with improvements in HbA_1c diminishing at each subsequent period. The study also demonstrated a significant decrease in weight at each time point through 18 months. The greatest decrease in weight was observed at both 6 and 12 months. Statistically significant decreases in TDD were observed at 3, 6, and 12 months. Insulin changes after 12 months were not found to be statistically significant.

Few studies have previously evaluated the use of GLP-1 RAs in patients with T2DM who are already taking basal/bolus insulin regimens. Gyorffy and colleagues reported significant improvements in glycemic control at 3 and 6 months in a sample of 54 patients taking basal/bolus insulin when liraglutide or exenatide was added, although statistical significance was not found at the final 12-month time point.¹³ That study also found a significant decrease in weight at 6 months; however there was not a significant reduction in weight at both 3 and 12 months of GLP-1 RA therapy. There was not a significant decrease in TDD at any of the collected time points. Nonetheless, Gyorffy and colleagues concluded that reduction in TDD leveled off after 12 months, which is consistent with this study’s findings. The small size of the study may have limited the ability to detect statistical significance; however, this study was conducted in a population that was racially diverse and included a higher proportion of women, though average age was similar.¹³

Yoon and colleagues reported weight loss through 18 months, then saw weight increase, though weights did remain lower than baseline. The study also showed no significant change in TDD of insulin after 12 months of concomitant exenatide and insulin therapy.¹¹ Although these results mirror the outcomes observed in this study, Yoon and colleagues did not differentiate results between basal and basal/bolus insulin groups.¹¹ Seino and colleagues observed no significant change in weight after 36 weeks of GLP-1 RA therapy in Japanese patients when used with basal and basal/bolus insulin regimens. Despite the consideration that the population in the study was not overweight (mean body mass index was 25.6), the results of these studies support the idea that effects of GLP-1 RAs on weight and TDD may diminish over time.¹⁴

Within the VHA, GLP-1 RAs are nonformulary medications. Patients must meet certain criteria in order to be approved for these agents, which may include diagnosis of CVD, renal disease, or failure to reach glycemic control with the use of oral agents or insulin. Therefore, participants of this study represent a particular subset of VHA patients, many of whom may have been selected for consideration due to long-standing or uncontrolled T2DM and failure of previous therapies. The baseline demographics support this idea, given poor glycemic control at baseline and high insulin requirements. Once approved for GLP-1 RA therapy, semaglutide is currently the preferred agent within the VHA, with other agents available for select considerations. It should be noted that albiglutide, which was the primary agent selected for some of the patients included in this study, was removed from the market in 2017 for economic considerations.¹⁵ In the case for these patients, a conversion to a formulary-preferred GLP-1 RA was made.

Most of the patients included in this study (70%) were maintained on metformin from baseline throughout the study period. Fifty-seven percent of patients were taking TDD of insulin > 150 units. Considering the significant cost of concentrated insulins, the addition of GLP-1 RAs to standard insulin may prove to be beneficial from a cost standpoint. Additional research in this area may be warranted to establish more data regarding this potential benefit of GLP-1 RAs as add-on therapy.

Many adverse drug reactions were reported at different periods; however, most of these were associated with the gastrointestinal system, which is consistent with current literature, drug labeling, and the mechanism of action.¹⁶ Hypoglycemia occurred in about one-third of the participants; however, it should be noted that alone, GLP-1 RAs are not associated with a high risk of hypoglycemia. Previous studies have found that GLP-1 RA monotherapy is associated with hypoglycemia in 1.6% to 12.6% of patients.^17,18 More likely, the combination of basal/bolus insulin and the GLP-1 RA’s effect on increasing insulin sensitivity through weight loss, improving glucose-dependent insulin secretion, or by decreasing appetite and therefore decreasing carbohydrate intake contributed to the hypoglycemia prevalence.

Limitations and Strengths

Limitations of this study include a small patient population and a gradual reduction in available data as time periods progressed, making even smaller sample sizes for subsequent time periods. A majority of participants were older, males and White race. This could have limited the determination of statistical significance and applicability of the results to other patient populations. Another potential limitation was the retrospective nature of the study design, which may have limited reporting of hypoglycemia and other AEs based on the documentation of the clinician.

Strengths included the study duration and the diversity of GLP-1 RAs used by participants, as the impact of many of these agents has not yet been assessed in the literature. In addition, the retrospective nature of the study allows for a more realistic representation of patient adherence, education, and motivation, which are likely different from those of patients included in prospective clinical trials.

