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Suicide notes left by elderly people provide a unique opportunity to better understand and prevent suicide in this often vulnerable population.

A new analysis of notes penned by seniors who died by suicide reveals several common themes. These include feeling as if they were a burden, feelings of guilt, experiencing mental illness, loneliness, or isolation, as well as poor health and/or disability.

“The most important message [in our findings] is that there is hope,” study investigator Ari B. Cuperfain, MD, Temerty Faculty of Medicine, University of Toronto, told this news organization.

“Suicide risk is modifiable, and we encourage that care providers sensitively explore thoughts of suicide in patients expressing depressive thoughts or difficulty coping with other life stressors,” he said.

The study was published online in The American Journal of Geriatric Psychiatry.
 

Opportunity for intervention

Most previous studies of late-life suicide have focused on risk factors rather than the themes and meaning underlying individuals’ distress.

Dr. Cuperfain’s group had previously analyzed suicide notes to “explore the relationship between suicide and an individual’s experience with mental health care in all age groups,” he said. For the current study, the investigators analyzed the subset of notes written exclusively by older adults.

The researchers “hypothesized that suicide notes could provide a unique window into the thought processes of older adults during a critical window for mental health intervention,” he added.

Although effective screening for suicidality in older adults can mitigate suicide risk, the frequency of suicide screening decreases with increasing age, the authors noted.

In addition, suicide attempts are typically more often fatal in older adults than in the general population. Understanding the motivations for suicide in this vulnerable population can inform potential interventions.

The researchers used a constructivist grounded theory framework to analyze suicide notes available from their previous study and notes obtained from the Office of the Coroner in Toronto from adults aged 65 years and older (n = 29; mean [SD], age 76.2 [8.3] years; 79% men).

The investigators began with open coding of the notes, “specifying a short name to a segment of data that summarizes and accounts for each piece of data.” They then used a series of techniques to identify terms and themes (repeated patterns of ideas reflected in the data).

Once themes had been determined, they identified “pathways between these themes and the final act of suicide.”
 

Common themes

Four major themes emerged in the analysis of the suicide notes.

Recurring terms included “pain,” “[poor] sleep,” or “[wakeful] nights,” as well as “sorry” (either about past actions or about the suicide), and “I just can’t” (referring to the inability to carry on).

The suicide notes “provided the older writers’ conceptual schema for suicide, elucidating the cognitive process linking their narratives to the acts of suicide.” Examples included the following:

• Suicide as a way out or solution to an insoluble problem.
• Suicide as the final act in a long road of suffering.
• Suicide as the logical culmination of life (the person “lived a good life”).

“Our study enriches the understanding of ‘why’ rather than just ‘which’ older adults die by suicide,” the authors noted.

“Care providers can help older adults at risk of suicide through a combination of treatment options. These include physician involvement to manage depression, psychosis, or pain, psychotherapy to reframe certain ways of thinking, or social activities to reduce isolation,” Dr. Cuperfain said.

“By understanding the experiences of older adults and what is underlying their suicidal thoughts, these interventions can be tailored specifically for the individual experiencing distress,” he added.
 

Untangling suicide drivers

Commenting on the study, Yeates Conwell, MD, professor and vice chair, department of psychiatry, University of Rochester (N.Y.) Medical Center, said that “by analyzing the suicide notes of older people who died by suicide, the paper lends a unique perspective to our understanding of why they may have taken their lives.”

University of Rochester Medical Center

Dr. Conwell, director of the geriatric psychiatry program and codirector of the Center for the Study and Prevention of Suicide, University of Rochester, and author of an accompanying editorial, said that “by including the decedent’s own voice, the analysis of notes is a useful complement to other approaches used for the study of suicide in this age group”.

However, “like all other approaches, it is subject to potential biases in interpretation. The meaning in the notes must be derived with careful consideration of context, both what is said and what is not said, and the likelihood that both overt and covert messages are contained in and between their lines,” cautioned Dr. Conwell.

“Acknowledging the strength and limitations of each approach to the study of suicide death, together they can help untangle its drivers and support the search for effective, acceptable, and scalable prevention interventions. No one approach alone, however, will reveal the ‘cause’ of suicide,” Dr. Conwell wrote.

No source of study funding was provided. Dr. Cuperfain reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Conwell reports no relevant financial relationships.

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

Suicide notes left by elderly people provide a unique opportunity to better understand and prevent suicide in this often vulnerable population.

A new analysis of notes penned by seniors who died by suicide reveals several common themes. These include feeling as if they were a burden, feelings of guilt, experiencing mental illness, loneliness, or isolation, as well as poor health and/or disability.

