A supplement to Cardiology News. This supplement was sponsored by Chiesi USA, Inc.

News included in the supplement:

• Ultrathin stent loses advantage at 3 years
• Adjunctive devices for TAVR boost outcomes
• MI alert device shows predictive value
• Readmissions high post STEMI with cardiogenic shock
• Endovascular device sustains BP reductions
• Alcohol renal denervation safe for BP reduction

A supplement to Cardiology News. This supplement was sponsored by Chiesi USA, Inc.

News included in the supplement:

• Ultrathin stent loses advantage at 3 years
• Adjunctive devices for TAVR boost outcomes
• MI alert device shows predictive value
• Readmissions high post STEMI with cardiogenic shock
• Endovascular device sustains BP reductions
• Alcohol renal denervation safe for BP reduction

A supplement to Cardiology News. This supplement was sponsored by Chiesi USA, Inc.

News included in the supplement:

• Ultrathin stent loses advantage at 3 years
• Adjunctive devices for TAVR boost outcomes
• MI alert device shows predictive value
• Readmissions high post STEMI with cardiogenic shock
• Endovascular device sustains BP reductions
• Alcohol renal denervation safe for BP reduction

The word legacy has been synonymous with death to me. When so and so dies, we discuss their legacy. I had a powerful experience that changed my mind on this word that is befitting for this Legacies column.

Seven years ago, I was sitting in a room of powerful women and I was the youngest one there. I wasn’t sure how I got there, but I was glad I did because it changed my life. At the time, I was panicked. The exercise was called “Craft your legacy statement.”

But, this exercise was different. The ask was to “live into your legacy.” Craft a legacy statement in THREE minutes that summarizes what you want your legacy to be … and then decide the three things you need to do now to get there. So, here is my exact legacy 3-minute statement: I am an innovator pushing teaching hospitals to optimize training and patient care delivery through novel technologies and systems science. Clearly, I did not aim high enough. One of the other attendees stated her legacy simply as “Unleash the impossible!” So clearly, I was not able to think big at that moment, but I trudged on.

Next, I had to write the three things I was going to do to enact my legacy today. Things went from bad to worse quickly since I knew this was not going to be easy. The #1 thing had to be something I was going to stop doing because it did not fit with my legacy; #2 was what I was going to start doing to enact this legacy now; and, #3 was something I was going to do to get me closer to what I wanted to be doing. So, my #1, resign my current leadership role that I had had for 8 years; #2, start joining national committees that bridge education and quality; and #3, meet with senior leadership to pitch this new role as a bridging leader, aligning education and quality.

Like all conferences, I went home and forgot what I had done and learned. I settled back into my old life and routines. A few weeks later, a plain looking envelope with awful penmanship showed up at my doorstep addressed to me. It wasn’t until after I opened it and read what was inside that I realized I was the one with horrible penmanship! I completely forgot that I wrote this letter to myself even though they told me it would come and I would forget I wrote it! So, how did I do? Let’s just say if the letter did not arrive, I am not sure where I would be. Fortunately, it did come, and I followed my own orders. Fast forward to present day and I recently stepped into a new role – associate chief medical officer: clinical learning environment – a bridging leader who aligns education and clinical care missions for our health system. Let’s just say again, had that letter not arrived, I am not sure where I would be now.

• Be bold. Years ago, when I was asked by my chair who they should pick to be chief resident, I thought “This must be a trick question – I should definitely tell him why I should be chosen – and then pick the next best person who I want to work with.” Apparently, I was the only person who did that, and that is why my chair chose me. Everyone else picked two other people. So the take-home point here is do not sell yourself short … ever.
• Look for the hidden gateways. A few years ago, I was asked if I wanted to be an institutional leader by the person who currently had that role. I was kind of thrown for a loop, since of course I would not want to appear like I wanted to take his job. I said everything was fine and I felt pretty good about my current positions. It was only a few weeks later that I realized that he was ascertaining my interest in his job since he was leaving. They gave the job to someone else and the word on the street was I was not interested. I totally missed the gate! While it wasn’t necessarily the job I missed out on, it was the opportunity to consider the job because I was afraid. So, don’t miss the gate. It’s the wormhole to a different life that may be the right one for you, but you need to “see it” to seize it.
• Work hard for the money and for the fun. There are many things Gwyneth Paltrow does that I do not agree with, but I will give her credit for one important lesson: she divides her movie roles into those she does for love (for example, The Royal Tenenbaums) and those she does for money (for example, Shallow Hal). It made me realize that even a Hollywood starlet has to do the stuff she may not want to do for the money. So, as a young person, you have to work hard for the money, but ideally it will help you take on a project you love, whatever it is. You’ve won the game when you’re mostly paid to work for the fun ... but that may take some time.
• Always optimize what is best for you personally AND professionally. While I was on maternity leave, the job of my dreams presented itself – or so I thought it did. It was at the intersection of policy, quality, and education, with a national stage, and I would not need to move. But, I knew I could not accept the travel commitment with a young child. While I wondered if I would have regrets, it turns out the right decision professionally also has to work personally. Likewise, there are professional obligations that I take on because it works personally.
• Figure out who your tea house pals are. A few years ago, I was in San Francisco with two close friends having an epic moment about what to do with our lives as adults. We were all on the cusp of changing our directions. Not surprisingly, we could see what the other needed to do, but we could not see it for ourselves. We still text each other sometimes about the need to go back to the Tea House. Sometimes your “tea house pals” are not necessarily those around you every day. They know you, but not everyone in your work place. This “arm’s length” or distance gives them the rational, unbiased perspective to advise you, that you or your colleagues will never have.
• Look for ways to enjoy the journey. Medicine is a very long road. I routinely think about this working with all the trainees and junior faculty I encounter. You can’t be in this solely for the end of the journey. The key is to find the joy in the journey. For me, that has always come from seeking out like-minded fellow travelers to share my highs and lows. While I tweet for many reasons, a big reason is that I take pleasure in watching others on the journey and also sharing my own journey.

Here’s to your journey and living your legacy!

Dr. Arora is associate chief medical officer, clinical learning environment, at University of Chicago Medicine, and assistant dean for scholarship and discovery at the University of Chicago Pritzker School of Medicine. You can follow her journey on Twitter.

The word legacy has been synonymous with death to me. When so and so dies, we discuss their legacy. I had a powerful experience that changed my mind on this word that is befitting for this Legacies column.

Seven years ago, I was sitting in a room of powerful women and I was the youngest one there. I wasn’t sure how I got there, but I was glad I did because it changed my life. At the time, I was panicked. The exercise was called “Craft your legacy statement.”