There are no clear guidelines dictating the optimal duration of concomitant GLP-1 RA and insulin therapy; however, our study suggests that there may be continued benefits past short-term use. Also our study suggests that patients with T2DM treated with basal/bolus insulin regimens may glean additional benefit from adding GLP-1 RAs; however, further randomized, controlled studies are warranted, particularly in poorly controlled patients requiring even more aggressive treatment regimens, such as concentrated insulins.

Conclusions

In our study, adding GLP-1 RA to basal/bolus insulin was associated with a significant decrease in HbA_1c from baseline through 18 months. An overall decrease in weight and TDD of insulin was observed through 24 months, but the change in weight was not significant past 18 months, and the change in insulin requirement was not significant past 12 months. Hypoglycemia was observed in almost one-third of patients, and gastrointestinal symptoms were the most common AE observed as a result of adding GLP-1 RAs. More studies are needed to better evaluate the durability and cost benefit of GLP-1 RAs, especially in patients with high insulin requirements.

Acknowledgments

This material is the result of work supported with resources and facilities at Veteran Health Indiana in Indianapolis. Study data were collected and managed using REDCap electronic data capture tools hosted at Veteran Health Indiana. The authors also acknowledge George Eckert for his assistance with data analysis.

In 2019, diabetes mellitus (DM) was the seventh leading cause of death in the United States, and currently, about 11% of the American population has a DM diagnosis.¹ Most have a diagnosis of type 2 diabetes (T2DM), which has a strong genetic predisposition, and the risk of developing T2DM increases with age, obesity, and lack of physical activity.^1,2 Nearly one-quarter of veterans have a diagnosis of DM, and DM is the leading cause of comorbidities, such as blindness, end-stage renal disease, and amputation for patients receiving care from the Veterans Health Administration (VHA).² The elevated incidence of DM in the veteran population is attributed to a variety of factors, including exposure to herbicides, such as Agent Orange, advanced age, increased risk of obesity, and limited access to high-quality food.³

After diagnosis, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) emphasize the appropriate use of lifestyle management and pharmacologic therapy for DM care. The use of pharmacologic agents (oral medications, insulin, or noninsulin injectables) is often determined by efficacy, cost, potential adverse effects (AEs), and patient factors and comorbidities.^4,5

The initial recommendation for pharmacologic treatment for T2DM differs slightly between expert guidelines. The ADA and AACE/ACE recommend any of the following as initial monotherapy, listed in order to represent a hierarchy of usage: metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 (SGLT-2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors, with the first 3 agents carrying the strongest recommendations.^4,5 For patients with established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure, it is recommended to start a long-acting GLP-1 RA or SGLT-2 inhibitor. For patients with T2DM and hemoglobin A_1c (HbA_1c) between 7.5% and 9.0% at diagnosis, the AACE/ACE recommend initiation of dual therapy using metformin alongside another first-line agent and recommend the addition of another antidiabetic agent if glycemic goals are not met after regular follow-up. AACE/ACE recommend the consideration of insulin therapy in symptomatic patients with HbA_1c > 9.0%.⁵ In contrast, the ADA recommends metformin as first-line therapy for all patients with T2DM and recommends dual therapy using metformin and another preferred agent (selection based on comorbidities) when HbA_1c is 1.5% to 2% above target. The ADA recommends the consideration of insulin with HbA_1c > 10% or with evidence of ongoing catabolism or symptoms of hyperglycemia.⁴ There are several reasons why insulin may be initiated prior to GLP-1 RAs, including profound hyperglycemia at time of diagnosis or implementation of insulin agents prior to commercial availability of GLP-1 RA.

GLP-1 RAs are analogs of the hormone incretin, which increases glucose-dependent insulin secretion, decreases postprandial glucagon secretion, increases satiety, and slows gastric emptying.^6,7 When used in combination with noninsulin agents, GLP-1 RAs have demonstrated HbA_1c reductions of 0.5% to 1.5%.⁸ The use of GLP-1 RAs with basal insulin also has been studied extensively.^6,8-10 When the combination of GLP-1 RAs and basal insulin was compared with basal/bolus insulin regimens, the use of the GLP-1 RAs resulted in lower HbA_1c levels and lower incidence of hypoglycemia.^6,9 Data have demonstrated the complementary mechanisms of using basal insulin and GLP 1 RAs in decreasing HbA_1c levels, insulin requirements, and weight compared with using basal insulin monotherapy and basal/bolus combinations.^6,9-13 Moreover, 3 GLP-1 RA medications currently on the market (liraglutide, dulaglutide, and semaglutide) have displayed cardiovascular and renal benefits, further supporting the use of these medications.^2,5