“The most important message [in our findings] is that there is hope,” study investigator Ari B. Cuperfain, MD, Temerty Faculty of Medicine, University of Toronto, told this news organization.

“Suicide risk is modifiable, and we encourage that care providers sensitively explore thoughts of suicide in patients expressing depressive thoughts or difficulty coping with other life stressors,” he said.

The study was published online in The American Journal of Geriatric Psychiatry.
 

Opportunity for intervention

Most previous studies of late-life suicide have focused on risk factors rather than the themes and meaning underlying individuals’ distress.

Dr. Cuperfain’s group had previously analyzed suicide notes to “explore the relationship between suicide and an individual’s experience with mental health care in all age groups,” he said. For the current study, the investigators analyzed the subset of notes written exclusively by older adults.

The researchers “hypothesized that suicide notes could provide a unique window into the thought processes of older adults during a critical window for mental health intervention,” he added.

Although effective screening for suicidality in older adults can mitigate suicide risk, the frequency of suicide screening decreases with increasing age, the authors noted.

In addition, suicide attempts are typically more often fatal in older adults than in the general population. Understanding the motivations for suicide in this vulnerable population can inform potential interventions.

The researchers used a constructivist grounded theory framework to analyze suicide notes available from their previous study and notes obtained from the Office of the Coroner in Toronto from adults aged 65 years and older (n = 29; mean [SD], age 76.2 [8.3] years; 79% men).

The investigators began with open coding of the notes, “specifying a short name to a segment of data that summarizes and accounts for each piece of data.” They then used a series of techniques to identify terms and themes (repeated patterns of ideas reflected in the data).

Once themes had been determined, they identified “pathways between these themes and the final act of suicide.”
 

Common themes

Four major themes emerged in the analysis of the suicide notes.

Recurring terms included “pain,” “[poor] sleep,” or “[wakeful] nights,” as well as “sorry” (either about past actions or about the suicide), and “I just can’t” (referring to the inability to carry on).

The suicide notes “provided the older writers’ conceptual schema for suicide, elucidating the cognitive process linking their narratives to the acts of suicide.” Examples included the following:

• Suicide as a way out or solution to an insoluble problem.
• Suicide as the final act in a long road of suffering.
• Suicide as the logical culmination of life (the person “lived a good life”).

“Our study enriches the understanding of ‘why’ rather than just ‘which’ older adults die by suicide,” the authors noted.

“Care providers can help older adults at risk of suicide through a combination of treatment options. These include physician involvement to manage depression, psychosis, or pain, psychotherapy to reframe certain ways of thinking, or social activities to reduce isolation,” Dr. Cuperfain said.

“By understanding the experiences of older adults and what is underlying their suicidal thoughts, these interventions can be tailored specifically for the individual experiencing distress,” he added.
 

Untangling suicide drivers

Commenting on the study, Yeates Conwell, MD, professor and vice chair, department of psychiatry, University of Rochester (N.Y.) Medical Center, said that “by analyzing the suicide notes of older people who died by suicide, the paper lends a unique perspective to our understanding of why they may have taken their lives.”

University of Rochester Medical Center

Dr. Conwell, director of the geriatric psychiatry program and codirector of the Center for the Study and Prevention of Suicide, University of Rochester, and author of an accompanying editorial, said that “by including the decedent’s own voice, the analysis of notes is a useful complement to other approaches used for the study of suicide in this age group”.

However, “like all other approaches, it is subject to potential biases in interpretation. The meaning in the notes must be derived with careful consideration of context, both what is said and what is not said, and the likelihood that both overt and covert messages are contained in and between their lines,” cautioned Dr. Conwell.

“Acknowledging the strength and limitations of each approach to the study of suicide death, together they can help untangle its drivers and support the search for effective, acceptable, and scalable prevention interventions. No one approach alone, however, will reveal the ‘cause’ of suicide,” Dr. Conwell wrote.

No source of study funding was provided. Dr. Cuperfain reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Conwell reports no relevant financial relationships.

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

Suicide notes left by elderly people provide a unique opportunity to better understand and prevent suicide in this often vulnerable population.

A new analysis of notes penned by seniors who died by suicide reveals several common themes. These include feeling as if they were a burden, feelings of guilt, experiencing mental illness, loneliness, or isolation, as well as poor health and/or disability.

“The most important message [in our findings] is that there is hope,” study investigator Ari B. Cuperfain, MD, Temerty Faculty of Medicine, University of Toronto, told this news organization.

