Colonoscopy remains the gold standard method for detecting colorectal cancer (CRC) and removing precancerous polyps.

The recommended age for CRC screening in the United States spans 45-75 years, with the benefits of colonoscopy diminishing considerably after this point.

Older adults are much more likely to experience complications before, during, and after a colonoscopy. Bowel preps can cause dehydration or electrolyte problems in some, while bleeding and bowel perforation can occur perioperatively, and pulmonary or cardiovascular complications may arise postoperatively.

These risks often outweigh the benefits of catching a precancerous lesion or early-stage cancer, especially given the low rates of advanced neoplasia and CRC detected from screening and surveillance after age 75. Yet the research overall suggests that more than half of older individuals continue to receive screening and surveillance colonoscopies outside the recommended screening window.

So is there a point in time when a person is too old to receive a colonoscopy? The answer is not always clear-cut, but life expectancy should be a key consideration.

“Taking the most extreme example, if you have 6 months to live, finding early-stage cancer is not going to help you,” Michael Rothberg, MD, vice chair for research at Cleveland Clinic’s Medical Institute and director of the Center for Value-Based Care Research, told Medscape Medical News.

For those with more time, the benefits of continued screening and surveillance may outweigh the risks, but when that balance shifts from helpful to not helpful remains inexact, Dr. Rothberg noted.

What’s Recommended?

In May 2021, the US Preventive Services Task Force (USPSTF) lowered the CRC screening threshold to age 45, recommending all adults aged between 45 and 75 years receive screening.

For those aged between 76 and 85 years, the USPSTF upheld its 2016 recommendation of selective screening, noting that the “net benefit of screening all persons in this age group is small” and should be determined on an individual basis. The USPSTF, however, did not provide recommendations on surveillance colonoscopies among those with previously identified polyps.

In November 2023, the American Gastroenterological Association (AGA) issued a clinical practice update that provided advice on risk stratification for CRC screening and post-polypectomy surveillance. For adults older than 75 years specifically, the AGA recommended that the decision to continue CRC screening or perform post-polypectomy surveillance be based on risks, benefits, comorbidities, and screening history and decided on a case-by-case basis.

For instance, previously unscreened patients without comorbidities could benefit from screening beyond age 75 — up to age 80 for men and 90 for women — while those who have had regular colonoscopies, per recommended guidelines, but severe comorbidities that may limit life expectancy could stop sooner, even by age 65.

Although an individualized approach leaves room for variation, it’s essential to consider life expectancy and the time it takes for a polyp to progress to CRC, as well as the risks associated with the procedure itself. Certain older adults are “less likely to live long enough to benefit from surveillance colonoscopy, due to competing, non-CRC mortality risks,” and clinicians should discuss these risks with their patients, the experts explained.
 

When to Stop Screening Colonoscopies

Research shows that screening colonoscopies continue well after the recommended stop age.

A 2023 JAMA Internal Medicine study found, for instance, that a large proportion of screening colonoscopies occurred among the 7067 patients who were 75 years and older with a life expectancy < 10 years. Overall, 30% of patients aged between 76 and 80 years with a limited life expectancy had a colonoscopy. That percentage increased to 71% for those aged 81-85 years and to 100% for those older than 85 years.

But the benefits of screening were minimal. Overall, colonoscopies detected advanced neoplasia in 5.4% of patients aged 76-80 years, 6.2% of those aged 81-85 years, and 9.5% of those older than 85 years. Only 15 patients (0.2%) had CRC detected via colonoscopy, five of whom underwent cancer treatment. Of those five, four had a life expectancy ≥ 10 years, and one had a life expectancy < 10 years.

At the same time, adverse events requiring hospitalization were common 10 days post-colonoscopy (13.58 per 1000), and the risk for hospitalization increased with age.

“For all kinds of screening, we’re not that comfortable in America with the idea that people are eventually going to die, but as you get older, the potential benefits for screening decrease,” study author Dr. Rothberg told this news organization.

In general, life expectancy provides a good predictor of whether people should continue screening or receive treatment following a CRC diagnosis.

Patients aged 76-80 years in good health, for instance, could benefit from screening and, potentially, treatment, Dr. Rothberg said. And “if doctors don’t feel comfortable or confident about predicting life expectancy, taking comorbid illnesses into account can be helpful, especially for that age range.”
 

Weighing Surveillance Benefits

Surveillance colonoscopy is often recommended post-polypectomy to reduce the risk for CRC. But even in this higher-risk population, those older than 75 years may not benefit.

Recent evidence indicates that those with a history of one or two adenomas less than 1 cm in size have only a slightly (1.3-fold) increased risk for incident CRC — and no significant increased risk for fatal CRC.

Another recent study found that detecting CRC at surveillance colonoscopy was rare among older adults. In surveillance colonoscopies performed among 9601 individuals aged 70-85 years with prior adenomas, 12% had advanced neoplasia detected, and only 0.3% had CRC detected.

Similar rates of advanced polyps (7.8%) or CRC (0.2%) were reported in another recent analysis of more than 9800 adults older than 65 years receiving surveillance colonoscopies.

Despite the low rates of polyp and CRC detection, nearly 90% of patients with recommendation information available received advice to return for a future colonoscopy. Even among patients with no polyps or small ones, almost 60% who had life expectancy of less than 5 years were told to return.

Although someone with prior adenomas has a higher risk for CRC, that doesn’t tell the whole story for an individual patient, Samir Gupta, MD, professor of gastroenterology at the University of California San Diego, and co-lead of the Cancer Control Program at Moores Cancer Center, told this news organization. For older adults, it’s vital to consider the competing risks and how much time it might take for CRC to develop.

At Digestive Disease Week in May, Dr. Gupta presented new research that looked at cumulative risk among patients aged 75 years and older with prior precancerous polyps vs prior normal colonoscopies. Although those with prior adenomas had a higher risk for CRC overall, their cumulative CRC risk was low — about 0.3% at 5 years and 0.8% at 10 years. Cumulative CRC deaths were even lower — 0.2% at 5 years and 0.7% at 10 years — while the risk of dying from something other than CRC was 20% at 5 years and 40% at 10 years.

“What this means to me is that patients who are 75 and older should think really carefully about whether they want to do surveillance,” said Dr. Gupta, who coauthored the AGA’s clinical practice update. “Someone who is very healthy and doesn’t have obvious medical problems can look at that risk for developing colon cancer and the risk of dying and make a decision about whether there’s enough concern to go ahead with surveillance.”

Those with competing health priorities, on other hand, should likely concentrate on those instead, he said, and feel reassured that even if they choose not to do surveillance, they’re probably not doing themselves any harm.

“The bottom line is that referring older adults or frail adults for surveillance colonoscopy shouldn’t be a rubber stamp or check-the-box action,” Dr. Gupta said. “We need to think about it carefully and give ourselves — as clinicians and patients — the room to decide that it may not need to take high priority.”
 

What to Tell Patients

Overall, older adults who have had prior colonoscopies, no or low-risk polyps, and low CRC risk will likely face greater risks from the procedure than benefits.

“The more invasive the screening the test, the more dangerous it could be,” Dr. Rothberg noted.

Many patients, however, are open to stopping and often trust their primary care provider in the decision-making process, said Audrey Calderwood, MD, director of the Comprehensive Gastroenterology Center at Dartmouth Hitchcock Medical Center. “But the systems we have in place don’t optimally support that decision-making at the time it matters most.”

For example, at a prior colonoscopy, a gastroenterologist may recommend surveillance again in 5-7 years. But in the interim, the patient could have new medications or develop comorbidities and other health issues. Rather than defer to the gastroenterologist’s recommendations from years ago, clinicians and patients can reassess the pros and cons of screening or surveillance based on current circumstances, Dr. Calderwood said.

“There should be lines of communication and systems of support to allow primary care providers to decide whether it is still needed,” she said.

While some may be ready to stop, other patients are going to continue to want and ask about CRC screening or surveillance, Dr. Rothberg said.

In these instances, communication style matters.

“You don’t want to tell a patient that they’re not going to be screened because they’re not going to live long enough to benefit,” Dr. Rothberg said.

However, steering people toward less invasive tests or telling them it’s important to give other health problems priority may be more sensitive ways to communicate that it’s time to ramp down or halt screening.

“Sometimes when you say you’re going to stop cancer screening, older adults misperceive that you’re giving up on them,” Dr. Gupta said. “We spend 30-40 years driving home the message that prevention and screening are important, and then it feels like we’re taking it away, so we need to find the best way to discuss it and make the choice that’s comfortable for them.”

Dr. Rothberg, Dr. Gupta, and Dr. Calderwood disclosed no relevant conflicts of interest.
 

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

Colonoscopy remains the gold standard method for detecting colorectal cancer (CRC) and removing precancerous polyps.

The recommended age for CRC screening in the United States spans 45-75 years, with the benefits of colonoscopy diminishing considerably after this point.

Older adults are much more likely to experience complications before, during, and after a colonoscopy. Bowel preps can cause dehydration or electrolyte problems in some, while bleeding and bowel perforation can occur perioperatively, and pulmonary or cardiovascular complications may arise postoperatively.

These risks often outweigh the benefits of catching a precancerous lesion or early-stage cancer, especially given the low rates of advanced neoplasia and CRC detected from screening and surveillance after age 75. Yet the research overall suggests that more than half of older individuals continue to receive screening and surveillance colonoscopies outside the recommended screening window.

So is there a point in time when a person is too old to receive a colonoscopy? The answer is not always clear-cut, but life expectancy should be a key consideration.