But, this exercise was different. The ask was to “live into your legacy.” Craft a legacy statement in THREE minutes that summarizes what you want your legacy to be … and then decide the three things you need to do now to get there. So, here is my exact legacy 3-minute statement: I am an innovator pushing teaching hospitals to optimize training and patient care delivery through novel technologies and systems science. Clearly, I did not aim high enough. One of the other attendees stated her legacy simply as “Unleash the impossible!” So clearly, I was not able to think big at that moment, but I trudged on.

Next, I had to write the three things I was going to do to enact my legacy today. Things went from bad to worse quickly since I knew this was not going to be easy. The #1 thing had to be something I was going to stop doing because it did not fit with my legacy; #2 was what I was going to start doing to enact this legacy now; and, #3 was something I was going to do to get me closer to what I wanted to be doing. So, my #1, resign my current leadership role that I had had for 8 years; #2, start joining national committees that bridge education and quality; and #3, meet with senior leadership to pitch this new role as a bridging leader, aligning education and quality.

Like all conferences, I went home and forgot what I had done and learned. I settled back into my old life and routines. A few weeks later, a plain looking envelope with awful penmanship showed up at my doorstep addressed to me. It wasn’t until after I opened it and read what was inside that I realized I was the one with horrible penmanship! I completely forgot that I wrote this letter to myself even though they told me it would come and I would forget I wrote it! So, how did I do? Let’s just say if the letter did not arrive, I am not sure where I would be. Fortunately, it did come, and I followed my own orders. Fast forward to present day and I recently stepped into a new role – associate chief medical officer: clinical learning environment – a bridging leader who aligns education and clinical care missions for our health system. Let’s just say again, had that letter not arrived, I am not sure where I would be now.

• Be bold. Years ago, when I was asked by my chair who they should pick to be chief resident, I thought “This must be a trick question – I should definitely tell him why I should be chosen – and then pick the next best person who I want to work with.” Apparently, I was the only person who did that, and that is why my chair chose me. Everyone else picked two other people. So the take-home point here is do not sell yourself short … ever.
• Look for the hidden gateways. A few years ago, I was asked if I wanted to be an institutional leader by the person who currently had that role. I was kind of thrown for a loop, since of course I would not want to appear like I wanted to take his job. I said everything was fine and I felt pretty good about my current positions. It was only a few weeks later that I realized that he was ascertaining my interest in his job since he was leaving. They gave the job to someone else and the word on the street was I was not interested. I totally missed the gate! While it wasn’t necessarily the job I missed out on, it was the opportunity to consider the job because I was afraid. So, don’t miss the gate. It’s the wormhole to a different life that may be the right one for you, but you need to “see it” to seize it.
• Work hard for the money and for the fun. There are many things Gwyneth Paltrow does that I do not agree with, but I will give her credit for one important lesson: she divides her movie roles into those she does for love (for example, The Royal Tenenbaums) and those she does for money (for example, Shallow Hal). It made me realize that even a Hollywood starlet has to do the stuff she may not want to do for the money. So, as a young person, you have to work hard for the money, but ideally it will help you take on a project you love, whatever it is. You’ve won the game when you’re mostly paid to work for the fun ... but that may take some time.
• Always optimize what is best for you personally AND professionally. While I was on maternity leave, the job of my dreams presented itself – or so I thought it did. It was at the intersection of policy, quality, and education, with a national stage, and I would not need to move. But, I knew I could not accept the travel commitment with a young child. While I wondered if I would have regrets, it turns out the right decision professionally also has to work personally. Likewise, there are professional obligations that I take on because it works personally.
• Figure out who your tea house pals are. A few years ago, I was in San Francisco with two close friends having an epic moment about what to do with our lives as adults. We were all on the cusp of changing our directions. Not surprisingly, we could see what the other needed to do, but we could not see it for ourselves. We still text each other sometimes about the need to go back to the Tea House. Sometimes your “tea house pals” are not necessarily those around you every day. They know you, but not everyone in your work place. This “arm’s length” or distance gives them the rational, unbiased perspective to advise you, that you or your colleagues will never have.
• Look for ways to enjoy the journey. Medicine is a very long road. I routinely think about this working with all the trainees and junior faculty I encounter. You can’t be in this solely for the end of the journey. The key is to find the joy in the journey. For me, that has always come from seeking out like-minded fellow travelers to share my highs and lows. While I tweet for many reasons, a big reason is that I take pleasure in watching others on the journey and also sharing my own journey.

Here’s to your journey and living your legacy!

Dr. Arora is associate chief medical officer, clinical learning environment, at University of Chicago Medicine, and assistant dean for scholarship and discovery at the University of Chicago Pritzker School of Medicine. You can follow her journey on Twitter.

The word legacy has been synonymous with death to me. When so and so dies, we discuss their legacy. I had a powerful experience that changed my mind on this word that is befitting for this Legacies column.

Seven years ago, I was sitting in a room of powerful women and I was the youngest one there. I wasn’t sure how I got there, but I was glad I did because it changed my life. At the time, I was panicked. The exercise was called “Craft your legacy statement.”

But, this exercise was different. The ask was to “live into your legacy.” Craft a legacy statement in THREE minutes that summarizes what you want your legacy to be … and then decide the three things you need to do now to get there. So, here is my exact legacy 3-minute statement: I am an innovator pushing teaching hospitals to optimize training and patient care delivery through novel technologies and systems science. Clearly, I did not aim high enough. One of the other attendees stated her legacy simply as “Unleash the impossible!” So clearly, I was not able to think big at that moment, but I trudged on.

Next, I had to write the three things I was going to do to enact my legacy today. Things went from bad to worse quickly since I knew this was not going to be easy. The #1 thing had to be something I was going to stop doing because it did not fit with my legacy; #2 was what I was going to start doing to enact this legacy now; and, #3 was something I was going to do to get me closer to what I wanted to be doing. So, my #1, resign my current leadership role that I had had for 8 years; #2, start joining national committees that bridge education and quality; and #3, meet with senior leadership to pitch this new role as a bridging leader, aligning education and quality.

Like all conferences, I went home and forgot what I had done and learned. I settled back into my old life and routines. A few weeks later, a plain looking envelope with awful penmanship showed up at my doorstep addressed to me. It wasn’t until after I opened it and read what was inside that I realized I was the one with horrible penmanship! I completely forgot that I wrote this letter to myself even though they told me it would come and I would forget I wrote it! So, how did I do? Let’s just say if the letter did not arrive, I am not sure where I would be. Fortunately, it did come, and I followed my own orders. Fast forward to present day and I recently stepped into a new role – associate chief medical officer: clinical learning environment – a bridging leader who aligns education and clinical care missions for our health system. Let’s just say again, had that letter not arrived, I am not sure where I would be now.