“Suicide risk is modifiable, and we encourage that care providers sensitively explore thoughts of suicide in patients expressing depressive thoughts or difficulty coping with other life stressors,” he said.

The study was published online in The American Journal of Geriatric Psychiatry.
 

Opportunity for intervention

Most previous studies of late-life suicide have focused on risk factors rather than the themes and meaning underlying individuals’ distress.

Dr. Cuperfain’s group had previously analyzed suicide notes to “explore the relationship between suicide and an individual’s experience with mental health care in all age groups,” he said. For the current study, the investigators analyzed the subset of notes written exclusively by older adults.

The researchers “hypothesized that suicide notes could provide a unique window into the thought processes of older adults during a critical window for mental health intervention,” he added.

Although effective screening for suicidality in older adults can mitigate suicide risk, the frequency of suicide screening decreases with increasing age, the authors noted.

In addition, suicide attempts are typically more often fatal in older adults than in the general population. Understanding the motivations for suicide in this vulnerable population can inform potential interventions.

The researchers used a constructivist grounded theory framework to analyze suicide notes available from their previous study and notes obtained from the Office of the Coroner in Toronto from adults aged 65 years and older (n = 29; mean [SD], age 76.2 [8.3] years; 79% men).

The investigators began with open coding of the notes, “specifying a short name to a segment of data that summarizes and accounts for each piece of data.” They then used a series of techniques to identify terms and themes (repeated patterns of ideas reflected in the data).

Once themes had been determined, they identified “pathways between these themes and the final act of suicide.”
 

Common themes

Four major themes emerged in the analysis of the suicide notes.

Recurring terms included “pain,” “[poor] sleep,” or “[wakeful] nights,” as well as “sorry” (either about past actions or about the suicide), and “I just can’t” (referring to the inability to carry on).

The suicide notes “provided the older writers’ conceptual schema for suicide, elucidating the cognitive process linking their narratives to the acts of suicide.” Examples included the following:

• Suicide as a way out or solution to an insoluble problem.
• Suicide as the final act in a long road of suffering.
• Suicide as the logical culmination of life (the person “lived a good life”).

“Our study enriches the understanding of ‘why’ rather than just ‘which’ older adults die by suicide,” the authors noted.

“Care providers can help older adults at risk of suicide through a combination of treatment options. These include physician involvement to manage depression, psychosis, or pain, psychotherapy to reframe certain ways of thinking, or social activities to reduce isolation,” Dr. Cuperfain said.

“By understanding the experiences of older adults and what is underlying their suicidal thoughts, these interventions can be tailored specifically for the individual experiencing distress,” he added.
 

Untangling suicide drivers

Commenting on the study, Yeates Conwell, MD, professor and vice chair, department of psychiatry, University of Rochester (N.Y.) Medical Center, said that “by analyzing the suicide notes of older people who died by suicide, the paper lends a unique perspective to our understanding of why they may have taken their lives.”

University of Rochester Medical Center

Dr. Conwell, director of the geriatric psychiatry program and codirector of the Center for the Study and Prevention of Suicide, University of Rochester, and author of an accompanying editorial, said that “by including the decedent’s own voice, the analysis of notes is a useful complement to other approaches used for the study of suicide in this age group”.

However, “like all other approaches, it is subject to potential biases in interpretation. The meaning in the notes must be derived with careful consideration of context, both what is said and what is not said, and the likelihood that both overt and covert messages are contained in and between their lines,” cautioned Dr. Conwell.

“Acknowledging the strength and limitations of each approach to the study of suicide death, together they can help untangle its drivers and support the search for effective, acceptable, and scalable prevention interventions. No one approach alone, however, will reveal the ‘cause’ of suicide,” Dr. Conwell wrote.

No source of study funding was provided. Dr. Cuperfain reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Dr. Conwell reports no relevant financial relationships.

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

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I run the division of medical ethics at New York University Grossman School of Medicine.

Many of you know that President Biden created a loan forgiveness program, forgiving up to $10,000 against federal student loans, including graduate and undergraduate education. The Department of Education is supposed to provide up to $20,000 in debt cancellation to Pell Grant recipients who have loans that are held by the Department of Education. Borrowers can get this relief if their income is less than $125,000 for an individual or $250,000 for married couples.

Many people have looked at this and said, “Hey, wait a minute. I paid off my loans. I didn’t get any reimbursement. That isn’t fair.”

One group saddled with massive debt are people who are still carrying their medical school loans, who often still have huge amounts of debt, and either because of the income limits or because they don’t qualify because this debt was accrued long in the past, they’re saying, “What about me? Don’t you want to give any relief to me?”