“Taking the most extreme example, if you have 6 months to live, finding early-stage cancer is not going to help you,” Michael Rothberg, MD, vice chair for research at Cleveland Clinic’s Medical Institute and director of the Center for Value-Based Care Research, told Medscape Medical News.

For those with more time, the benefits of continued screening and surveillance may outweigh the risks, but when that balance shifts from helpful to not helpful remains inexact, Dr. Rothberg noted.

What’s Recommended?

In May 2021, the US Preventive Services Task Force (USPSTF) lowered the CRC screening threshold to age 45, recommending all adults aged between 45 and 75 years receive screening.

For those aged between 76 and 85 years, the USPSTF upheld its 2016 recommendation of selective screening, noting that the “net benefit of screening all persons in this age group is small” and should be determined on an individual basis. The USPSTF, however, did not provide recommendations on surveillance colonoscopies among those with previously identified polyps.

In November 2023, the American Gastroenterological Association (AGA) issued a clinical practice update that provided advice on risk stratification for CRC screening and post-polypectomy surveillance. For adults older than 75 years specifically, the AGA recommended that the decision to continue CRC screening or perform post-polypectomy surveillance be based on risks, benefits, comorbidities, and screening history and decided on a case-by-case basis.

For instance, previously unscreened patients without comorbidities could benefit from screening beyond age 75 — up to age 80 for men and 90 for women — while those who have had regular colonoscopies, per recommended guidelines, but severe comorbidities that may limit life expectancy could stop sooner, even by age 65.

Although an individualized approach leaves room for variation, it’s essential to consider life expectancy and the time it takes for a polyp to progress to CRC, as well as the risks associated with the procedure itself. Certain older adults are “less likely to live long enough to benefit from surveillance colonoscopy, due to competing, non-CRC mortality risks,” and clinicians should discuss these risks with their patients, the experts explained.
 

When to Stop Screening Colonoscopies

Research shows that screening colonoscopies continue well after the recommended stop age.

A 2023 JAMA Internal Medicine study found, for instance, that a large proportion of screening colonoscopies occurred among the 7067 patients who were 75 years and older with a life expectancy < 10 years. Overall, 30% of patients aged between 76 and 80 years with a limited life expectancy had a colonoscopy. That percentage increased to 71% for those aged 81-85 years and to 100% for those older than 85 years.

But the benefits of screening were minimal. Overall, colonoscopies detected advanced neoplasia in 5.4% of patients aged 76-80 years, 6.2% of those aged 81-85 years, and 9.5% of those older than 85 years. Only 15 patients (0.2%) had CRC detected via colonoscopy, five of whom underwent cancer treatment. Of those five, four had a life expectancy ≥ 10 years, and one had a life expectancy < 10 years.

At the same time, adverse events requiring hospitalization were common 10 days post-colonoscopy (13.58 per 1000), and the risk for hospitalization increased with age.

“For all kinds of screening, we’re not that comfortable in America with the idea that people are eventually going to die, but as you get older, the potential benefits for screening decrease,” study author Dr. Rothberg told this news organization.

In general, life expectancy provides a good predictor of whether people should continue screening or receive treatment following a CRC diagnosis.

Patients aged 76-80 years in good health, for instance, could benefit from screening and, potentially, treatment, Dr. Rothberg said. And “if doctors don’t feel comfortable or confident about predicting life expectancy, taking comorbid illnesses into account can be helpful, especially for that age range.”
 

Weighing Surveillance Benefits

Surveillance colonoscopy is often recommended post-polypectomy to reduce the risk for CRC. But even in this higher-risk population, those older than 75 years may not benefit.

Recent evidence indicates that those with a history of one or two adenomas less than 1 cm in size have only a slightly (1.3-fold) increased risk for incident CRC — and no significant increased risk for fatal CRC.

Another recent study found that detecting CRC at surveillance colonoscopy was rare among older adults. In surveillance colonoscopies performed among 9601 individuals aged 70-85 years with prior adenomas, 12% had advanced neoplasia detected, and only 0.3% had CRC detected.

Similar rates of advanced polyps (7.8%) or CRC (0.2%) were reported in another recent analysis of more than 9800 adults older than 65 years receiving surveillance colonoscopies.

Despite the low rates of polyp and CRC detection, nearly 90% of patients with recommendation information available received advice to return for a future colonoscopy. Even among patients with no polyps or small ones, almost 60% who had life expectancy of less than 5 years were told to return.

Although someone with prior adenomas has a higher risk for CRC, that doesn’t tell the whole story for an individual patient, Samir Gupta, MD, professor of gastroenterology at the University of California San Diego, and co-lead of the Cancer Control Program at Moores Cancer Center, told this news organization. For older adults, it’s vital to consider the competing risks and how much time it might take for CRC to develop.

At Digestive Disease Week in May, Dr. Gupta presented new research that looked at cumulative risk among patients aged 75 years and older with prior precancerous polyps vs prior normal colonoscopies. Although those with prior adenomas had a higher risk for CRC overall, their cumulative CRC risk was low — about 0.3% at 5 years and 0.8% at 10 years. Cumulative CRC deaths were even lower — 0.2% at 5 years and 0.7% at 10 years — while the risk of dying from something other than CRC was 20% at 5 years and 40% at 10 years.

“What this means to me is that patients who are 75 and older should think really carefully about whether they want to do surveillance,” said Dr. Gupta, who coauthored the AGA’s clinical practice update. “Someone who is very healthy and doesn’t have obvious medical problems can look at that risk for developing colon cancer and the risk of dying and make a decision about whether there’s enough concern to go ahead with surveillance.”

Those with competing health priorities, on other hand, should likely concentrate on those instead, he said, and feel reassured that even if they choose not to do surveillance, they’re probably not doing themselves any harm.

“The bottom line is that referring older adults or frail adults for surveillance colonoscopy shouldn’t be a rubber stamp or check-the-box action,” Dr. Gupta said. “We need to think about it carefully and give ourselves — as clinicians and patients — the room to decide that it may not need to take high priority.”
 

What to Tell Patients

Overall, older adults who have had prior colonoscopies, no or low-risk polyps, and low CRC risk will likely face greater risks from the procedure than benefits.

“The more invasive the screening the test, the more dangerous it could be,” Dr. Rothberg noted.

Many patients, however, are open to stopping and often trust their primary care provider in the decision-making process, said Audrey Calderwood, MD, director of the Comprehensive Gastroenterology Center at Dartmouth Hitchcock Medical Center. “But the systems we have in place don’t optimally support that decision-making at the time it matters most.”

For example, at a prior colonoscopy, a gastroenterologist may recommend surveillance again in 5-7 years. But in the interim, the patient could have new medications or develop comorbidities and other health issues. Rather than defer to the gastroenterologist’s recommendations from years ago, clinicians and patients can reassess the pros and cons of screening or surveillance based on current circumstances, Dr. Calderwood said.

“There should be lines of communication and systems of support to allow primary care providers to decide whether it is still needed,” she said.

While some may be ready to stop, other patients are going to continue to want and ask about CRC screening or surveillance, Dr. Rothberg said.

In these instances, communication style matters.

“You don’t want to tell a patient that they’re not going to be screened because they’re not going to live long enough to benefit,” Dr. Rothberg said.

However, steering people toward less invasive tests or telling them it’s important to give other health problems priority may be more sensitive ways to communicate that it’s time to ramp down or halt screening.

“Sometimes when you say you’re going to stop cancer screening, older adults misperceive that you’re giving up on them,” Dr. Gupta said. “We spend 30-40 years driving home the message that prevention and screening are important, and then it feels like we’re taking it away, so we need to find the best way to discuss it and make the choice that’s comfortable for them.”

Dr. Rothberg, Dr. Gupta, and Dr. Calderwood disclosed no relevant conflicts of interest.
 

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

Colonoscopy remains the gold standard method for detecting colorectal cancer (CRC) and removing precancerous polyps.

The recommended age for CRC screening in the United States spans 45-75 years, with the benefits of colonoscopy diminishing considerably after this point.

Older adults are much more likely to experience complications before, during, and after a colonoscopy. Bowel preps can cause dehydration or electrolyte problems in some, while bleeding and bowel perforation can occur perioperatively, and pulmonary or cardiovascular complications may arise postoperatively.

These risks often outweigh the benefits of catching a precancerous lesion or early-stage cancer, especially given the low rates of advanced neoplasia and CRC detected from screening and surveillance after age 75. Yet the research overall suggests that more than half of older individuals continue to receive screening and surveillance colonoscopies outside the recommended screening window.

So is there a point in time when a person is too old to receive a colonoscopy? The answer is not always clear-cut, but life expectancy should be a key consideration.

“Taking the most extreme example, if you have 6 months to live, finding early-stage cancer is not going to help you,” Michael Rothberg, MD, vice chair for research at Cleveland Clinic’s Medical Institute and director of the Center for Value-Based Care Research, told Medscape Medical News.

For those with more time, the benefits of continued screening and surveillance may outweigh the risks, but when that balance shifts from helpful to not helpful remains inexact, Dr. Rothberg noted.

What’s Recommended?

In May 2021, the US Preventive Services Task Force (USPSTF) lowered the CRC screening threshold to age 45, recommending all adults aged between 45 and 75 years receive screening.

For those aged between 76 and 85 years, the USPSTF upheld its 2016 recommendation of selective screening, noting that the “net benefit of screening all persons in this age group is small” and should be determined on an individual basis. The USPSTF, however, did not provide recommendations on surveillance colonoscopies among those with previously identified polyps.

In November 2023, the American Gastroenterological Association (AGA) issued a clinical practice update that provided advice on risk stratification for CRC screening and post-polypectomy surveillance. For adults older than 75 years specifically, the AGA recommended that the decision to continue CRC screening or perform post-polypectomy surveillance be based on risks, benefits, comorbidities, and screening history and decided on a case-by-case basis.