• Be bold. Years ago, when I was asked by my chair who they should pick to be chief resident, I thought “This must be a trick question – I should definitely tell him why I should be chosen – and then pick the next best person who I want to work with.” Apparently, I was the only person who did that, and that is why my chair chose me. Everyone else picked two other people. So the take-home point here is do not sell yourself short … ever.
• Look for the hidden gateways. A few years ago, I was asked if I wanted to be an institutional leader by the person who currently had that role. I was kind of thrown for a loop, since of course I would not want to appear like I wanted to take his job. I said everything was fine and I felt pretty good about my current positions. It was only a few weeks later that I realized that he was ascertaining my interest in his job since he was leaving. They gave the job to someone else and the word on the street was I was not interested. I totally missed the gate! While it wasn’t necessarily the job I missed out on, it was the opportunity to consider the job because I was afraid. So, don’t miss the gate. It’s the wormhole to a different life that may be the right one for you, but you need to “see it” to seize it.
• Work hard for the money and for the fun. There are many things Gwyneth Paltrow does that I do not agree with, but I will give her credit for one important lesson: she divides her movie roles into those she does for love (for example, The Royal Tenenbaums) and those she does for money (for example, Shallow Hal). It made me realize that even a Hollywood starlet has to do the stuff she may not want to do for the money. So, as a young person, you have to work hard for the money, but ideally it will help you take on a project you love, whatever it is. You’ve won the game when you’re mostly paid to work for the fun ... but that may take some time.
• Always optimize what is best for you personally AND professionally. While I was on maternity leave, the job of my dreams presented itself – or so I thought it did. It was at the intersection of policy, quality, and education, with a national stage, and I would not need to move. But, I knew I could not accept the travel commitment with a young child. While I wondered if I would have regrets, it turns out the right decision professionally also has to work personally. Likewise, there are professional obligations that I take on because it works personally.
• Figure out who your tea house pals are. A few years ago, I was in San Francisco with two close friends having an epic moment about what to do with our lives as adults. We were all on the cusp of changing our directions. Not surprisingly, we could see what the other needed to do, but we could not see it for ourselves. We still text each other sometimes about the need to go back to the Tea House. Sometimes your “tea house pals” are not necessarily those around you every day. They know you, but not everyone in your work place. This “arm’s length” or distance gives them the rational, unbiased perspective to advise you, that you or your colleagues will never have.
• Look for ways to enjoy the journey. Medicine is a very long road. I routinely think about this working with all the trainees and junior faculty I encounter. You can’t be in this solely for the end of the journey. The key is to find the joy in the journey. For me, that has always come from seeking out like-minded fellow travelers to share my highs and lows. While I tweet for many reasons, a big reason is that I take pleasure in watching others on the journey and also sharing my own journey.

Here’s to your journey and living your legacy!

Dr. Arora is associate chief medical officer, clinical learning environment, at University of Chicago Medicine, and assistant dean for scholarship and discovery at the University of Chicago Pritzker School of Medicine. You can follow her journey on Twitter.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

African American men with diabetes may be at risk for significantly low levels of oxytocin (OT), according to a study of 92 veterans by researchers from the Jesse Brown Veterans Administration Medical Center in Chicago, Illinois. Research has recently been revealing oxytocin’s role in energy homeostasis; OT derangements have also been implicated in a variety of diseases, including schizophrenia, autism, dysthymia, and attention-deficit/hyperactivity disorder.

The researchers note that their study participants represent a “unique population” of African American male veterans for whom no data on OT levels exist in the literature. The population has a disproportionately high rate of obesity and dysglycemia, as well as high rates of comorbid psychiatric disease.

In the study, urinary oxytocin was higher in men with lower weight, body mass index (BMI), and hemoglobin A_1c and better renal function. Men with the highest levels of oxytocin were about 80% less likely to have type 2 diabetes. The researchers say several studies have appeared to show that intranasal OT may reduce reward-driven food intake, and that OT administration may result in weight reduction.

Men with high oxytocin levels were 4 times more likely to be using psychiatric medications. Although there was no difference in psychiatric conditions based on OT levels, the use of psychiatric medications remained significant after adjustment for BMI. The influence of psychiatric medications on oxytocinergic systems is not well understood, the researchers say. However, they add that medication-related improved psychological health outcome might result in OT changes.

Men with high oxytocin levels were also 4 times more likely to be smokers. The researchers note that chronic administration of nicotine seems to upregulate OT receptor binding in regions of the brain involved in stress and emotion regulation, and these neuro-adaptations likely influence nicotine-seeking behavior. Intranasal OT is being investigated for smoking cessation.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.

A 5-member panel of experts in primary care, geriatrics, and behavioral sciences, among others, convened by the  National Institutes of Health (NIH), sought to answer that question. In the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention, the panel discussed the available evidence on long-term drug therapies, in hopes of identifying research gaps and ways to “advance the field.” Then they published a report that summarizes their findings, along with recommendations for “new strengthened research.”

Trials have found 3 to 5 years of ODT is safe and effective, the panel notes, and that some ODTs reduce the incidence of nonvertebral fractures. But those studies have been done mainly in white postmenopausal women. Men, people of other race and ethnicity, residents in facilities, people with advanced and multiple comorbid conditions, and other populations are absent or underrepresented. Thus, estimates on benefits and harms may differ in practice. Moreover, the trial results presented no data on nonfracture patient outcomes or sequelae, such as mobility, hospitalizations, and nursing home placement. The studies also offered limited or no evidence on whether patient characteristics would result in different fracture outcomes.

The panel also noted that few trials extended beyond 5 years, although some observational studies provided “limited evidence” on potential benefits and harms from longer term use. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that might modify the effects of ODT, the panel concluded.

 One of the main issues the panel investigated was how to make sure that the people at highest risk of fracture get the medicine they need. Only about one-third of women at high risk have reported treatment with osteoporosis medication. And among older adults with a hip fracture, only 11% to 13% filled any prescription for osteoporosis medication within 3 months of the fracture.

Information about ODT use and adherence was not included in the systematic evidence review, so the report relies on material provided by the workshop speakers, who say low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For instance, they said, with regard to clinicians, the problems may be lack of time, knowledge gaps, and lack of appropriate systems in primary care.

The panelists also cited another gap: in communication between clinicians about treatment as patients transition from one setting to another. One solution could be a hospital-based fracture liaison service to coordinate care, they suggest.

Patient factors include perceptions that osteoporosis is a normal part of aging, or that drugs do not work or that they are harmful and risky. Studies about decision making have found that people often overestimate their risk for rare adverse effects (AEs) and underestimate the likelihood of having a fracture.

In their assessment of studies, the workshop panelists found education-based interventions sometimes increase rates of filled prescriptions but not adherence 6 or 10 months down the road. They also found coaching and counseling have been “largely ineffective.”

“We need to identify the reasons why,” the panelists concluded, and made a number of recommendations about how to do the research. For instance, they suggest using a broader array of trial designs, such as innovative platform trials as used in cancer research, where the target of the investigation is the disease and not the drug. Studies also should focus on fracture sequelae, and include diverse populations that “more closely match” the characteristics of people who actually have fractures.