This is a topic near and dear to my heart because I happen to be at a medical school, NYU, that has decided for the two medical schools it runs – our main campus, NYU in Manhattan and NYU Langone out on Long Island – that we’re going to go tuition free. We’ve done it for a couple of years.

We did it because I think all the administrators and faculty understood the tremendous burden that debt poses on people who both carry forward their undergraduate debt and then have medical school debt. This really leads to very difficult situations – which we have great empathy for – about what specialty you’re going to go into, whether you have to moonlight, and how you’re going to manage a huge burden of debt.

Many people don’t have sympathy out in the public. They say doctors make a large amount of money and they live a nice lifestyle, so we’re not going to relieve their debt. The reality is that, whoever you are, short of Bill Gates or Elon Musk, having hundreds of thousands of dollars of debt is no easy task to live with and to work off.

Still, when we created free tuition at NYU for our medical school, there were many people who paid high tuition fees in the past. Some of them said to us, “What about me?” We decided not to try to do anything retrospectively. The plan was to build up enough money so that we could handle no-cost tuition going forward. We didn’t really have it in our pocketbook to help people who’d already paid their debts or were saddled with NYU debt. Is it fair? No, it’s probably not fair, but it’s an improvement.

That’s what I want people to think about who are saying, “What about my medical school debt? What about my undergraduate plus medical school debt?” I think we should be grateful when efforts are being made to reduce very burdensome student loans that people have. It’s good to give that benefit and move it forward.

Does that mean no one should get anything unless everyone with any kind of debt from school is covered? I don’t think so. I don’t think that’s fair either.

It is possible that we could continue to agitate politically and say, let’s go after some of the health care debt. Let’s go after some of the things that are still driving people to have to work more than they would or to choose specialties that they really don’t want to be in because they have to make up that debt.

It doesn’t mean the last word has been said about the politics of debt relief or, for that matter, the price of going to medical school in the first place and trying to see whether that can be driven down.

I don’t think it’s right to say, “If I can’t benefit, given the huge burden that I’m carrying, then I’m not going to try to give relief to others.” I think we’re relieving debt to the extent that we can do it. The nation can afford it. Going forward is a good thing. It’s wrong to create those gigantic debts in the first place.

What are we going to do about the past? We may decide that we need some sort of forgiveness or reparations for loans that were built up for others going backwards. I wouldn’t hold hostage the future and our children to what was probably a very poor, unethical practice about saddling doctors and others in the past with huge debt.

I’m Art Caplan at the division of medical ethics at New York University Grossman School of Medicine. Thank you for watching.

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

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I run the division of medical ethics at New York University Grossman School of Medicine.

Many of you know that President Biden created a loan forgiveness program, forgiving up to $10,000 against federal student loans, including graduate and undergraduate education. The Department of Education is supposed to provide up to $20,000 in debt cancellation to Pell Grant recipients who have loans that are held by the Department of Education. Borrowers can get this relief if their income is less than $125,000 for an individual or $250,000 for married couples.

Many people have looked at this and said, “Hey, wait a minute. I paid off my loans. I didn’t get any reimbursement. That isn’t fair.”

One group saddled with massive debt are people who are still carrying their medical school loans, who often still have huge amounts of debt, and either because of the income limits or because they don’t qualify because this debt was accrued long in the past, they’re saying, “What about me? Don’t you want to give any relief to me?”

This is a topic near and dear to my heart because I happen to be at a medical school, NYU, that has decided for the two medical schools it runs – our main campus, NYU in Manhattan and NYU Langone out on Long Island – that we’re going to go tuition free. We’ve done it for a couple of years.

We did it because I think all the administrators and faculty understood the tremendous burden that debt poses on people who both carry forward their undergraduate debt and then have medical school debt. This really leads to very difficult situations – which we have great empathy for – about what specialty you’re going to go into, whether you have to moonlight, and how you’re going to manage a huge burden of debt.

Many people don’t have sympathy out in the public. They say doctors make a large amount of money and they live a nice lifestyle, so we’re not going to relieve their debt. The reality is that, whoever you are, short of Bill Gates or Elon Musk, having hundreds of thousands of dollars of debt is no easy task to live with and to work off.

Still, when we created free tuition at NYU for our medical school, there were many people who paid high tuition fees in the past. Some of them said to us, “What about me?” We decided not to try to do anything retrospectively. The plan was to build up enough money so that we could handle no-cost tuition going forward. We didn’t really have it in our pocketbook to help people who’d already paid their debts or were saddled with NYU debt. Is it fair? No, it’s probably not fair, but it’s an improvement.