For instance, previously unscreened patients without comorbidities could benefit from screening beyond age 75 — up to age 80 for men and 90 for women — while those who have had regular colonoscopies, per recommended guidelines, but severe comorbidities that may limit life expectancy could stop sooner, even by age 65.

Although an individualized approach leaves room for variation, it’s essential to consider life expectancy and the time it takes for a polyp to progress to CRC, as well as the risks associated with the procedure itself. Certain older adults are “less likely to live long enough to benefit from surveillance colonoscopy, due to competing, non-CRC mortality risks,” and clinicians should discuss these risks with their patients, the experts explained.
 

When to Stop Screening Colonoscopies

Research shows that screening colonoscopies continue well after the recommended stop age.

A 2023 JAMA Internal Medicine study found, for instance, that a large proportion of screening colonoscopies occurred among the 7067 patients who were 75 years and older with a life expectancy < 10 years. Overall, 30% of patients aged between 76 and 80 years with a limited life expectancy had a colonoscopy. That percentage increased to 71% for those aged 81-85 years and to 100% for those older than 85 years.

But the benefits of screening were minimal. Overall, colonoscopies detected advanced neoplasia in 5.4% of patients aged 76-80 years, 6.2% of those aged 81-85 years, and 9.5% of those older than 85 years. Only 15 patients (0.2%) had CRC detected via colonoscopy, five of whom underwent cancer treatment. Of those five, four had a life expectancy ≥ 10 years, and one had a life expectancy < 10 years.

At the same time, adverse events requiring hospitalization were common 10 days post-colonoscopy (13.58 per 1000), and the risk for hospitalization increased with age.

“For all kinds of screening, we’re not that comfortable in America with the idea that people are eventually going to die, but as you get older, the potential benefits for screening decrease,” study author Dr. Rothberg told this news organization.

In general, life expectancy provides a good predictor of whether people should continue screening or receive treatment following a CRC diagnosis.

Patients aged 76-80 years in good health, for instance, could benefit from screening and, potentially, treatment, Dr. Rothberg said. And “if doctors don’t feel comfortable or confident about predicting life expectancy, taking comorbid illnesses into account can be helpful, especially for that age range.”
 

Weighing Surveillance Benefits

Surveillance colonoscopy is often recommended post-polypectomy to reduce the risk for CRC. But even in this higher-risk population, those older than 75 years may not benefit.

Recent evidence indicates that those with a history of one or two adenomas less than 1 cm in size have only a slightly (1.3-fold) increased risk for incident CRC — and no significant increased risk for fatal CRC.

Another recent study found that detecting CRC at surveillance colonoscopy was rare among older adults. In surveillance colonoscopies performed among 9601 individuals aged 70-85 years with prior adenomas, 12% had advanced neoplasia detected, and only 0.3% had CRC detected.

Similar rates of advanced polyps (7.8%) or CRC (0.2%) were reported in another recent analysis of more than 9800 adults older than 65 years receiving surveillance colonoscopies.

Despite the low rates of polyp and CRC detection, nearly 90% of patients with recommendation information available received advice to return for a future colonoscopy. Even among patients with no polyps or small ones, almost 60% who had life expectancy of less than 5 years were told to return.

Although someone with prior adenomas has a higher risk for CRC, that doesn’t tell the whole story for an individual patient, Samir Gupta, MD, professor of gastroenterology at the University of California San Diego, and co-lead of the Cancer Control Program at Moores Cancer Center, told this news organization. For older adults, it’s vital to consider the competing risks and how much time it might take for CRC to develop.

At Digestive Disease Week in May, Dr. Gupta presented new research that looked at cumulative risk among patients aged 75 years and older with prior precancerous polyps vs prior normal colonoscopies. Although those with prior adenomas had a higher risk for CRC overall, their cumulative CRC risk was low — about 0.3% at 5 years and 0.8% at 10 years. Cumulative CRC deaths were even lower — 0.2% at 5 years and 0.7% at 10 years — while the risk of dying from something other than CRC was 20% at 5 years and 40% at 10 years.

“What this means to me is that patients who are 75 and older should think really carefully about whether they want to do surveillance,” said Dr. Gupta, who coauthored the AGA’s clinical practice update. “Someone who is very healthy and doesn’t have obvious medical problems can look at that risk for developing colon cancer and the risk of dying and make a decision about whether there’s enough concern to go ahead with surveillance.”

Those with competing health priorities, on other hand, should likely concentrate on those instead, he said, and feel reassured that even if they choose not to do surveillance, they’re probably not doing themselves any harm.

“The bottom line is that referring older adults or frail adults for surveillance colonoscopy shouldn’t be a rubber stamp or check-the-box action,” Dr. Gupta said. “We need to think about it carefully and give ourselves — as clinicians and patients — the room to decide that it may not need to take high priority.”
 

What to Tell Patients

Overall, older adults who have had prior colonoscopies, no or low-risk polyps, and low CRC risk will likely face greater risks from the procedure than benefits.

“The more invasive the screening the test, the more dangerous it could be,” Dr. Rothberg noted.

Many patients, however, are open to stopping and often trust their primary care provider in the decision-making process, said Audrey Calderwood, MD, director of the Comprehensive Gastroenterology Center at Dartmouth Hitchcock Medical Center. “But the systems we have in place don’t optimally support that decision-making at the time it matters most.”

For example, at a prior colonoscopy, a gastroenterologist may recommend surveillance again in 5-7 years. But in the interim, the patient could have new medications or develop comorbidities and other health issues. Rather than defer to the gastroenterologist’s recommendations from years ago, clinicians and patients can reassess the pros and cons of screening or surveillance based on current circumstances, Dr. Calderwood said.

“There should be lines of communication and systems of support to allow primary care providers to decide whether it is still needed,” she said.

While some may be ready to stop, other patients are going to continue to want and ask about CRC screening or surveillance, Dr. Rothberg said.

In these instances, communication style matters.

“You don’t want to tell a patient that they’re not going to be screened because they’re not going to live long enough to benefit,” Dr. Rothberg said.

However, steering people toward less invasive tests or telling them it’s important to give other health problems priority may be more sensitive ways to communicate that it’s time to ramp down or halt screening.

“Sometimes when you say you’re going to stop cancer screening, older adults misperceive that you’re giving up on them,” Dr. Gupta said. “We spend 30-40 years driving home the message that prevention and screening are important, and then it feels like we’re taking it away, so we need to find the best way to discuss it and make the choice that’s comfortable for them.”

Dr. Rothberg, Dr. Gupta, and Dr. Calderwood disclosed no relevant conflicts of interest.
 

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

TOPLINE:

Zasocitinib, a tyrosine kinase 2 (TYK2) inhibitor, at oral doses of ≥ 5 mg led to greater skin clearance than placebo over a period of 12 weeks, in a phase 2b study.
 

METHODOLOGY:

• Researchers performed a phase 2b, randomized, double-blind trial to assess the efficacy, safety, and tolerability of different doses of zasocitinib in adults with moderate to severe psoriasis (mean age, 47 years; 32% women) at 47 centers in the United States and eight centers in Canada. Most (83%) were White, 7% were Black, and 8% were Asian.
• A total of 287 patients were randomly assigned to receive one of the four oral doses of zasocitinib (2 mg, 5 mg, 15 mg, or 30 mg, once daily) or a matched placebo for 12 weeks, followed by a 4-week safety monitoring period.
• The primary outcome was the proportion of patients achieving a ≥ 75% improvement in the Psoriasis Area and Severity Index score (PASI 75) from baseline at week 12.

TAKEAWAY:

• At week 12, PASI 75 was achieved by 18%, 44%, 68%, and 67% of patients receiving zasocitinib at doses of 2 mg, 5 mg, 15 mg, and 30 mg, respectively, vs 6% of patients receiving placebo.
• PASI 90 was achieved in 8%, 21%, 45%, and 46% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, and in no patients in the placebo group.
• At week 12, 10%, 27%, 49%, and 52% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, had no or mild disease (a score of 0 or 1) according to the Physician Global Assessment tool vs 4% in the placebo group.
• Treatment-emergent adverse events occurred in 53%-62% of patients in the zasocitinib groups compared with 44% in the placebo group. The most common were COVID-19, acne/acneiform dermatitis, and diarrhea. There were no reports of major adverse cardiovascular events, thromboembolic events, or opportunistic infections.

IN PRACTICE:

“Zasocitinib, an advanced, potent, and highly selective oral TYK2 inhibitor bioengineered to optimize target coverage and functional selectivity, achieved biologic-level efficacy with complete skin clearance observed after only a 12-week treatment period in up to one third of patients, with a low incidence of known tolerability issues and absence of serious toxic effects that are characteristic of [Janus kinase] 1-3 inhibition,” the authors wrote.

SOURCE:

The study was led by April W. Armstrong, MD, MPH, University of California, Los Angeles, and was published online on August 21, 2024, in JAMA Dermatology.
 

LIMITATIONS:

The study was limited by a relatively small sample size and a short duration. In addition, the inclusion of predominantly White patients may limit the generalizability of findings to a diverse population.
 

DISCLOSURES:

The study was funded by Nimbus Discovery, which includes Nimbus Therapeutics and Nimbus Lakshmi. Dr. Armstrong’s disclosures included receiving grants and/or personal fees from various pharmaceutical companies, including Nimbus Therapeutics and Nimbus. Three authors were employees of and reported holding equity, stocks, or shares in Nimbus. Several authors had disclosures related to pharmaceutical companies, including Nimbus.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Zasocitinib, a tyrosine kinase 2 (TYK2) inhibitor, at oral doses of ≥ 5 mg led to greater skin clearance than placebo over a period of 12 weeks, in a phase 2b study.
 