Despite these benefits, GLP-1 RAs may have bothersome AEs and are associated with a high cost.⁶ In addition, some studies have found that as the length of therapy increases, the positive effects of these agents may diminish.^9,11 In one study, which looked at the impact of the addition of exenatide to patients taking basal or basal/bolus insulin regimens, mean changes in weight were −2.4 kg at 0 to 6 months, −4.3 kg at 6 to 12 months, −6.2 kg at 12 to 18 months, and −5.5 kg at 18 to 27 months. After 18 months, an increase in weight was observed, but the increase remained lower than baseline.¹¹ Another study, conducted over 12 months, found no significant decrease in weight or total daily dose (TDD) of insulin when exenatide or liraglutide were added to various insulin regimens (basal or basal/bolus).¹³ To date, minimal published data exist regarding the addition of newer GLP-1 RAs and the long-term use of these agents beyond 12 months in patients taking basal/bolus insulin regimens. The primary goal of this study was to evaluate the effect of adding GLP-1 RAs to basal/bolus insulin regimens over a 24-month period.

Methods

This study was a retrospective, electronic health record review of all patients on basal and bolus insulin regimens who received additional therapy with a GLP-1 RA at Veteran Health Indiana in Indianapolis from September 1, 2015, to June 30, 2019. Patients meeting inclusion criteria served as their own control. The primary outcome was change in HbA_1c at 3, 6, 12, 18, and 24 months after initiation of the GLP-1 RA. Secondary outcomes included change in weight and TDD of insulin at 3, 6, 12, 18, and 24 months after the initiation of the GLP-1 RAs and incidence of patient-reported or laboratory-confirmed hypoglycemia and other AEs.

Patients were included if they were aged ≥ 18 years with a diagnosis of T2DM, had concomitant prescriptions for both a basal insulin (glargine, detemir, or NPH) and a bolus insulin (aspart, lispro, or regular) before receiving add-on therapy with a GLP-1 RA (exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide, or semaglutide) from September 1, 2015, to June 30, 2019, and had baseline and subsequent HbA_1c measurements available in the electronic health record. Patients were excluded if they had a diagnosis of type 1 DM (T1DM), were followed by an outside clinician for DM care, or if the GLP-1 RA was discontinued before subsequent HbA_1c measurement. The study protocol was approved by the Research and Development Office of Veteran Health Indiana, and the project was deemed exempt from review by the Indiana University Institutional Review Board due to the retrospective nature of the study.

Data analysis was performed using Excel. Change from baseline for each interval was computed, and 1 sample t tests (2-tailed) compared change from baseline to no change. Due to the disparity in the number of patients with data available at each of the time intervals, a mean plot was presented for each group of patients within each interval, allowing mean changes in individual groups to be observed over time.

Results

One hundred twenty-three subjects met inclusion criteria; 16 patients were excluded due to GLP-1 RA discontinuation before follow-up measurement of HbA_1c; 14 were excluded due to patients being managed by a clinician outside of the facility; 1 patient was excluded for lack of documentation regarding baseline and subsequent insulin doses. Ninety-two patient charts were reviewed. Participants had a mean age of 64 years, 95% were male, and 89% were White. Mean baseline HbA_1c was 9.2%, mean body mass index was 38.9, and the mean TDD of insulin was 184 units.

Since some patients switched between GLP-1 RAs throughout the study and there was variation in timing of laboratory and clinic follow-up,

Discussion

Adding a GLP-1 RA to basal/bolus insulin regimens was associated with a statistically significant decrease in HbA_1c at each time point through 18 months. The greatest improvement in glycemic control from baseline was seen at 3 months, with improvements in HbA_1c diminishing at each subsequent period. The study also demonstrated a significant decrease in weight at each time point through 18 months. The greatest decrease in weight was observed at both 6 and 12 months. Statistically significant decreases in TDD were observed at 3, 6, and 12 months. Insulin changes after 12 months were not found to be statistically significant.

Few studies have previously evaluated the use of GLP-1 RAs in patients with T2DM who are already taking basal/bolus insulin regimens. Gyorffy and colleagues reported significant improvements in glycemic control at 3 and 6 months in a sample of 54 patients taking basal/bolus insulin when liraglutide or exenatide was added, although statistical significance was not found at the final 12-month time point.¹³ That study also found a significant decrease in weight at 6 months; however there was not a significant reduction in weight at both 3 and 12 months of GLP-1 RA therapy. There was not a significant decrease in TDD at any of the collected time points. Nonetheless, Gyorffy and colleagues concluded that reduction in TDD leveled off after 12 months, which is consistent with this study’s findings. The small size of the study may have limited the ability to detect statistical significance; however, this study was conducted in a population that was racially diverse and included a higher proportion of women, though average age was similar.¹³