That’s what I want people to think about who are saying, “What about my medical school debt? What about my undergraduate plus medical school debt?” I think we should be grateful when efforts are being made to reduce very burdensome student loans that people have. It’s good to give that benefit and move it forward.

Does that mean no one should get anything unless everyone with any kind of debt from school is covered? I don’t think so. I don’t think that’s fair either.

It is possible that we could continue to agitate politically and say, let’s go after some of the health care debt. Let’s go after some of the things that are still driving people to have to work more than they would or to choose specialties that they really don’t want to be in because they have to make up that debt.

It doesn’t mean the last word has been said about the politics of debt relief or, for that matter, the price of going to medical school in the first place and trying to see whether that can be driven down.

I don’t think it’s right to say, “If I can’t benefit, given the huge burden that I’m carrying, then I’m not going to try to give relief to others.” I think we’re relieving debt to the extent that we can do it. The nation can afford it. Going forward is a good thing. It’s wrong to create those gigantic debts in the first place.

What are we going to do about the past? We may decide that we need some sort of forgiveness or reparations for loans that were built up for others going backwards. I wouldn’t hold hostage the future and our children to what was probably a very poor, unethical practice about saddling doctors and others in the past with huge debt.

I’m Art Caplan at the division of medical ethics at New York University Grossman School of Medicine. Thank you for watching.

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

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I run the division of medical ethics at New York University Grossman School of Medicine.

Many of you know that President Biden created a loan forgiveness program, forgiving up to $10,000 against federal student loans, including graduate and undergraduate education. The Department of Education is supposed to provide up to $20,000 in debt cancellation to Pell Grant recipients who have loans that are held by the Department of Education. Borrowers can get this relief if their income is less than $125,000 for an individual or $250,000 for married couples.

Many people have looked at this and said, “Hey, wait a minute. I paid off my loans. I didn’t get any reimbursement. That isn’t fair.”

One group saddled with massive debt are people who are still carrying their medical school loans, who often still have huge amounts of debt, and either because of the income limits or because they don’t qualify because this debt was accrued long in the past, they’re saying, “What about me? Don’t you want to give any relief to me?”

This is a topic near and dear to my heart because I happen to be at a medical school, NYU, that has decided for the two medical schools it runs – our main campus, NYU in Manhattan and NYU Langone out on Long Island – that we’re going to go tuition free. We’ve done it for a couple of years.

We did it because I think all the administrators and faculty understood the tremendous burden that debt poses on people who both carry forward their undergraduate debt and then have medical school debt. This really leads to very difficult situations – which we have great empathy for – about what specialty you’re going to go into, whether you have to moonlight, and how you’re going to manage a huge burden of debt.

Many people don’t have sympathy out in the public. They say doctors make a large amount of money and they live a nice lifestyle, so we’re not going to relieve their debt. The reality is that, whoever you are, short of Bill Gates or Elon Musk, having hundreds of thousands of dollars of debt is no easy task to live with and to work off.

Still, when we created free tuition at NYU for our medical school, there were many people who paid high tuition fees in the past. Some of them said to us, “What about me?” We decided not to try to do anything retrospectively. The plan was to build up enough money so that we could handle no-cost tuition going forward. We didn’t really have it in our pocketbook to help people who’d already paid their debts or were saddled with NYU debt. Is it fair? No, it’s probably not fair, but it’s an improvement.

That’s what I want people to think about who are saying, “What about my medical school debt? What about my undergraduate plus medical school debt?” I think we should be grateful when efforts are being made to reduce very burdensome student loans that people have. It’s good to give that benefit and move it forward.

Does that mean no one should get anything unless everyone with any kind of debt from school is covered? I don’t think so. I don’t think that’s fair either.

It is possible that we could continue to agitate politically and say, let’s go after some of the health care debt. Let’s go after some of the things that are still driving people to have to work more than they would or to choose specialties that they really don’t want to be in because they have to make up that debt.

It doesn’t mean the last word has been said about the politics of debt relief or, for that matter, the price of going to medical school in the first place and trying to see whether that can be driven down.

I don’t think it’s right to say, “If I can’t benefit, given the huge burden that I’m carrying, then I’m not going to try to give relief to others.” I think we’re relieving debt to the extent that we can do it. The nation can afford it. Going forward is a good thing. It’s wrong to create those gigantic debts in the first place.