METHODOLOGY:

• Researchers performed a phase 2b, randomized, double-blind trial to assess the efficacy, safety, and tolerability of different doses of zasocitinib in adults with moderate to severe psoriasis (mean age, 47 years; 32% women) at 47 centers in the United States and eight centers in Canada. Most (83%) were White, 7% were Black, and 8% were Asian.
• A total of 287 patients were randomly assigned to receive one of the four oral doses of zasocitinib (2 mg, 5 mg, 15 mg, or 30 mg, once daily) or a matched placebo for 12 weeks, followed by a 4-week safety monitoring period.
• The primary outcome was the proportion of patients achieving a ≥ 75% improvement in the Psoriasis Area and Severity Index score (PASI 75) from baseline at week 12.

TAKEAWAY:

• At week 12, PASI 75 was achieved by 18%, 44%, 68%, and 67% of patients receiving zasocitinib at doses of 2 mg, 5 mg, 15 mg, and 30 mg, respectively, vs 6% of patients receiving placebo.
• PASI 90 was achieved in 8%, 21%, 45%, and 46% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, and in no patients in the placebo group.
• At week 12, 10%, 27%, 49%, and 52% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, had no or mild disease (a score of 0 or 1) according to the Physician Global Assessment tool vs 4% in the placebo group.
• Treatment-emergent adverse events occurred in 53%-62% of patients in the zasocitinib groups compared with 44% in the placebo group. The most common were COVID-19, acne/acneiform dermatitis, and diarrhea. There were no reports of major adverse cardiovascular events, thromboembolic events, or opportunistic infections.

IN PRACTICE:

“Zasocitinib, an advanced, potent, and highly selective oral TYK2 inhibitor bioengineered to optimize target coverage and functional selectivity, achieved biologic-level efficacy with complete skin clearance observed after only a 12-week treatment period in up to one third of patients, with a low incidence of known tolerability issues and absence of serious toxic effects that are characteristic of [Janus kinase] 1-3 inhibition,” the authors wrote.

SOURCE:

The study was led by April W. Armstrong, MD, MPH, University of California, Los Angeles, and was published online on August 21, 2024, in JAMA Dermatology.
 

LIMITATIONS:

The study was limited by a relatively small sample size and a short duration. In addition, the inclusion of predominantly White patients may limit the generalizability of findings to a diverse population.
 

DISCLOSURES:

The study was funded by Nimbus Discovery, which includes Nimbus Therapeutics and Nimbus Lakshmi. Dr. Armstrong’s disclosures included receiving grants and/or personal fees from various pharmaceutical companies, including Nimbus Therapeutics and Nimbus. Three authors were employees of and reported holding equity, stocks, or shares in Nimbus. Several authors had disclosures related to pharmaceutical companies, including Nimbus.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Zasocitinib, a tyrosine kinase 2 (TYK2) inhibitor, at oral doses of ≥ 5 mg led to greater skin clearance than placebo over a period of 12 weeks, in a phase 2b study.
 

METHODOLOGY:

• Researchers performed a phase 2b, randomized, double-blind trial to assess the efficacy, safety, and tolerability of different doses of zasocitinib in adults with moderate to severe psoriasis (mean age, 47 years; 32% women) at 47 centers in the United States and eight centers in Canada. Most (83%) were White, 7% were Black, and 8% were Asian.
• A total of 287 patients were randomly assigned to receive one of the four oral doses of zasocitinib (2 mg, 5 mg, 15 mg, or 30 mg, once daily) or a matched placebo for 12 weeks, followed by a 4-week safety monitoring period.
• The primary outcome was the proportion of patients achieving a ≥ 75% improvement in the Psoriasis Area and Severity Index score (PASI 75) from baseline at week 12.

TAKEAWAY:

• At week 12, PASI 75 was achieved by 18%, 44%, 68%, and 67% of patients receiving zasocitinib at doses of 2 mg, 5 mg, 15 mg, and 30 mg, respectively, vs 6% of patients receiving placebo.
• PASI 90 was achieved in 8%, 21%, 45%, and 46% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, and in no patients in the placebo group.
• At week 12, 10%, 27%, 49%, and 52% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively, had no or mild disease (a score of 0 or 1) according to the Physician Global Assessment tool vs 4% in the placebo group.
• Treatment-emergent adverse events occurred in 53%-62% of patients in the zasocitinib groups compared with 44% in the placebo group. The most common were COVID-19, acne/acneiform dermatitis, and diarrhea. There were no reports of major adverse cardiovascular events, thromboembolic events, or opportunistic infections.

IN PRACTICE:

“Zasocitinib, an advanced, potent, and highly selective oral TYK2 inhibitor bioengineered to optimize target coverage and functional selectivity, achieved biologic-level efficacy with complete skin clearance observed after only a 12-week treatment period in up to one third of patients, with a low incidence of known tolerability issues and absence of serious toxic effects that are characteristic of [Janus kinase] 1-3 inhibition,” the authors wrote.

SOURCE:

The study was led by April W. Armstrong, MD, MPH, University of California, Los Angeles, and was published online on August 21, 2024, in JAMA Dermatology.
 

LIMITATIONS:

The study was limited by a relatively small sample size and a short duration. In addition, the inclusion of predominantly White patients may limit the generalizability of findings to a diverse population.
 

DISCLOSURES:

The study was funded by Nimbus Discovery, which includes Nimbus Therapeutics and Nimbus Lakshmi. Dr. Armstrong’s disclosures included receiving grants and/or personal fees from various pharmaceutical companies, including Nimbus Therapeutics and Nimbus. Three authors were employees of and reported holding equity, stocks, or shares in Nimbus. Several authors had disclosures related to pharmaceutical companies, including Nimbus.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The prevalence of recurrent urinary tract infections (rUTIs) and the use of antibiotics for prevention are substantial among women in Wales, particularly among those over the age of 57 years. A high level of resistance to two recommended antibiotics was observed, suggesting that more frequent urine cultures could better guide antibiotic selection for treatment and prophylaxis.

METHODOLOGY:

• The researchers conducted a retrospective cross-sectional study using a large databank of patients in Wales to describe the characteristics and urine profiles of women with rUTIs between 2010 and 2022.
• They created two cohorts: One with 92,213 women (median age, 60 years) who experienced rUTIs, defined as two or more acute episodes within 6 months or three or more acute episodes within 12 months.
• Another cohort comprised of 26,862 women (median age, 71 years) were prescribed prophylactic antibiotics, which was defined as receiving three or more consecutive prescriptions of the same UTI-specific antibiotic (trimethoprim, nitrofurantoin, or cefalexin), with intervals of 21-56 days between prescriptions.
• Urine culture results in the 12 months before a rUTI diagnosis and 18 months before prophylactic antibiotic initiation and all urine culture results within 7 days of an acute UTI were analyzed to assess antibiotic resistance patterns.

TAKEAWAY:

• Overall, 6% of women had rUTIs, 1.7% of which were prescribed prophylactic antibiotics with proportions increasing sharply after age 57.
• Nearly half of the women (49%) who were prescribed a prophylactic antibiotic qualified as having rUTIs in the 18 months before initiation.
• This study showed that 80.8% of women with rUTIs had a urine culture result documented in the 12 months preceding the diagnosis.
• More than half (64%) of the women taking prophylactic antibiotics had a urine culture result documented before starting treatment, and 18% of those prescribed trimethoprim had resistance to the antibiotic.

IN PRACTICE:

“More frequent urine cultures in the workup of rUTI diagnosis and prophylactic antibiotic initiation could better inform antibiotic choice,” the authors wrote.

SOURCE:

The study was led by Leigh Sanyaolu, BSc (Hons), MRCS, MRCGP, PGDip, a general practitioner from the Division of Population Medicine and PRIME Centre Wales at Cardiff University in Cardiff, and was published online in the British Journal of General Practice.

LIMITATIONS:

The study’s reliance on electronic health records may have led to coding errors and missing data. The diagnosis of UTIs may have been difficult in older women with increased frailty as they can have fewer specific symptoms and asymptomatic bacteriuria, which can be misdiagnosed as a UTI.

DISCLOSURES:

This work was supported by Health and Care Research Wales. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.

Early Problems

After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.¹ Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
 

Studies on Neuropathy

In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.² A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.³ The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).

Side Effects of Gabapentin

From the Cochrane review, the most common side effects were:  dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.⁵ The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.⁴

New Warnings

In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.⁵ Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).⁶

Off-Label Uses

Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.⁷ In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.^8,9

Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.¹⁰

Pearl of the Month:

Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.

2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.

3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.

4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.

5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).

6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.

7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.

8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.

9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.

10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.

Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.

Early Problems

After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.¹ Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
 

Studies on Neuropathy

In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.² A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.³ The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).

Side Effects of Gabapentin

From the Cochrane review, the most common side effects were:  dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.⁵ The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.⁴

New Warnings

In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.⁵ Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).⁶

Off-Label Uses

Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.⁷ In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.^8,9

Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.¹⁰

Pearl of the Month:

Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.

2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.

3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.

4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.

5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).

6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.

7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.

8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.

9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.

10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.

Since gabapentin was approved by the US Food and Drug Administration (FDA) for treatment of partial-onset seizures and postherpetic neuralgia, it has been used in many different ways, many off-label indications, and with several recent safety warnings.

Early Problems

After FDA approval in 1993 (for partial seizures), gabapentin was promoted by its maker (Park-Davis) for off-label indications, especially for pain. There was no FDA approval for that indication and the studies the company had done were deemed to have been manipulated in a subsequent lawsuit.¹ Gabapentin became the nonopioid go-to medication for treatment of pain despite underwhelming evidence.
 