Gaps in knowledge about the uncommon AEs reported with bisphosphonates and other questions mean questions to be answered include which class of drugs should be used first, when treatment should start and how long it should last, and which doses are preferable.

Knowing how to treat can help clinicians and their patients decide whom to treat, the report suggests. Addressing the research gaps will improve the shared decision making needed for answering those questions.

The report was published in Annals of Internal Medicine on April 23, 2019.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

Unrecognized severe obstructive sleep apnea is a risk factor for cardiovascular complications after major noncardiac surgery, according to a study published in JAMA.

The researchers state that perioperative mismanagement of obstructive sleep apnea can lead to serious medical consequences. “General anesthetics, sedatives, and postoperative analgesics are potent respiratory depressants that relax the upper airway dilator muscles and impair ventilatory response to hypoxemia and hypercapnia. Each of these events exacerbates [obstructive sleep apnea] and may predispose patients to postoperative cardiovascular complications,” said researchers who conducted the The Postoperative vascular complications in unrecognised Obstructive Sleep apnoea (POSA) study (NCT01494181).

They undertook a prospective observational cohort study involving 1,218 patients undergoing major noncardiac surgery, who were already considered at high risk of postoperative cardiovascular events – having, for example, a history of coronary artery disease, stroke, diabetes, or renal impairment. However, none had a prior diagnosis of obstructive sleep apnea.

Preoperative sleep monitoring revealed that two-thirds of the cohort had unrecognized and untreated obstructive sleep apnea, including 11.2% with severe obstructive sleep apnea.

At 30 days after surgery, patients with obstructive sleep apnea had a 49% higher risk of the primary outcome of myocardial injury, cardiac death, heart failure, thromboembolism, atrial fibrillation, or stroke, compared with those without obstructive sleep apnea.

However, this association was largely due to a significant 2.23-fold higher risk among patients with severe obstructive sleep apnea, while those with only moderate or mild sleep apnea did not show a significant increased risk of cardiovascular complications.

Patients in this study with severe obstructive sleep apnea had a 13-fold higher risk of cardiac death, 80% higher risk of myocardial injury, more than sixfold higher risk of heart failure, and nearly fourfold higher risk of atrial fibrillation.

Researchers also saw an association between obstructive sleep apnea and increased risk of infective outcomes, unplanned tracheal intubation, postoperative lung ventilation, and readmission to the ICU.

The majority of patients received nocturnal oximetry monitoring during their first 3 nights after surgery. This revealed that patients without obstructive sleep apnea had significant increases in oxygen desaturation index during their first night after surgery, while those with sleep apnea did not return to their baseline oxygen desaturation index until the third night after surgery.

“Despite a substantial decrease in ODI [oxygen desaturation index] with oxygen therapy in patients with OSA during the first 3 postoperative nights, supplemental oxygen did not modify the association between OSA and postoperative cardiovascular event,” wrote Matthew T.V. Chan, MD, of Chinese University of Hong Kong, Prince of Wales Hospital, and coauthors.

Given that the events were associated with longer durations of severe oxyhemoglobin desaturation, more aggressive interventions such as positive airway pressure or oral appliances may be required, they noted.

“However, high-level evidence demonstrating the effect of these measures on perioperative outcomes is lacking [and] further clinical trials are now required to test if additional monitoring or alternative interventions would reduce the risk,” they wrote.

The study was supported by the Health and Medical Research Fund (Hong Kong), National Healthcare Group–Khoo Teck Puat Hospital, University Health Network Foundation, University of Malaya, Malaysian Society of Anaesthesiologists, Auckland Medical Research Foundation, and ResMed. One author declared grants from private industry and a patent pending on an obstructive sleep apnea risk questionnaire used in the study.

SOURCE: Chan M et al. JAMA 2019;321[18]:1788-98. doi: 10.1001/jama.2019.4783.

BALTIMORE – An analysis of sleeve gastrectomy (SG) operations reported to a statewide registry over a 5-year period has found that the proportion of patients with worsening gastroesophageal reflux disease (GERD) symptoms varied widely among surgeons despite similarities in surgeon training, experience, skills, technique, and complication rates, according to findings presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“We found that about a third of patients undergoing sleeve gastrectomy within this data registry developed worsening symptoms after sleeve gastrectomy, and the severity of these symptoms actually varied considerably, from 1 to 13.8 increase in their [GERD–Health Related Quality of Life Questionnaire (HRQL)] score,” said Oliver Varban, MD, of the University of Michigan, Ann Arbor. “Among the surgeons themselves, the rates of severe symptoms varied despite the surgeon’s experience and rate of hiatal hernia repair being similar between the groups.”

This study involved 7,358 patients in the Michigan Bariatric Surgery Collaborative (MBSC) registry who had SG from 2013 to 2017 and 52 surgeons who performed 25 or more SG cases per year. The patients completed the GERD-HRQL survey at baseline and 1 year after SG. The two scores were compared and patients were divided into terciles – mild, moderate, and severe – for worsening of symptoms, then matched with the surgeons who performed the operation. In all, 31.2% of patients (n = 2,294) reported worsening symptoms a year after SG, divided into the following terciles: mild with a 1.4-point increase in GERD-HRQL score (11.7%, n = 866); moderate, a 4.2-point increase (9.7%, n = 716); and severe, 13.8-point increase (9.7%, n = 712).

Among surgeons, the highest rate of patients with severe worsening of GERD was 44.7%, the lowest rate, 18.7%. So the researchers compared characteristics among the surgeons with the highest and lowest rates. “We found that they’re quite similar, actually, in terms of years of bariatric fellowship training, annual sleeve gastrectomy volume, total bariatric annual volume, as well as operative time,” Dr. Varban said. “Interestingly, the rate of concurrent hiatal hernia repair within these two groups is similar as well, which is about one-third for each group” (34.3% for the highest-rate group and 27% for the lowest-rate surgeons).

Likewise, 30-day risk adjusted complication rates were similar between both groups, 3.7% for the high group and 4.3% for the low group.

“Total–body weight loss or excess–body weight loss was actually fairly similar clinically between the two groups, but there was a statistical significance with more weight loss in the GERD patients who had higher severe worsening of symptoms,” Dr. Varban noted.

Surgeons with the highest rates of severe reflux symptoms in their patients tended to operate on more patients with diabetes, hypertension, and cardiovascular disease, whereas the surgeons with the lowest rate of severe symptoms had a higher proportion of patients who were male, white, and had hyperlipidemia and sleep apnea.

Dr. Varban has no financial relationships to disclose. Blue Cross Blue Shield of Michigan provided salary support through the MBSC.

SOURCE: Varban O et al. SAGES 2019; Session SS29, Abstract S139.