What are we going to do about the past? We may decide that we need some sort of forgiveness or reparations for loans that were built up for others going backwards. I wouldn’t hold hostage the future and our children to what was probably a very poor, unethical practice about saddling doctors and others in the past with huge debt.

I’m Art Caplan at the division of medical ethics at New York University Grossman School of Medicine. Thank you for watching.

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

This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack. 

A recent piece in The Economist about masks, and how at least half of the people in Japan are planning to continue to use masks indefinitely (where there was never a mandate), prompts a deeper look into what has been the secret of Japan’s extraordinary success in the pandemic. Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.

Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.

Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.

Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.

But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.

Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.

And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.

Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.

Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.

There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.

That’s why I had previously modified the Swiss cheese model to add Paxlovid.

But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.

Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.

No less the previous data through May 2022 showing protection from death across all ages with two boosters

And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.

We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.

Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.

This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack. 

A recent piece in The Economist about masks, and how at least half of the people in Japan are planning to continue to use masks indefinitely (where there was never a mandate), prompts a deeper look into what has been the secret of Japan’s extraordinary success in the pandemic. Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.

Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.

Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.

Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.

But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.

Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.

And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.

Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.

Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.

There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.

That’s why I had previously modified the Swiss cheese model to add Paxlovid.

But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.

Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.

No less the previous data through May 2022 showing protection from death across all ages with two boosters

And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.

We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.

Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.

This article was originally published Oct. 8 on Medscape Editor-In-Chief Eric Topol’s “Ground Truths” column on Substack. 

A recent piece in The Economist about masks, and how at least half of the people in Japan are planning to continue to use masks indefinitely (where there was never a mandate), prompts a deeper look into what has been the secret of Japan’s extraordinary success in the pandemic. Over time it has the least cumulative deaths per capita of any major country in the world. That’s without a zero-Covid policy or any national lockdowns, which is why I have not included China as a comparator.

Before we get into that data, let’s take a look at the age pyramids for Japan and the United States. The No. 1 risk factor for death from COVID-19 is advanced age, and you can see that in Japan about 25% of the population is age 65 and older, whereas in the United States that proportion is substantially reduced at 15%. Sure there are differences in comorbidities such as obesity and diabetes, but there is also the trade-off of a much higher population density in Japan.

Besides masks, which were distributed early on by the government to the population in Japan, there was the “Avoid the 3Cs” cluster-busting strategy, widely disseminated in the spring of 2020, leveraging Pareto’s 80-20 principle, long before there were any vaccines available. For a good portion of the pandemic, the Ministry of Foreign Affairs of Japan maintained a strict policy for border control, which while hard to quantify, may certainly have contributed to its success.

Besides these factors, once vaccines became available, Japan got the population with the primary series to 83% rapidly, even after getting a late start by many months compared with the United States, which has peaked at 68%. That’s a big gap.

But that gap got much worse when it came to boosters. Ninety-five percent of Japanese eligible compared with 40.8% of Americans have had a booster shot. Of note, that 95% in Japan pertains to the whole population. In the United States the percentage of people age 65 and older who have had two boosters is currently only 42%. I’ve previously reviewed the important lifesaving impact of two boosters among people age 65 and older from five independent studies during Omicron waves throughout the world.

Now let’s turn to cumulative fatalities in the two countries. There’s a huge, nearly ninefold difference, per capita. Using today’s Covid-19 Dashboard, there are cumulatively 45,533 deaths in Japan and 1,062,560 American deaths. That translates to 1 in 2,758 people in Japan compared with 1 in 315 Americans dying of COVID.

And if we look at excess mortality instead of confirmed COVID deaths, that enormous gap doesn’t change.

Obviously it would be good to have data for other COVID outcomes, such as hospitalizations, ICUs, and Long COVID, but they are not accessible.

Comparing Japan, the country that has fared the best, with the United States, one of the worst pandemic outcome results, leaves us with a sense that Prof Ian MacKay’s “Swiss cheese model” is the best explanation. It’s not just one thing. Masks, consistent evidence-based communication (3Cs) with attention to ventilation and air quality, and the outstanding uptake of vaccines and boosters all contributed to Japan’s success.

There is another factor to add to that model – Paxlovid. Its benefit of reducing hospitalizations and deaths for people over age 65 is unquestionable.

That’s why I had previously modified the Swiss cheese model to add Paxlovid.

But in the United States, where 15% of the population is 65 and older, they account for over 75% of the daily death toll, still in the range of 400 per day. Here, with a very high proportion of people age 65 and older left vulnerable without boosters, or primary vaccines, Paxlovid is only being given to less than 25% of the eligible (age 50+), and less people age 80 and older are getting Paxlovid than those age 45. The reasons that doctors are not prescribing it – worried about interactions for a 5-day course and rebound – are not substantiated.