Studies on Neuropathy

In the largest trial of gabapentin for diabetic peripheral neuropathy, Rauck and colleagues found no significant difference in pain relief between gabapentin and placebo.² A Cochrane review of gabapentin for neuropathic pain concluded that about 30%-40% of patients taking gabapentin for diabetic neuropathy achieved meaningful pain relief with gabapentin use, with a number needed to treat (NNT) of 6.6.³ The review also concluded that for postherpetic neuralgia (an FDA-approved indication) 78% of patients had moderate to substantial benefit with gabapentin (NNT 4.8 for moderate benefit).

Side Effects of Gabapentin

From the Cochrane review, the most common side effects were:  dizziness (19%), somnolence (14%), peripheral edema (7%), and gait disturbance (14%). The number needed to harm for gabapentin was 7.⁵ The two side effects listed here that are often overlooked that I want to highlight are peripheral edema and gait disturbance. I have seen these both fairly frequently over the years. A side effect not found in the Cochrane review was weight gain. Weight gain with gabapentin was reported in a meta-analysis of drugs that can cause weight gain.⁴

New Warnings

In December 2019, the FDA released a warning on the potential for serious respiratory problems with gabapentin and pregabalin in patients with certain risk factors: opioid use or use of other drugs that depress the central nervous system, COPD, and other severe lung diseases.⁵ Rahman and colleagues found that compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation (hazard ratio, 1.39; 95% confidence interval, 1.29-1.50).⁶

Off-Label Uses

Primary care professionals frequently use gabapentin for two off-label indications that are incorporated into practice guidelines. Ryan et al. studied gabapentin in patients with refractory, unexplained chronic cough.⁷ In a randomized, placebo-controlled trial, gabapentin improved cough-specific quality of life compared with placebo (P = .004; NNT 3.58). Use of gabapentin for treatment of unexplained, refractory cough has been included in several chronic cough practice guidelines.^8,9

Gabapentin has been studied for the treatment of restless legs syndrome and has been recommended as an option to treat moderate to severe restless legs syndrome in the American Academy of Sleep Medicine Guidelines.¹⁰

Pearl of the Month:

Gabapentin is used widely for many different pain syndromes. The best evidence is for postherpetic neuralgia and diabetic neuropathy. Be aware of the side effects and risks of use in patients with pulmonary disease and who are taking CNS-depressant medications.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Landefeld CS, Steinman MA. The Neurontin legacy: marketing through misinformation and manipulation. N Engl J Med. 2009;360(2):103-6.

2. Rauck R et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485-96.

3. Wiffen PJ et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938.

4. Domecq JP et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.

5. 12-19-2019 FDA Drug Safety Communication. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).

6. Rahman AA et al. Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: A population-based cohort study. Ann Intern Med. 2024 Feb;177(2):144-54.

7. Ryan NM et al. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 2012;380(9853):1583-9.

8. Gibson P et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016 Jan;149(1):27-44.

9. De Vincentis A et al. Chronic cough in adults: recommendations from an Italian intersociety consensus. Aging Clin Exp Res 2022;34:1529.

10. Aurora RN et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults — an update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039.

A single night of sleep deprivation had a significant impact on human blood serum, based on new data from an analysis of nearly 500 proteins. Compromised sleep has demonstrated negative effects on cardiovascular, immune, and neuronal systems, and previous studies have shown human serum proteome changes after a simulation of night shift work, wrote Alvhild Alette Bjørkum, MD, of Western Norway University of Applied Sciences, Bergen, and colleagues.

In a pilot study published in Sleep Advances, the researchers recruited eight healthy adult women aged 22-57 years with no history of neurologic or psychiatric problems to participate in a study of the effect of compromised sleep on protein profiles, with implications for effects on cells, tissues, and organ systems. Each of the participants served as their own controls, and blood samples were taken after 6 hours of sleep at night, and again after 6 hours of sleep deprivation the following night.

The researchers identified analyzed 494 proteins using mass spectrometry. Of these, 66 were differentially expressed after 6 hours of sleep deprivation. The top enriched biologic processes of these significantly changed proteins were protein activation cascade, platelet degranulation, blood coagulation, and hemostasis.

Further analysis using gene ontology showed changes in response to sleep deprivation in biologic process, molecular function, and immune system process categories, including specific associations related to wound healing, cholesterol transport, high-density lipoprotein particle receptor binding, and granulocyte chemotaxis.

The findings were limited by several factors including the small sample size, inclusion only of adult females, and the use of data from only 1 night of sleep deprivation, the researchers noted. However, the results support previous studies showing a negative impact of sleep deprivation on biologic functions, they said.

“Our study was able to reveal another set of human serum proteins that were altered by sleep deprivation and could connect similar biological processes to sleep deprivation that have been identified before with slightly different methods,” the researchers concluded. The study findings add to the knowledge base for the protein profiling of sleep deprivation, which may inform the development of tools to manage lack of sleep and mistimed sleep, particularly in shift workers.
 

Too Soon for Clinical Implications

“The adverse impact of poor sleep across many organ systems is gaining recognition, but the mechanisms underlying sleep-related pathology are not well understood,” Evan L. Brittain, MD, of Vanderbilt University, Nashville, Tennessee, said in an interview. “Studies like this begin to shed light on the mechanisms by which poor or reduced sleep affects specific bodily functions,” added Dr. Brittain, who was not involved in the study.

“The effects of other acute physiologic stressor such as exercise on the circulating proteome are well described. In that regard, it is not surprising that a brief episode of sleep deprivation would lead to detectable changes in the circulation,” Dr. Brittain said.

However, the specific changes reported in this study are difficult to interpret because of methodological and analytical concerns, particularly the small sample size, lack of an external validation cohort, and absence of appropriate statistical adjustments in the results, Dr. Brittain noted. These limitations prevent consideration of clinical implications without further study.

The study received no outside funding. Neither the researchers nor Dr. Brittain disclosed any conflicts of interest.

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

A single night of sleep deprivation had a significant impact on human blood serum, based on new data from an analysis of nearly 500 proteins. Compromised sleep has demonstrated negative effects on cardiovascular, immune, and neuronal systems, and previous studies have shown human serum proteome changes after a simulation of night shift work, wrote Alvhild Alette Bjørkum, MD, of Western Norway University of Applied Sciences, Bergen, and colleagues.

In a pilot study published in Sleep Advances, the researchers recruited eight healthy adult women aged 22-57 years with no history of neurologic or psychiatric problems to participate in a study of the effect of compromised sleep on protein profiles, with implications for effects on cells, tissues, and organ systems. Each of the participants served as their own controls, and blood samples were taken after 6 hours of sleep at night, and again after 6 hours of sleep deprivation the following night.

The researchers identified analyzed 494 proteins using mass spectrometry. Of these, 66 were differentially expressed after 6 hours of sleep deprivation. The top enriched biologic processes of these significantly changed proteins were protein activation cascade, platelet degranulation, blood coagulation, and hemostasis.

Further analysis using gene ontology showed changes in response to sleep deprivation in biologic process, molecular function, and immune system process categories, including specific associations related to wound healing, cholesterol transport, high-density lipoprotein particle receptor binding, and granulocyte chemotaxis.

The findings were limited by several factors including the small sample size, inclusion only of adult females, and the use of data from only 1 night of sleep deprivation, the researchers noted. However, the results support previous studies showing a negative impact of sleep deprivation on biologic functions, they said.

“Our study was able to reveal another set of human serum proteins that were altered by sleep deprivation and could connect similar biological processes to sleep deprivation that have been identified before with slightly different methods,” the researchers concluded. The study findings add to the knowledge base for the protein profiling of sleep deprivation, which may inform the development of tools to manage lack of sleep and mistimed sleep, particularly in shift workers.
 

Too Soon for Clinical Implications

“The adverse impact of poor sleep across many organ systems is gaining recognition, but the mechanisms underlying sleep-related pathology are not well understood,” Evan L. Brittain, MD, of Vanderbilt University, Nashville, Tennessee, said in an interview. “Studies like this begin to shed light on the mechanisms by which poor or reduced sleep affects specific bodily functions,” added Dr. Brittain, who was not involved in the study.

“The effects of other acute physiologic stressor such as exercise on the circulating proteome are well described. In that regard, it is not surprising that a brief episode of sleep deprivation would lead to detectable changes in the circulation,” Dr. Brittain said.

However, the specific changes reported in this study are difficult to interpret because of methodological and analytical concerns, particularly the small sample size, lack of an external validation cohort, and absence of appropriate statistical adjustments in the results, Dr. Brittain noted. These limitations prevent consideration of clinical implications without further study.

The study received no outside funding. Neither the researchers nor Dr. Brittain disclosed any conflicts of interest.

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

A single night of sleep deprivation had a significant impact on human blood serum, based on new data from an analysis of nearly 500 proteins. Compromised sleep has demonstrated negative effects on cardiovascular, immune, and neuronal systems, and previous studies have shown human serum proteome changes after a simulation of night shift work, wrote Alvhild Alette Bjørkum, MD, of Western Norway University of Applied Sciences, Bergen, and colleagues.

In a pilot study published in Sleep Advances, the researchers recruited eight healthy adult women aged 22-57 years with no history of neurologic or psychiatric problems to participate in a study of the effect of compromised sleep on protein profiles, with implications for effects on cells, tissues, and organ systems. Each of the participants served as their own controls, and blood samples were taken after 6 hours of sleep at night, and again after 6 hours of sleep deprivation the following night.