BALTIMORE – An analysis of sleeve gastrectomy (SG) operations reported to a statewide registry over a 5-year period has found that the proportion of patients with worsening gastroesophageal reflux disease (GERD) symptoms varied widely among surgeons despite similarities in surgeon training, experience, skills, technique, and complication rates, according to findings presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“We found that about a third of patients undergoing sleeve gastrectomy within this data registry developed worsening symptoms after sleeve gastrectomy, and the severity of these symptoms actually varied considerably, from 1 to 13.8 increase in their [GERD–Health Related Quality of Life Questionnaire (HRQL)] score,” said Oliver Varban, MD, of the University of Michigan, Ann Arbor. “Among the surgeons themselves, the rates of severe symptoms varied despite the surgeon’s experience and rate of hiatal hernia repair being similar between the groups.”

This study involved 7,358 patients in the Michigan Bariatric Surgery Collaborative (MBSC) registry who had SG from 2013 to 2017 and 52 surgeons who performed 25 or more SG cases per year. The patients completed the GERD-HRQL survey at baseline and 1 year after SG. The two scores were compared and patients were divided into terciles – mild, moderate, and severe – for worsening of symptoms, then matched with the surgeons who performed the operation. In all, 31.2% of patients (n = 2,294) reported worsening symptoms a year after SG, divided into the following terciles: mild with a 1.4-point increase in GERD-HRQL score (11.7%, n = 866); moderate, a 4.2-point increase (9.7%, n = 716); and severe, 13.8-point increase (9.7%, n = 712).

Among surgeons, the highest rate of patients with severe worsening of GERD was 44.7%, the lowest rate, 18.7%. So the researchers compared characteristics among the surgeons with the highest and lowest rates. “We found that they’re quite similar, actually, in terms of years of bariatric fellowship training, annual sleeve gastrectomy volume, total bariatric annual volume, as well as operative time,” Dr. Varban said. “Interestingly, the rate of concurrent hiatal hernia repair within these two groups is similar as well, which is about one-third for each group” (34.3% for the highest-rate group and 27% for the lowest-rate surgeons).

Likewise, 30-day risk adjusted complication rates were similar between both groups, 3.7% for the high group and 4.3% for the low group.

“Total–body weight loss or excess–body weight loss was actually fairly similar clinically between the two groups, but there was a statistical significance with more weight loss in the GERD patients who had higher severe worsening of symptoms,” Dr. Varban noted.

Surgeons with the highest rates of severe reflux symptoms in their patients tended to operate on more patients with diabetes, hypertension, and cardiovascular disease, whereas the surgeons with the lowest rate of severe symptoms had a higher proportion of patients who were male, white, and had hyperlipidemia and sleep apnea.

Dr. Varban has no financial relationships to disclose. Blue Cross Blue Shield of Michigan provided salary support through the MBSC.

SOURCE: Varban O et al. SAGES 2019; Session SS29, Abstract S139.

BALTIMORE – An analysis of sleeve gastrectomy (SG) operations reported to a statewide registry over a 5-year period has found that the proportion of patients with worsening gastroesophageal reflux disease (GERD) symptoms varied widely among surgeons despite similarities in surgeon training, experience, skills, technique, and complication rates, according to findings presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“We found that about a third of patients undergoing sleeve gastrectomy within this data registry developed worsening symptoms after sleeve gastrectomy, and the severity of these symptoms actually varied considerably, from 1 to 13.8 increase in their [GERD–Health Related Quality of Life Questionnaire (HRQL)] score,” said Oliver Varban, MD, of the University of Michigan, Ann Arbor. “Among the surgeons themselves, the rates of severe symptoms varied despite the surgeon’s experience and rate of hiatal hernia repair being similar between the groups.”

This study involved 7,358 patients in the Michigan Bariatric Surgery Collaborative (MBSC) registry who had SG from 2013 to 2017 and 52 surgeons who performed 25 or more SG cases per year. The patients completed the GERD-HRQL survey at baseline and 1 year after SG. The two scores were compared and patients were divided into terciles – mild, moderate, and severe – for worsening of symptoms, then matched with the surgeons who performed the operation. In all, 31.2% of patients (n = 2,294) reported worsening symptoms a year after SG, divided into the following terciles: mild with a 1.4-point increase in GERD-HRQL score (11.7%, n = 866); moderate, a 4.2-point increase (9.7%, n = 716); and severe, 13.8-point increase (9.7%, n = 712).

Among surgeons, the highest rate of patients with severe worsening of GERD was 44.7%, the lowest rate, 18.7%. So the researchers compared characteristics among the surgeons with the highest and lowest rates. “We found that they’re quite similar, actually, in terms of years of bariatric fellowship training, annual sleeve gastrectomy volume, total bariatric annual volume, as well as operative time,” Dr. Varban said. “Interestingly, the rate of concurrent hiatal hernia repair within these two groups is similar as well, which is about one-third for each group” (34.3% for the highest-rate group and 27% for the lowest-rate surgeons).

Likewise, 30-day risk adjusted complication rates were similar between both groups, 3.7% for the high group and 4.3% for the low group.

“Total–body weight loss or excess–body weight loss was actually fairly similar clinically between the two groups, but there was a statistical significance with more weight loss in the GERD patients who had higher severe worsening of symptoms,” Dr. Varban noted.

Surgeons with the highest rates of severe reflux symptoms in their patients tended to operate on more patients with diabetes, hypertension, and cardiovascular disease, whereas the surgeons with the lowest rate of severe symptoms had a higher proportion of patients who were male, white, and had hyperlipidemia and sleep apnea.

Dr. Varban has no financial relationships to disclose. Blue Cross Blue Shield of Michigan provided salary support through the MBSC.

SOURCE: Varban O et al. SAGES 2019; Session SS29, Abstract S139.

Young Native Americans had increased left ventricular thickness and left ventricular hypertrophy after being exposed to arsenic, and had a greater risk if they showed signs of prehypertension or hypertension, according to recent research.

“The stronger association in subjects with elevated blood pressure suggests that individuals with preclinical heart disease might be more prone to the toxic effects of arsenic on the heart,” Gernot Pichler, MD, PhD, a cardiologist at Hospital Hietzing/Heart Center Clinic Floridsdorf in Vienna, stated in a press release.

Dr. Pichler and colleagues evaluated 1,337 individuals (mean age, 31 years; 61% female) in the Strong Heart Family Study, an extension of the Strong Heart Study that was designed to study cardiovascular disease in Native Americans. The researchers noted that, while the studies were not originally intended to evaluate arsenic exposure in these populations, “the importance of studying arsenic was recognized overtime as increasing evidence supported the role of arsenic in cardiovascular disease and the relatively high arsenic exposure in tribal communities, compared to other general populations in the United States.”