Bottom line: In the United States we are not protecting our population anywhere near as well as Japan, as grossly evident by the fatalities among people at the highest risk. There needs to be far better uptake of boosters and use of Paxlovid in the age 65+ group, but the need for amped up protection is not at all restricted to this age subgroup. Across all age groups age 18 and over there is an 81% reduction of hospitalizations with two boosters with the most updated CDC data available, through the Omicron BA.5 wave.

No less the previous data through May 2022 showing protection from death across all ages with two boosters

And please don’t forget that around the world, over 20 million lives were saved, just in 2021, the first year of vaccines.

We can learn so much from a model country like Japan. Yes, we need nasal and variant-proof vaccines to effectively deal with the new variants that are already getting legs in places like XBB in Singapore and ones not on the radar yet. But right now we’ve got to do far better for people getting boosters and, when a person age 65 or older gets COVID, Paxlovid. Take a look at the Chris Hayes video segment when he pleaded for Americans to get a booster shot. Every day that vaccine waning of the U.S. population exceeds the small percentage of people who get a booster, our vulnerability increases. If we don’t get that on track, it’s likely going to be a rough winter ahead.

Dr. Topol is director of the Scripps Translational Science Institute in La Jolla, Calif. He has received research grants from the National Institutes of Health and reported conflicts of interest involving Dexcom, Illumina, Molecular Stethoscope, Quest Diagnostics, and Blue Cross Blue Shield Association. A version of this article appeared on Medscape.com.

STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.

Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.

Mitchel L. Zoler/MDedge News

And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.

Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.

SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.

For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.

Cutting fat mass, boosting lean mass

New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.

Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”

These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
 

Focus on diet quality

People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.

Mitchel L. Zoler/MDedge News

Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.

The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.

The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.

Lipids improve in those with type 2 diabetes

Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).

Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.

Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.

These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.

The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.

STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.

Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.

Mitchel L. Zoler/MDedge News

And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.

Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.

SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.

For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.

Cutting fat mass, boosting lean mass

New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.

Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”

These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
 

Focus on diet quality

People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.

Mitchel L. Zoler/MDedge News

Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.

The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.

The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.

Lipids improve in those with type 2 diabetes

Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).

Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.

Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.

These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.

The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.

STOCKHOLM – New insights into the benefits of treatment with the “twincretin” tirzepatide for people with overweight or obesity – with or without diabetes – come from new findings reported at the annual meeting of the European Association for the Study of Diabetes.

Additional results from the SURMOUNT-1 trial, which matched tirzepatide against placebo in people with overweight or obesity, provide further details on the favorable changes produced by 72 weeks of tirzepatide treatment on outcomes that included fat and lean mass, insulin sensitivity, and patient-reported outcomes related to functional health and well being, reported Ania M. Jastreboff, MD, PhD.

Mitchel L. Zoler/MDedge News

And results from a meta-analysis of six trials that compared tirzepatide (Mounjaro) against several different comparators in patients with type 2 diabetes further confirm the drug’s ability to reliably produce positive changes in blood lipids, especially by significantly lowering levels of triglycerides, LDL cholesterol, and very LDL (VLDL) cholesterol, said Thomas Karagiannis, MD, PhD, in a separate report at the meeting.

Tirzepatide works as an agonist on receptors for both the glucagonlike peptide–1 (GLP-1), and for the glucose-dependent insulinotropic polypeptide, and received Food and Drug Administration approval for treating people with type 2 diabetes in May 2022. On the basis of results from SURMOUNT-1, the FDA on Oct. 6 granted tirzepatide fast-track designation for a proposed labeling of the agent for treating people with overweight or obesity. This FDA decision will likely remain pending at least until results from a second trial in people with overweight or obesity but without diabetes, SURMOUNT-2, become available in 2023.

SURMOUNT-1 randomized 2,539 people with obesity or overweight and at least one weight-related complication to a weekly injection of tirzepatide or placebo for 72 weeks. The study’s primary efficacy endpoints were the average reduction in weight from baseline, and the percentage of people in each treatment arm achieving weight loss of at least 5% from baseline.

For both endpoints, the outcomes with tirzepatide significantly surpassed placebo effects. Average weight loss ranged from 15%-21% from baseline, depending on dose, compared with 3% on placebo. The rate of participants with at least a 5% weight loss ranged from 85% to 91%, compared with 35% with placebo, as reported in July 2022 in the New England Journal of Medicine.