The researchers identified analyzed 494 proteins using mass spectrometry. Of these, 66 were differentially expressed after 6 hours of sleep deprivation. The top enriched biologic processes of these significantly changed proteins were protein activation cascade, platelet degranulation, blood coagulation, and hemostasis.

Further analysis using gene ontology showed changes in response to sleep deprivation in biologic process, molecular function, and immune system process categories, including specific associations related to wound healing, cholesterol transport, high-density lipoprotein particle receptor binding, and granulocyte chemotaxis.

The findings were limited by several factors including the small sample size, inclusion only of adult females, and the use of data from only 1 night of sleep deprivation, the researchers noted. However, the results support previous studies showing a negative impact of sleep deprivation on biologic functions, they said.

“Our study was able to reveal another set of human serum proteins that were altered by sleep deprivation and could connect similar biological processes to sleep deprivation that have been identified before with slightly different methods,” the researchers concluded. The study findings add to the knowledge base for the protein profiling of sleep deprivation, which may inform the development of tools to manage lack of sleep and mistimed sleep, particularly in shift workers.
 

Too Soon for Clinical Implications

“The adverse impact of poor sleep across many organ systems is gaining recognition, but the mechanisms underlying sleep-related pathology are not well understood,” Evan L. Brittain, MD, of Vanderbilt University, Nashville, Tennessee, said in an interview. “Studies like this begin to shed light on the mechanisms by which poor or reduced sleep affects specific bodily functions,” added Dr. Brittain, who was not involved in the study.

“The effects of other acute physiologic stressor such as exercise on the circulating proteome are well described. In that regard, it is not surprising that a brief episode of sleep deprivation would lead to detectable changes in the circulation,” Dr. Brittain said.

However, the specific changes reported in this study are difficult to interpret because of methodological and analytical concerns, particularly the small sample size, lack of an external validation cohort, and absence of appropriate statistical adjustments in the results, Dr. Brittain noted. These limitations prevent consideration of clinical implications without further study.

The study received no outside funding. Neither the researchers nor Dr. Brittain disclosed any conflicts of interest.

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

Higher levels of air pollution from wildfires were associated with significant spikes in hospitalizations for asthma and a slight increase in hospitalizations for COPD in surrounding areas, based on data from approximately 80,000 individuals.

Short-term increases in fine particulate matter (PM_2.5) resulting from wildfire smoke are becoming a greater global problem and have been associated with poor asthma and COPD outcomes, wrote Benjamin D. Horne, PhD, of the Intermountain Medical Center Heart Institute, Salt Lake City, Utah, and colleagues. However, the effect of short-term increases in PM_2.5 on hospitalizations for asthma and COPD has not been well studied, they noted.

“Our primary reason for studying the association of air pollution in the summer/fall wildfire season separately from the winter is that the drought conditions in the western United States from 2012-2022 resulted in more wildfires and increasingly large wildfires across the west,” Dr. Horne said in an interview. “In part, this provided a chance to measure an increase of fine particulate matter (PM_2.5) air pollution from wildfires and also to track what happened to their health when people were exposed to the PM_2.5 from wildfire,” he said. 

During 2020-2022, the PM_2.5 produced during the wildfire season exceeded the PM_2.5 levels measured in the winter for the first time, Dr. Horne said. In the part of Utah where the study was conducted, PM_2.5 increases in winter because of a combination of concentrated PM_2.5 from cars and industry and a weather phenomenon known as a temperature inversion, he said. 

A temperature inversion occurs when mountain topography traps pollutants near the ground where the people are, but only during times of cold and snowy weather, Dr. Horne said. 

“Past studies in the region were conducted with the assumption that the winter inversion was the primary source of pollution-related health risks, and public and healthcare guidance for health was based on avoiding winter air pollution,” Dr. Horne noted. However, “it may be that the smoke from wildfires requires people to also anticipate how to avoid exposure to PM_2.5 during the summer,” he said. 

In a study published in CHEST Pulmonary, the researchers reviewed data from 63,976 patients hospitalized with asthma and 18,514 hospitalized with COPD between January 1999 and March 2022 who lived in an area of Utah in which PM_2.5 and ozone are measured by the Environmental Protection Agency. The average age of the asthma patients was 22.6 years; 51.0% were women, 16.0% had hypertension, and 10.1% had a history of smoking. The average age of the COPD patients was 63.5 years, 50.3% were women, 69.1% had hypertension, and 42.3% had a history of smoking.

In a regression analysis, the risk for asthma was significantly associated with days of increased PM_2.5 during wildfire season and similar to the winter inversion (when cold air traps air pollutants), with odds ratios (ORs) of 1.057 and 1.023 for every 10 µg per m³ of particulate matter, respectively. 

Although the risk for asthma hospitalization decreased after a week, a rebound occurred during wildfire season after a 4-week lag, with an OR of 1.098 for every 10 µg per m³ of particulate matter, the researchers wrote. A review of all months showed a significant association between a concurrent day increase in PM_2.5 and asthma hospitalization (OR, 1.020 per every 10 µg per m³ of particulate matter, P = .0006).

By contrast, PM_2.5 increases had only a weak association with hospitalizations for COPD during either wildfire season or winter inversion season, and ozone was not associated with increased risks for patients with asthma or COPD. 

The findings were limited by several factors including the observational design, potential for confounding, and relatively homogeneous study population, the researchers noted.

However, “these findings suggest that people should be aware of the risks from wildfire-generated PM_2.5 during the summer and fall, including following best practices for people with asthma such as anticipating symptoms in warm months, carrying medications during summer activities, and expecting to stay indoors to avoid smoke exposure when wildfires have polluted the outdoor air,” Dr. Horne told this news organization.

In the current study, Dr. Horne and colleagues expected to see increases in the risk for asthma and COPD during summer wildfire season. “What was surprising was that the size of the risk of needing care of asthma appeared to occur just as rapidly after the PM_2.5 became elevated during wildfire events as it did in the winter,” said Dr. Horne. “Further, the risk in the summer appeared to be greater than during the winter. Increases in hospitalization for asthma occurred on the same day and throughout the first week after a rise in air pollution in summer and early fall, and especially in children that risk remained increased for up to a month after the rise in air pollution,” he said. 

Clinicians should be aware of environmental sources of respiratory declines caused by wildfire smoke that may prompt patients to seek care during wildfire events, said Horne. Finally, the general population should recognize the smell of smoke during warm months as an alert that leads to greater caution about spending time outdoors during wildfire events, he said. “Short-term PM_2.5 elevations may affect respiratory health and have other effects such as on heart health,” Dr. Horne said. “In general, people should avoid outdoor exercise when air pollution is elevated, since the amount of air that is breathed in during exercise is substantially increased,” he added. 

“Further research is needed regarding the mechanisms of effect from PM_2.5 on health risk, including effects on respiratory and cardiovascular health,” said Dr. Horne. “This includes evaluating what biomarkers in the blood are changed by air pollution such as inflammatory factors, determining whether some medications may block or reduce the adverse effects of air pollution, and examining whether masks or indoor air purifiers have a meaningful benefit in protecting health during short-term air pollution elevations,” he said.
 

Data Reveal Respiratory Impact of Wildfires

“Fine particle air pollution has been linked to poor respiratory health outcomes, but relatively little is known about the specific impact of wildfire particulate pollution on patients living in urban population centers,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, said in an interview. 

“Although it is known that wildfire risk is increasing throughout the western United States, the increase in the number of days per month with elevated fine particulate matter from 1999 to 2022 was striking,” said Dr. Rabin, who was not involved in the current study. “Over the same period, there was a decrease in the number of high fine particulate matter air pollution days related to the wintertime temperature inversion phenomenon when air pollutants are trapped in Utah’s valleys,” he said. “These data underscore the increased risk of wildfire-related air pollution relative to ‘traditional sources of air pollution from industrial and transportation sources,” he added. 

Although the adverse effects of exposure to wildfire smoke and inversion season pollution on asthma were not unexpected, the degree of the effect size of wildfire smoke relative to inversion season was surprising, said Dr. Rabin.

“Why the wildfire smoke seems to have a worse impact on asthma outcomes could not be determined from this study, but there may be something inherently more dangerous about the cocktail of pollutants released when large wildfires burn uncontrolled,” he said. “I was surprised by the lack of association between wildfire smoke and adverse COPD outcomes; whether this relates to physiological differences or variations in healthcare-seeking behaviors between patients with asthma vs COPD is unknown,” he added. 

The current study underscores the harmful effects of fine particulate pollution from wildfire smoke on health, and the increased risk for hospitalization for those with asthma even in urban environments far from the source of the fire, Dr. Rabin said.

However, limitations include the use of estimates of fine particulate pollution taken from monitoring stations that were an average of 14 km from the participants’ primary residences, and air quality measurements may not have accurately reflected exposure, Dr. Rabin noted. “Additionally, the population studied was not reflective of the US population, with approximately 80% of study participants described as non-Hispanic white,” he said. “Patients of color may have increased vulnerability to adverse outcomes from air pollution and therefore additional study is needed in these populations,” Dr. Rabin added.

The study was supported in part by the AIRHEALTH program project and by internal institutional funds. Dr. Horne disclosed serving on the advisory board of Opsis Health, previously consulting for Pfizer regarding risk scores and serving as site principal investigator of a grant funded by the Task Force for Global Health and a grant from the Patient-Centered Outcomes Research Institute and the NIH-funded RECOVER initiative. Dr. Rabin had no financial conflicts to disclose.
 

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

Higher levels of air pollution from wildfires were associated with significant spikes in hospitalizations for asthma and a slight increase in hospitalizations for COPD in surrounding areas, based on data from approximately 80,000 individuals.