Arsenic exposure was determined through the sum of inorganic and methylated arsenic concentrations in urine, and researchers used transthoracic ECG at baseline and follow-up to compare left ventricular geometry and function. The mean follow-up was 5.6 years and baseline median sum of inorganic and methylated arsenic concentrations in urine was 4.24 (interquartile range, 2.82-6.90) mcg/g creatinine.

Prevalence of left ventricular hypertrophy was 4.6% overall, and the odds ratio of left ventricular hypertrophy per 100% increase in arsenic in the urine was 1.47 (95% confidence interval, 1.05-2.08) overall and 1.58 for individuals with prehypertension or hypertension (95% CI, 1.04-2.41).

“People drinking water from private wells, which are not regulated, need to be aware that arsenic may increase the risk for cardiovascular disease,” said Dr. Pichler. “Testing those wells is a critical first step to take action and prevent exposure.”

Prospective and cross-sectional analyses both showed changes in left ventricular geometry – such as in the left atrial systolic diameter, interventricular septum, and left ventricular posterior wall thickness and mass index – were associated with exposure to arsenic. In addition, left ventricular function factors such as isovolumic relaxation time and stroke volume were also affected by arsenic exposure. However, the researchers noted that their study was limited by a single method of arsenic exposure and having no long-term follow-up for participants.

“The study raises the question of whether the changes in heart structure are reversible if exposure is reduced. Some changes have occurred in water sources in the study communities, and it will be important to check the potential health impact of reducing arsenic exposure,” said Dr. Pichler.

This study was funded by the National Institute of Health Sciences and grants from the National Heart, Lung, and Blood Institute. The authors reported no relevant conflicts of interest.

SOURCE: Pichler G et al. Circ Cardiovasc Imaging. 2019 May 1. doi: 10.1161/CIRCIMAGING.119.009018.

Young Native Americans had increased left ventricular thickness and left ventricular hypertrophy after being exposed to arsenic, and had a greater risk if they showed signs of prehypertension or hypertension, according to recent research.

“The stronger association in subjects with elevated blood pressure suggests that individuals with preclinical heart disease might be more prone to the toxic effects of arsenic on the heart,” Gernot Pichler, MD, PhD, a cardiologist at Hospital Hietzing/Heart Center Clinic Floridsdorf in Vienna, stated in a press release.

Dr. Pichler and colleagues evaluated 1,337 individuals (mean age, 31 years; 61% female) in the Strong Heart Family Study, an extension of the Strong Heart Study that was designed to study cardiovascular disease in Native Americans. The researchers noted that, while the studies were not originally intended to evaluate arsenic exposure in these populations, “the importance of studying arsenic was recognized overtime as increasing evidence supported the role of arsenic in cardiovascular disease and the relatively high arsenic exposure in tribal communities, compared to other general populations in the United States.”

Arsenic exposure was determined through the sum of inorganic and methylated arsenic concentrations in urine, and researchers used transthoracic ECG at baseline and follow-up to compare left ventricular geometry and function. The mean follow-up was 5.6 years and baseline median sum of inorganic and methylated arsenic concentrations in urine was 4.24 (interquartile range, 2.82-6.90) mcg/g creatinine.

Prevalence of left ventricular hypertrophy was 4.6% overall, and the odds ratio of left ventricular hypertrophy per 100% increase in arsenic in the urine was 1.47 (95% confidence interval, 1.05-2.08) overall and 1.58 for individuals with prehypertension or hypertension (95% CI, 1.04-2.41).

“People drinking water from private wells, which are not regulated, need to be aware that arsenic may increase the risk for cardiovascular disease,” said Dr. Pichler. “Testing those wells is a critical first step to take action and prevent exposure.”

Prospective and cross-sectional analyses both showed changes in left ventricular geometry – such as in the left atrial systolic diameter, interventricular septum, and left ventricular posterior wall thickness and mass index – were associated with exposure to arsenic. In addition, left ventricular function factors such as isovolumic relaxation time and stroke volume were also affected by arsenic exposure. However, the researchers noted that their study was limited by a single method of arsenic exposure and having no long-term follow-up for participants.

“The study raises the question of whether the changes in heart structure are reversible if exposure is reduced. Some changes have occurred in water sources in the study communities, and it will be important to check the potential health impact of reducing arsenic exposure,” said Dr. Pichler.

This study was funded by the National Institute of Health Sciences and grants from the National Heart, Lung, and Blood Institute. The authors reported no relevant conflicts of interest.

SOURCE: Pichler G et al. Circ Cardiovasc Imaging. 2019 May 1. doi: 10.1161/CIRCIMAGING.119.009018.

Young Native Americans had increased left ventricular thickness and left ventricular hypertrophy after being exposed to arsenic, and had a greater risk if they showed signs of prehypertension or hypertension, according to recent research.

“The stronger association in subjects with elevated blood pressure suggests that individuals with preclinical heart disease might be more prone to the toxic effects of arsenic on the heart,” Gernot Pichler, MD, PhD, a cardiologist at Hospital Hietzing/Heart Center Clinic Floridsdorf in Vienna, stated in a press release.

Dr. Pichler and colleagues evaluated 1,337 individuals (mean age, 31 years; 61% female) in the Strong Heart Family Study, an extension of the Strong Heart Study that was designed to study cardiovascular disease in Native Americans. The researchers noted that, while the studies were not originally intended to evaluate arsenic exposure in these populations, “the importance of studying arsenic was recognized overtime as increasing evidence supported the role of arsenic in cardiovascular disease and the relatively high arsenic exposure in tribal communities, compared to other general populations in the United States.”

Arsenic exposure was determined through the sum of inorganic and methylated arsenic concentrations in urine, and researchers used transthoracic ECG at baseline and follow-up to compare left ventricular geometry and function. The mean follow-up was 5.6 years and baseline median sum of inorganic and methylated arsenic concentrations in urine was 4.24 (interquartile range, 2.82-6.90) mcg/g creatinine.

Prevalence of left ventricular hypertrophy was 4.6% overall, and the odds ratio of left ventricular hypertrophy per 100% increase in arsenic in the urine was 1.47 (95% confidence interval, 1.05-2.08) overall and 1.58 for individuals with prehypertension or hypertension (95% CI, 1.04-2.41).

“People drinking water from private wells, which are not regulated, need to be aware that arsenic may increase the risk for cardiovascular disease,” said Dr. Pichler. “Testing those wells is a critical first step to take action and prevent exposure.”

Prospective and cross-sectional analyses both showed changes in left ventricular geometry – such as in the left atrial systolic diameter, interventricular septum, and left ventricular posterior wall thickness and mass index – were associated with exposure to arsenic. In addition, left ventricular function factors such as isovolumic relaxation time and stroke volume were also affected by arsenic exposure. However, the researchers noted that their study was limited by a single method of arsenic exposure and having no long-term follow-up for participants.