Yoon and colleagues reported weight loss through 18 months, then saw weight increase, though weights did remain lower than baseline. The study also showed no significant change in TDD of insulin after 12 months of concomitant exenatide and insulin therapy.¹¹ Although these results mirror the outcomes observed in this study, Yoon and colleagues did not differentiate results between basal and basal/bolus insulin groups.¹¹ Seino and colleagues observed no significant change in weight after 36 weeks of GLP-1 RA therapy in Japanese patients when used with basal and basal/bolus insulin regimens. Despite the consideration that the population in the study was not overweight (mean body mass index was 25.6), the results of these studies support the idea that effects of GLP-1 RAs on weight and TDD may diminish over time.¹⁴

Within the VHA, GLP-1 RAs are nonformulary medications. Patients must meet certain criteria in order to be approved for these agents, which may include diagnosis of CVD, renal disease, or failure to reach glycemic control with the use of oral agents or insulin. Therefore, participants of this study represent a particular subset of VHA patients, many of whom may have been selected for consideration due to long-standing or uncontrolled T2DM and failure of previous therapies. The baseline demographics support this idea, given poor glycemic control at baseline and high insulin requirements. Once approved for GLP-1 RA therapy, semaglutide is currently the preferred agent within the VHA, with other agents available for select considerations. It should be noted that albiglutide, which was the primary agent selected for some of the patients included in this study, was removed from the market in 2017 for economic considerations.¹⁵ In the case for these patients, a conversion to a formulary-preferred GLP-1 RA was made.

Most of the patients included in this study (70%) were maintained on metformin from baseline throughout the study period. Fifty-seven percent of patients were taking TDD of insulin > 150 units. Considering the significant cost of concentrated insulins, the addition of GLP-1 RAs to standard insulin may prove to be beneficial from a cost standpoint. Additional research in this area may be warranted to establish more data regarding this potential benefit of GLP-1 RAs as add-on therapy.

Many adverse drug reactions were reported at different periods; however, most of these were associated with the gastrointestinal system, which is consistent with current literature, drug labeling, and the mechanism of action.¹⁶ Hypoglycemia occurred in about one-third of the participants; however, it should be noted that alone, GLP-1 RAs are not associated with a high risk of hypoglycemia. Previous studies have found that GLP-1 RA monotherapy is associated with hypoglycemia in 1.6% to 12.6% of patients.^17,18 More likely, the combination of basal/bolus insulin and the GLP-1 RA’s effect on increasing insulin sensitivity through weight loss, improving glucose-dependent insulin secretion, or by decreasing appetite and therefore decreasing carbohydrate intake contributed to the hypoglycemia prevalence.

Limitations and Strengths

Limitations of this study include a small patient population and a gradual reduction in available data as time periods progressed, making even smaller sample sizes for subsequent time periods. A majority of participants were older, males and White race. This could have limited the determination of statistical significance and applicability of the results to other patient populations. Another potential limitation was the retrospective nature of the study design, which may have limited reporting of hypoglycemia and other AEs based on the documentation of the clinician.

Strengths included the study duration and the diversity of GLP-1 RAs used by participants, as the impact of many of these agents has not yet been assessed in the literature. In addition, the retrospective nature of the study allows for a more realistic representation of patient adherence, education, and motivation, which are likely different from those of patients included in prospective clinical trials.

There are no clear guidelines dictating the optimal duration of concomitant GLP-1 RA and insulin therapy; however, our study suggests that there may be continued benefits past short-term use. Also our study suggests that patients with T2DM treated with basal/bolus insulin regimens may glean additional benefit from adding GLP-1 RAs; however, further randomized, controlled studies are warranted, particularly in poorly controlled patients requiring even more aggressive treatment regimens, such as concentrated insulins.

Conclusions

In our study, adding GLP-1 RA to basal/bolus insulin was associated with a significant decrease in HbA_1c from baseline through 18 months. An overall decrease in weight and TDD of insulin was observed through 24 months, but the change in weight was not significant past 18 months, and the change in insulin requirement was not significant past 12 months. Hypoglycemia was observed in almost one-third of patients, and gastrointestinal symptoms were the most common AE observed as a result of adding GLP-1 RAs. More studies are needed to better evaluate the durability and cost benefit of GLP-1 RAs, especially in patients with high insulin requirements.

Acknowledgments

This material is the result of work supported with resources and facilities at Veteran Health Indiana in Indianapolis. Study data were collected and managed using REDCap electronic data capture tools hosted at Veteran Health Indiana. The authors also acknowledge George Eckert for his assistance with data analysis.