Short-term increases in fine particulate matter (PM_2.5) resulting from wildfire smoke are becoming a greater global problem and have been associated with poor asthma and COPD outcomes, wrote Benjamin D. Horne, PhD, of the Intermountain Medical Center Heart Institute, Salt Lake City, Utah, and colleagues. However, the effect of short-term increases in PM_2.5 on hospitalizations for asthma and COPD has not been well studied, they noted.

“Our primary reason for studying the association of air pollution in the summer/fall wildfire season separately from the winter is that the drought conditions in the western United States from 2012-2022 resulted in more wildfires and increasingly large wildfires across the west,” Dr. Horne said in an interview. “In part, this provided a chance to measure an increase of fine particulate matter (PM_2.5) air pollution from wildfires and also to track what happened to their health when people were exposed to the PM_2.5 from wildfire,” he said. 

During 2020-2022, the PM_2.5 produced during the wildfire season exceeded the PM_2.5 levels measured in the winter for the first time, Dr. Horne said. In the part of Utah where the study was conducted, PM_2.5 increases in winter because of a combination of concentrated PM_2.5 from cars and industry and a weather phenomenon known as a temperature inversion, he said. 

A temperature inversion occurs when mountain topography traps pollutants near the ground where the people are, but only during times of cold and snowy weather, Dr. Horne said. 

“Past studies in the region were conducted with the assumption that the winter inversion was the primary source of pollution-related health risks, and public and healthcare guidance for health was based on avoiding winter air pollution,” Dr. Horne noted. However, “it may be that the smoke from wildfires requires people to also anticipate how to avoid exposure to PM_2.5 during the summer,” he said. 

In a study published in CHEST Pulmonary, the researchers reviewed data from 63,976 patients hospitalized with asthma and 18,514 hospitalized with COPD between January 1999 and March 2022 who lived in an area of Utah in which PM_2.5 and ozone are measured by the Environmental Protection Agency. The average age of the asthma patients was 22.6 years; 51.0% were women, 16.0% had hypertension, and 10.1% had a history of smoking. The average age of the COPD patients was 63.5 years, 50.3% were women, 69.1% had hypertension, and 42.3% had a history of smoking.

In a regression analysis, the risk for asthma was significantly associated with days of increased PM_2.5 during wildfire season and similar to the winter inversion (when cold air traps air pollutants), with odds ratios (ORs) of 1.057 and 1.023 for every 10 µg per m³ of particulate matter, respectively. 

Although the risk for asthma hospitalization decreased after a week, a rebound occurred during wildfire season after a 4-week lag, with an OR of 1.098 for every 10 µg per m³ of particulate matter, the researchers wrote. A review of all months showed a significant association between a concurrent day increase in PM_2.5 and asthma hospitalization (OR, 1.020 per every 10 µg per m³ of particulate matter, P = .0006).

By contrast, PM_2.5 increases had only a weak association with hospitalizations for COPD during either wildfire season or winter inversion season, and ozone was not associated with increased risks for patients with asthma or COPD. 

The findings were limited by several factors including the observational design, potential for confounding, and relatively homogeneous study population, the researchers noted.

However, “these findings suggest that people should be aware of the risks from wildfire-generated PM_2.5 during the summer and fall, including following best practices for people with asthma such as anticipating symptoms in warm months, carrying medications during summer activities, and expecting to stay indoors to avoid smoke exposure when wildfires have polluted the outdoor air,” Dr. Horne told this news organization.

In the current study, Dr. Horne and colleagues expected to see increases in the risk for asthma and COPD during summer wildfire season. “What was surprising was that the size of the risk of needing care of asthma appeared to occur just as rapidly after the PM_2.5 became elevated during wildfire events as it did in the winter,” said Dr. Horne. “Further, the risk in the summer appeared to be greater than during the winter. Increases in hospitalization for asthma occurred on the same day and throughout the first week after a rise in air pollution in summer and early fall, and especially in children that risk remained increased for up to a month after the rise in air pollution,” he said. 

Clinicians should be aware of environmental sources of respiratory declines caused by wildfire smoke that may prompt patients to seek care during wildfire events, said Horne. Finally, the general population should recognize the smell of smoke during warm months as an alert that leads to greater caution about spending time outdoors during wildfire events, he said. “Short-term PM_2.5 elevations may affect respiratory health and have other effects such as on heart health,” Dr. Horne said. “In general, people should avoid outdoor exercise when air pollution is elevated, since the amount of air that is breathed in during exercise is substantially increased,” he added. 

“Further research is needed regarding the mechanisms of effect from PM_2.5 on health risk, including effects on respiratory and cardiovascular health,” said Dr. Horne. “This includes evaluating what biomarkers in the blood are changed by air pollution such as inflammatory factors, determining whether some medications may block or reduce the adverse effects of air pollution, and examining whether masks or indoor air purifiers have a meaningful benefit in protecting health during short-term air pollution elevations,” he said.
 

Data Reveal Respiratory Impact of Wildfires

“Fine particle air pollution has been linked to poor respiratory health outcomes, but relatively little is known about the specific impact of wildfire particulate pollution on patients living in urban population centers,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, said in an interview. 

“Although it is known that wildfire risk is increasing throughout the western United States, the increase in the number of days per month with elevated fine particulate matter from 1999 to 2022 was striking,” said Dr. Rabin, who was not involved in the current study. “Over the same period, there was a decrease in the number of high fine particulate matter air pollution days related to the wintertime temperature inversion phenomenon when air pollutants are trapped in Utah’s valleys,” he said. “These data underscore the increased risk of wildfire-related air pollution relative to ‘traditional sources of air pollution from industrial and transportation sources,” he added. 

Although the adverse effects of exposure to wildfire smoke and inversion season pollution on asthma were not unexpected, the degree of the effect size of wildfire smoke relative to inversion season was surprising, said Dr. Rabin.

“Why the wildfire smoke seems to have a worse impact on asthma outcomes could not be determined from this study, but there may be something inherently more dangerous about the cocktail of pollutants released when large wildfires burn uncontrolled,” he said. “I was surprised by the lack of association between wildfire smoke and adverse COPD outcomes; whether this relates to physiological differences or variations in healthcare-seeking behaviors between patients with asthma vs COPD is unknown,” he added. 

The current study underscores the harmful effects of fine particulate pollution from wildfire smoke on health, and the increased risk for hospitalization for those with asthma even in urban environments far from the source of the fire, Dr. Rabin said.

However, limitations include the use of estimates of fine particulate pollution taken from monitoring stations that were an average of 14 km from the participants’ primary residences, and air quality measurements may not have accurately reflected exposure, Dr. Rabin noted. “Additionally, the population studied was not reflective of the US population, with approximately 80% of study participants described as non-Hispanic white,” he said. “Patients of color may have increased vulnerability to adverse outcomes from air pollution and therefore additional study is needed in these populations,” Dr. Rabin added.

The study was supported in part by the AIRHEALTH program project and by internal institutional funds. Dr. Horne disclosed serving on the advisory board of Opsis Health, previously consulting for Pfizer regarding risk scores and serving as site principal investigator of a grant funded by the Task Force for Global Health and a grant from the Patient-Centered Outcomes Research Institute and the NIH-funded RECOVER initiative. Dr. Rabin had no financial conflicts to disclose.
 

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

Higher levels of air pollution from wildfires were associated with significant spikes in hospitalizations for asthma and a slight increase in hospitalizations for COPD in surrounding areas, based on data from approximately 80,000 individuals.

Short-term increases in fine particulate matter (PM_2.5) resulting from wildfire smoke are becoming a greater global problem and have been associated with poor asthma and COPD outcomes, wrote Benjamin D. Horne, PhD, of the Intermountain Medical Center Heart Institute, Salt Lake City, Utah, and colleagues. However, the effect of short-term increases in PM_2.5 on hospitalizations for asthma and COPD has not been well studied, they noted.

“Our primary reason for studying the association of air pollution in the summer/fall wildfire season separately from the winter is that the drought conditions in the western United States from 2012-2022 resulted in more wildfires and increasingly large wildfires across the west,” Dr. Horne said in an interview. “In part, this provided a chance to measure an increase of fine particulate matter (PM_2.5) air pollution from wildfires and also to track what happened to their health when people were exposed to the PM_2.5 from wildfire,” he said. 

During 2020-2022, the PM_2.5 produced during the wildfire season exceeded the PM_2.5 levels measured in the winter for the first time, Dr. Horne said. In the part of Utah where the study was conducted, PM_2.5 increases in winter because of a combination of concentrated PM_2.5 from cars and industry and a weather phenomenon known as a temperature inversion, he said. 

A temperature inversion occurs when mountain topography traps pollutants near the ground where the people are, but only during times of cold and snowy weather, Dr. Horne said. 

“Past studies in the region were conducted with the assumption that the winter inversion was the primary source of pollution-related health risks, and public and healthcare guidance for health was based on avoiding winter air pollution,” Dr. Horne noted. However, “it may be that the smoke from wildfires requires people to also anticipate how to avoid exposure to PM_2.5 during the summer,” he said. 

In a study published in CHEST Pulmonary, the researchers reviewed data from 63,976 patients hospitalized with asthma and 18,514 hospitalized with COPD between January 1999 and March 2022 who lived in an area of Utah in which PM_2.5 and ozone are measured by the Environmental Protection Agency. The average age of the asthma patients was 22.6 years; 51.0% were women, 16.0% had hypertension, and 10.1% had a history of smoking. The average age of the COPD patients was 63.5 years, 50.3% were women, 69.1% had hypertension, and 42.3% had a history of smoking.