“The study raises the question of whether the changes in heart structure are reversible if exposure is reduced. Some changes have occurred in water sources in the study communities, and it will be important to check the potential health impact of reducing arsenic exposure,” said Dr. Pichler.

This study was funded by the National Institute of Health Sciences and grants from the National Heart, Lung, and Blood Institute. The authors reported no relevant conflicts of interest.

SOURCE: Pichler G et al. Circ Cardiovasc Imaging. 2019 May 1. doi: 10.1161/CIRCIMAGING.119.009018.

BALTIMORE – A head-to-head comparison of robotic and laparoscopic surgery for locally advanced rectal cancer has found that the operations achieve similar outcomes in terms of composite negative margins, overall survival, and readmissions, but that robotic surgery is associated with lower rates of conversion to open surgery and shorter hospital stays, according to an analysis of cases in the National Cancer Database presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The gold standard for how we’re taking care of our patients, of course, is how we’re doing with the cancer survival, and we found no difference for overall survival in the robotic arm and the laparoscopic arm,” said M. Benjamin Hopkins, MD, of Vanderbilt University, Nashville, Tenn. He reported on a retrospective review of 7,616 operations for rectal adenocarcinoma in the National Cancer Database from 2010 to 2014. The study population included 2,472 (32%) robotic procedures. The hazard ratio for 5-year overall survival was 0.87 (P = .18), Dr. Hopkins noted, with virtually identical Kaplan-Meier survival curves between the two approaches.

The negative margin rates were also similar between the two groups: 93.7% for the robotic patients and 92.9% for the laparoscopic cohort (odds ratio 0.86, P = .23), Dr. Hopkins noted. Readmission rates were 9% and 8%, respectively (odds ratio 1.02, P = .44).

There were two significant differences in outcomes between the two groups: The conversion rate to open surgery for the robotic group “was about half that from what we saw with laparoscopic surgery,” he said – 8% vs. 15%; and “a slightly decreased length of stay” in the robotic group – 6.3 vs. 6.7 days (P less than .001).

Dr. Hopkins noted that the science supporting robotic surgery for rectal resection is still somewhat nascent, pointing to the ROLARR randomized trial, which showed conversion rates similar to those of open between the two minimally invasive approaches (8.1% for robotic and 12.2% for laparoscopy [P = .16] JAMA. 2017; 318[16]:1569-80). “Surgeons in this study were still on their learning curve, and what the results showed was that among surgeons, even with varied experience, robotic surgery was [equal] to laparoscopic surgery in relation to conversion rates and composite margin for cancer specimens,” he said of the ROLARR trial.

That led to the premise for his group’s study. “The hypothesis that we had going into this study was that we are able to get a better composite negative margin with robotic surgery as opposed to laparoscopic surgery, which would then translate into improved cancer survival for our patients,” he said. Like the ROLARR trial, the 2010-2014 National Cancer Database dataset Dr. Hopkins and colleagues used includes a window for the learning curve, he added.

“One of the questions that always comes at us from hospital administration and from insurance companies is whether or not there’s a cost benefit for the patient: What is the value to the patient?” Dr. Hopkins noted. “I’d like to see future studies where we’re looking at this value and, as we decrease our operative time and anesthesia costs, and hopefully some decreased cost in the instrumentation, we start to see some more benefits as we get more facile with robotic surgery.”

Dr. Hopkins has no financial relationships to disclose.

SOURCE: Hopkins B et al. SAGES 2019. Session SS13; abstract S058

CORRECTION 5/14/2109 :  The hazard ratio for 5-year overall survival and p-value were updated. 

BALTIMORE – A head-to-head comparison of robotic and laparoscopic surgery for locally advanced rectal cancer has found that the operations achieve similar outcomes in terms of composite negative margins, overall survival, and readmissions, but that robotic surgery is associated with lower rates of conversion to open surgery and shorter hospital stays, according to an analysis of cases in the National Cancer Database presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The gold standard for how we’re taking care of our patients, of course, is how we’re doing with the cancer survival, and we found no difference for overall survival in the robotic arm and the laparoscopic arm,” said M. Benjamin Hopkins, MD, of Vanderbilt University, Nashville, Tenn. He reported on a retrospective review of 7,616 operations for rectal adenocarcinoma in the National Cancer Database from 2010 to 2014. The study population included 2,472 (32%) robotic procedures. The hazard ratio for 5-year overall survival was 0.87 (P = .18), Dr. Hopkins noted, with virtually identical Kaplan-Meier survival curves between the two approaches.

The negative margin rates were also similar between the two groups: 93.7% for the robotic patients and 92.9% for the laparoscopic cohort (odds ratio 0.86, P = .23), Dr. Hopkins noted. Readmission rates were 9% and 8%, respectively (odds ratio 1.02, P = .44).

There were two significant differences in outcomes between the two groups: The conversion rate to open surgery for the robotic group “was about half that from what we saw with laparoscopic surgery,” he said – 8% vs. 15%; and “a slightly decreased length of stay” in the robotic group – 6.3 vs. 6.7 days (P less than .001).

Dr. Hopkins noted that the science supporting robotic surgery for rectal resection is still somewhat nascent, pointing to the ROLARR randomized trial, which showed conversion rates similar to those of open between the two minimally invasive approaches (8.1% for robotic and 12.2% for laparoscopy [P = .16] JAMA. 2017; 318[16]:1569-80). “Surgeons in this study were still on their learning curve, and what the results showed was that among surgeons, even with varied experience, robotic surgery was [equal] to laparoscopic surgery in relation to conversion rates and composite margin for cancer specimens,” he said of the ROLARR trial.

That led to the premise for his group’s study. “The hypothesis that we had going into this study was that we are able to get a better composite negative margin with robotic surgery as opposed to laparoscopic surgery, which would then translate into improved cancer survival for our patients,” he said. Like the ROLARR trial, the 2010-2014 National Cancer Database dataset Dr. Hopkins and colleagues used includes a window for the learning curve, he added.

“One of the questions that always comes at us from hospital administration and from insurance companies is whether or not there’s a cost benefit for the patient: What is the value to the patient?” Dr. Hopkins noted. “I’d like to see future studies where we’re looking at this value and, as we decrease our operative time and anesthesia costs, and hopefully some decreased cost in the instrumentation, we start to see some more benefits as we get more facile with robotic surgery.”

Dr. Hopkins has no financial relationships to disclose.

SOURCE: Hopkins B et al. SAGES 2019. Session SS13; abstract S058

CORRECTION 5/14/2109 :  The hazard ratio for 5-year overall survival and p-value were updated. 