Cutting fat mass, boosting lean mass

New results from the trial reported by Dr. Jastreboff included a cut in fat mass from 46.2% of total body mass at baseline to 38.5% after 72 weeks, compared with a change from 46.8% at baseline to 44.7% after 72 weeks in the placebo group. Concurrently, lean mass increased with tirzepatide treatment from 51.0% at baseline to 58.1% after 72 weeks.

Participants who received tirzepatide, compared with those who received placebo, had “proportionately greater decrease in fat mass and proportionately greater increase in lean mass” compared with those who received placebo, said Dr. Jastreboff, an endocrinologist and obesity medicine specialist with Yale Medicine in New Haven, Conn. “I was impressed by the amount of visceral fat lost.”

These effects translated into a significant reduction in fat mass-to-lean mass ratio among the people treated with tirzepatide, with the greatest reduction in those who lost at least 15% of their starting weight. In that subgroup the fat-to-lean mass ratio dropped from 0.94 at baseline to 0.64 after 72 weeks of treatment, she said.
 

Focus on diet quality

People treated with tirzepatide “eat so little food that we need to improve the quality of what they eat to protect their muscle,” commented Carel le Roux, MBChB, PhD, a professor in the Diabetes Complications Research Centre of University College Dublin. “You no longer need a dietitian to help people lose weight, because the drug does that. You need dietitians to look after the nutritional health of patients while they lose weight,” Dr. le Roux said in a separate session at the meeting.

Mitchel L. Zoler/MDedge News

Additional tests showed that blood glucose and insulin levels were all significantly lower among trial participants on all three doses of tirzepatide compared with those on placebo, and the tirzepatide-treated subjects also had significant, roughly twofold elevations in their insulin sensitivity measured by the Matsuda Index.

The impact of tirzepatide on glucose and insulin levels and on insulin sensitivity was similar regardless of whether study participants had normoglycemia or prediabetes at entry. By design, no study participants had diabetes.

The trial assessed patient-reported quality-of-life outcomes using the 36-Item Short Form Survey (SF-36). Participants had significant increases in all eight domains within the SF-36 at all three tirzepatide doses, compared with placebo, at 72 weeks, Dr. Jastreboff reported. Improvements in the physical function domain increased most notably among study participants on tirzepatide who had functional limitations at baseline. Heart rate rose among participants who received either of the two highest tirzepatide doses by 2.3-2.5 beats/min, comparable with the effect of other injected incretin-based treatments.

Lipids improve in those with type 2 diabetes

Tirzepatide treatment also results in a “secondary effect” of improving levels of several lipids in people with type 2 diabetes, according to a meta-analysis of findings from six randomized trials. The meta-analysis collectively involved 4,502 participants treated for numerous weeks with one of three doses of tirzepatide and 2,144 people in comparator groups, reported Dr. Karagiannis, a diabetes researcher at Aristotle University of Thessaloniki (Greece).

Among the significant lipid changes linked with tirzepatide treatment, compared with placebo, were an average 13 mg/dL decrease in LDL cholesterol, an average 6 mg/dL decrease in VLDL cholesterol, and an average 50 mg/dL decrease in triglycerides. In comparison to a GLP-1 receptor agonist, an average 25 mg/dL decrease in triglycerides and an average 4 mg/dL reduction in VLDL cholesterol were seen. And trials comparing tirzepatide with basal insulin saw average reductions of 7% in LDL cholesterol, 15% in VLDL cholesterol, 15% in triglycerides, and an 8% increase in HDL cholesterol.

Dr. Karagiannis highlighted that the clinical impact of these effects is unclear, although he noted that the average reduction in LDL cholesterol relative to placebo is of a magnitude that could have a modest effect on long-term outcomes.

These lipid effects of tirzepatide “should be considered alongside” tirzepatide’s “key metabolic effects” on weight and hemoglobin A1c as well as the drug’s safety, concluded Dr. Karagiannis.

The tirzepatide trials were all funded by Eli Lilly, which markets tirzepatide (Mounjaro). Dr. Jastreboff has been an adviser and consultant to Eli Lilly, as well as to Intellihealth, Novo Nordisk, Pfizer, Rhythm Scholars, Roche, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Karagiannis had no disclosures. Dr. le Roux has had financial relationships with Eli Lilly, as well as with Boehringer Ingelheim, Consilient Health, Covidion, Fractyl, GL Dynamics, Herbalife, Johnson & Johnson, Keyron, and Novo Nordisk.

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

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

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

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

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

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

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.