BALTIMORE – A head-to-head comparison of robotic and laparoscopic surgery for locally advanced rectal cancer has found that the operations achieve similar outcomes in terms of composite negative margins, overall survival, and readmissions, but that robotic surgery is associated with lower rates of conversion to open surgery and shorter hospital stays, according to an analysis of cases in the National Cancer Database presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The gold standard for how we’re taking care of our patients, of course, is how we’re doing with the cancer survival, and we found no difference for overall survival in the robotic arm and the laparoscopic arm,” said M. Benjamin Hopkins, MD, of Vanderbilt University, Nashville, Tenn. He reported on a retrospective review of 7,616 operations for rectal adenocarcinoma in the National Cancer Database from 2010 to 2014. The study population included 2,472 (32%) robotic procedures. The hazard ratio for 5-year overall survival was 0.87 (P = .18), Dr. Hopkins noted, with virtually identical Kaplan-Meier survival curves between the two approaches.

The negative margin rates were also similar between the two groups: 93.7% for the robotic patients and 92.9% for the laparoscopic cohort (odds ratio 0.86, P = .23), Dr. Hopkins noted. Readmission rates were 9% and 8%, respectively (odds ratio 1.02, P = .44).

There were two significant differences in outcomes between the two groups: The conversion rate to open surgery for the robotic group “was about half that from what we saw with laparoscopic surgery,” he said – 8% vs. 15%; and “a slightly decreased length of stay” in the robotic group – 6.3 vs. 6.7 days (P less than .001).

Dr. Hopkins noted that the science supporting robotic surgery for rectal resection is still somewhat nascent, pointing to the ROLARR randomized trial, which showed conversion rates similar to those of open between the two minimally invasive approaches (8.1% for robotic and 12.2% for laparoscopy [P = .16] JAMA. 2017; 318[16]:1569-80). “Surgeons in this study were still on their learning curve, and what the results showed was that among surgeons, even with varied experience, robotic surgery was [equal] to laparoscopic surgery in relation to conversion rates and composite margin for cancer specimens,” he said of the ROLARR trial.

That led to the premise for his group’s study. “The hypothesis that we had going into this study was that we are able to get a better composite negative margin with robotic surgery as opposed to laparoscopic surgery, which would then translate into improved cancer survival for our patients,” he said. Like the ROLARR trial, the 2010-2014 National Cancer Database dataset Dr. Hopkins and colleagues used includes a window for the learning curve, he added.

“One of the questions that always comes at us from hospital administration and from insurance companies is whether or not there’s a cost benefit for the patient: What is the value to the patient?” Dr. Hopkins noted. “I’d like to see future studies where we’re looking at this value and, as we decrease our operative time and anesthesia costs, and hopefully some decreased cost in the instrumentation, we start to see some more benefits as we get more facile with robotic surgery.”

Dr. Hopkins has no financial relationships to disclose.

SOURCE: Hopkins B et al. SAGES 2019. Session SS13; abstract S058

CORRECTION 5/14/2109 :  The hazard ratio for 5-year overall survival and p-value were updated. 

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

PHILADELPHIA – Treatment with evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis (MS), according to results of a phase 2 study. Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.

Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.

This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.

In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.

Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.

The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.

There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.

There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.

Most treatment-emergent adverse events were mild or moderate, according to the investigators.

Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.

Results of the study were published concurrently in the New England Journal of Medicine.

Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.

PHILADELPHIA – Treatment with evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis (MS), according to results of a phase 2 study. Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.

Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.

This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.

In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.

Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.

The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.

There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.

There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.

Most treatment-emergent adverse events were mild or moderate, according to the investigators.

Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.

Results of the study were published concurrently in the New England Journal of Medicine.

Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.

PHILADELPHIA – Treatment with evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, reduced the number of enhancing lesions versus placebo in patients with relapsing multiple sclerosis (MS), according to results of a phase 2 study. Higher doses of evobrutinib significantly improved that study endpoint, and were associated with numerical decreases in the annualized relapse rate versus placebo, according to a report presented at the annual meeting of the American Academy of Neurology.

Some grade 3-4 transaminase elevations were associated with evobrutinib, though these were asymptomatic, reversible, and occurred within the first 24 weeks of the 48-week treatment period, said investigator Xavier Montalban, MD, PhD, chairman and director of the department of neurology-neuroimmunology at Vall d’Hebron University Hospital in Barcelona.

“Overall, we do believe the results of the phase 2 study support further clinical development in relapsing multiple sclerosis,” Dr. Montalban said.

This study builds on previous observations that BTK plays an important role in immune functions related to the pathogenesis of MS, Dr. Montalban said. Evobrutinib in particular impacts B cells and myeloid cells along with pathways involved in MS-related inflammation, he added.

In the current randomized, phase 2, placebo-controlled study, 267 patients with relapsing MS were randomized to one of five arms: placebo, evobrutinib 25-mg daily, 75-mg daily, or 75-mg twice daily, or an open-label reference arm of dimethyl fumarate 240 mg twice daily.

Dr. Montalban presented the results of a 24-week treatment period plus a 24-week blinded extension period, during which placebo-treated patients crossed over to evobrutinib 25 mg daily, for a total of 48 weeks of treatment.

The primary study endpoint was the cumulative number of MRI-assessed T1 Gd+ lesions at weeks 12, 16, 20, and 24. Dr. Montalban said that evobrutinib in the two 75-mg arms significantly reduced enhancing lesions versus placebo over weeks 12-24, with lesion rate ratios of 0.30 for the 75-mg daily arm, and 0.44 for the 75-mg twice-daily arm, with unadjusted P values of .002 and .031, respectively. By contrast, the evobrutinib 25-mg arm did not significantly reduce the cumulative number of enhancing lesions versus placebo over that time period.

There was a rapid reduction in the mean number of enhancing lesions from baseline to the week-12 visit for those 75-mg dosing arms, which was sustained through subsequent visits, Dr. Montalban said.

There were no significant differences between arms in the annualized relapse rate at week 24, a key secondary endpoint of the study, according to the investigators. The annualized relapse rate was 0.37 for placebo, 0.57 for evobrutinib 25 mg daily, 0.13 for the 75-mg daily dose, 0.08 for the 75-mg twice-daily dose, and 0.20 for dimethyl fumarate. The magnitude of reduction was maintained at the 48-week evaluation for evobrutinib 75 mg twice daily, with an annualized relapse rate of 0.11, Dr. Montalban reported.

Most treatment-emergent adverse events were mild or moderate, according to the investigators.

Reported ALT elevations in the evobrutinib arms were mainly grade 1. While some grade 3-4 elevations were seen in the first 24 weeks of the study, they were reversible and did not have clinical consequences, according to Dr. Montalban.

Results of the study were published concurrently in the New England Journal of Medicine.

Dr. Montalban provided disclosures related to Biogen, Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Roche, Celgene, Actelion, National Multiple Sclerosis Society, and Multiple Sclerosis International Federation.

SOURCE: Montalban X et al. AAN 2019. Abstract S56.004.