In a regression analysis, the risk for asthma was significantly associated with days of increased PM_2.5 during wildfire season and similar to the winter inversion (when cold air traps air pollutants), with odds ratios (ORs) of 1.057 and 1.023 for every 10 µg per m³ of particulate matter, respectively. 

Although the risk for asthma hospitalization decreased after a week, a rebound occurred during wildfire season after a 4-week lag, with an OR of 1.098 for every 10 µg per m³ of particulate matter, the researchers wrote. A review of all months showed a significant association between a concurrent day increase in PM_2.5 and asthma hospitalization (OR, 1.020 per every 10 µg per m³ of particulate matter, P = .0006).

By contrast, PM_2.5 increases had only a weak association with hospitalizations for COPD during either wildfire season or winter inversion season, and ozone was not associated with increased risks for patients with asthma or COPD. 

The findings were limited by several factors including the observational design, potential for confounding, and relatively homogeneous study population, the researchers noted.

However, “these findings suggest that people should be aware of the risks from wildfire-generated PM_2.5 during the summer and fall, including following best practices for people with asthma such as anticipating symptoms in warm months, carrying medications during summer activities, and expecting to stay indoors to avoid smoke exposure when wildfires have polluted the outdoor air,” Dr. Horne told this news organization.

In the current study, Dr. Horne and colleagues expected to see increases in the risk for asthma and COPD during summer wildfire season. “What was surprising was that the size of the risk of needing care of asthma appeared to occur just as rapidly after the PM_2.5 became elevated during wildfire events as it did in the winter,” said Dr. Horne. “Further, the risk in the summer appeared to be greater than during the winter. Increases in hospitalization for asthma occurred on the same day and throughout the first week after a rise in air pollution in summer and early fall, and especially in children that risk remained increased for up to a month after the rise in air pollution,” he said. 

Clinicians should be aware of environmental sources of respiratory declines caused by wildfire smoke that may prompt patients to seek care during wildfire events, said Horne. Finally, the general population should recognize the smell of smoke during warm months as an alert that leads to greater caution about spending time outdoors during wildfire events, he said. “Short-term PM_2.5 elevations may affect respiratory health and have other effects such as on heart health,” Dr. Horne said. “In general, people should avoid outdoor exercise when air pollution is elevated, since the amount of air that is breathed in during exercise is substantially increased,” he added. 

“Further research is needed regarding the mechanisms of effect from PM_2.5 on health risk, including effects on respiratory and cardiovascular health,” said Dr. Horne. “This includes evaluating what biomarkers in the blood are changed by air pollution such as inflammatory factors, determining whether some medications may block or reduce the adverse effects of air pollution, and examining whether masks or indoor air purifiers have a meaningful benefit in protecting health during short-term air pollution elevations,” he said.
 

Data Reveal Respiratory Impact of Wildfires

“Fine particle air pollution has been linked to poor respiratory health outcomes, but relatively little is known about the specific impact of wildfire particulate pollution on patients living in urban population centers,” Alexander S. Rabin, MD, of the University of Michigan, Ann Arbor, said in an interview. 

“Although it is known that wildfire risk is increasing throughout the western United States, the increase in the number of days per month with elevated fine particulate matter from 1999 to 2022 was striking,” said Dr. Rabin, who was not involved in the current study. “Over the same period, there was a decrease in the number of high fine particulate matter air pollution days related to the wintertime temperature inversion phenomenon when air pollutants are trapped in Utah’s valleys,” he said. “These data underscore the increased risk of wildfire-related air pollution relative to ‘traditional sources of air pollution from industrial and transportation sources,” he added. 

Although the adverse effects of exposure to wildfire smoke and inversion season pollution on asthma were not unexpected, the degree of the effect size of wildfire smoke relative to inversion season was surprising, said Dr. Rabin.

“Why the wildfire smoke seems to have a worse impact on asthma outcomes could not be determined from this study, but there may be something inherently more dangerous about the cocktail of pollutants released when large wildfires burn uncontrolled,” he said. “I was surprised by the lack of association between wildfire smoke and adverse COPD outcomes; whether this relates to physiological differences or variations in healthcare-seeking behaviors between patients with asthma vs COPD is unknown,” he added. 

The current study underscores the harmful effects of fine particulate pollution from wildfire smoke on health, and the increased risk for hospitalization for those with asthma even in urban environments far from the source of the fire, Dr. Rabin said.

However, limitations include the use of estimates of fine particulate pollution taken from monitoring stations that were an average of 14 km from the participants’ primary residences, and air quality measurements may not have accurately reflected exposure, Dr. Rabin noted. “Additionally, the population studied was not reflective of the US population, with approximately 80% of study participants described as non-Hispanic white,” he said. “Patients of color may have increased vulnerability to adverse outcomes from air pollution and therefore additional study is needed in these populations,” Dr. Rabin added.

The study was supported in part by the AIRHEALTH program project and by internal institutional funds. Dr. Horne disclosed serving on the advisory board of Opsis Health, previously consulting for Pfizer regarding risk scores and serving as site principal investigator of a grant funded by the Task Force for Global Health and a grant from the Patient-Centered Outcomes Research Institute and the NIH-funded RECOVER initiative. Dr. Rabin had no financial conflicts to disclose.
 

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

Four organizations owned by private equity firms — including two provider groups — dominated the No Surprises Act’s disputed bill arbitration process in its first year, filing about 70% of 657,040 cases against insurers in 2023, a new report finds. 

The findings, recently published in Health Affairs, suggest that private equity–owned organizations are forcefully challenging insurers about payments for certain kinds of out-of-network care. 

Their fighting stance has paid off: The percentage of resolved arbitration cases won by providers jumped from 72% in the first quarter of 2023 to 85% in the last quarter, and they were awarded a median of more than 300% the contracted in-network rates for the services in question.

With many more out-of-network bills disputed by providers than expected, “the system is not working exactly the way it was anticipated when this law was written,” lead author Jack Hoadley, PhD, a research professor emeritus at Georgetown University’s McCourt School of Public Policy, Washington, DC, told this news organization.

And, he said, the public and the federal government may end up paying a price. 

Congress passed the No Surprises Act in 2020 and then-President Donald Trump signed it. The landmark bill, which went into effect in 2022, was designed to protect patients from unexpected and often exorbitant “surprise” bills after they received some kinds of out-of-network care. 

Now, many types of providers are forbidden from billing patients beyond normal in-network costs. In these cases, health plans and out-of-network providers — who don’t have mutual agreements — must wrangle over payment amounts, which are intended to not exceed inflation-adjusted 2019 median levels. 

A binding arbitration process kicks in when a provider and a health plan fail to agree about how much the plan will pay for a service. Then, a third-party arbitrator is called in to make a ruling that’s binding. The process is controversial, and a flurry of lawsuits from providers have challenged it. 

The new report, which updates an earlier analysis, examines data about disputed cases from all of 2023.

Of the 657,040 new cases filed in 2023, about 70% came from four private equity-funded organizations: Team Health, SCP Health, Radiology Partners, and Envision, which each provide physician services.

About half of the 2023 cases were from just four states: Texas, Florida, Tennessee, and Georgia. The report says the four organizations are especially active in those states. In contrast, Connecticut, Maryland, Massachusetts, and Washington state each had just 1500 or fewer cases filed last year. 

Health plans challenged a third of cases as ineligible, and 22% of all resolved cases were deemed ineligible.

Providers won 80% of resolved challenges in 2023, although it’s not clear how much money they reaped. Still, it’s clear that “in the vast majority of the cases, insurers have to pay larger amounts to the provider,” Dr. Hoadley said.

Radiologists made a median of at least 500% of the in-network rate in their cases. Surgeons and neurologists made even more money — a median of at least 800% of the in-network rate. Overall, providers made 322%-350% of in-network rates, depending on the quarter.

Dr. Hoadley cautioned that only a small percentage of medical payments are disputed. In those cases, “the amount that the insurer offers is accepted, and that’s the end of the story.”

Why are the providers often reaping much more than typical payments for in-network services? It’s “really hard to know,” Dr. Hoadley said. But one factor, he said, may be the fact that providers are able to offer evidence challenging that amounts that insurers say they paid previously: “Hey, when we were in network, we were paid this much.”

It’s not clear whether the dispute-and-arbitration system will cost insurers — and patients — more in the long run. The Congressional Budget Office actually thought the No Surprises Act might lower the growth of premiums slightly and save the federal government money, Dr. Hoadley said, but that could potentially not happen. The flood of litigation also contributes to uncertainty, he said. 

Alan Sager, PhD, professor of Health Law, Policy, and Management at Boston University School of Public Health, told this news organization that premiums are bound to rise as insurers react to higher costs. He also expects that providers will question the value of being in-network. “If you’re out-of-network and can obtain much higher payments, why would any doctor or hospital remain in-network, especially since they don’t lose out on patient volume?”

Why are provider groups owned by private equity firms so aggressive at challenging health plans? Loren Adler, a fellow and associate director of the Brookings Institution’s Center on Health Policy, told this news organization that these companies play large roles in fields affected by the No Surprises Act. These include emergency medicine, radiology, and anesthesiology, said Mr. Adler, who’s also studied the No Surprises Act’s dispute/arbitration system.

Mr. Adler added that larger companies “are better suited to deal with technical complexities of this process and spend the sort of upfront money to go through it.”

In the big picture, Mr. Adler said, the new study “raises question of whether Congress at some point wants to try to basically bring prices from the arbitration process back in line with average in-network prices.”

The study was funded by the Commonwealth Fund and Arnold Ventures. Dr. Hoadley, Dr. Sager, and Mr. Adler had no disclosures.

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

Four organizations owned by private equity firms — including two provider groups — dominated the No Surprises Act’s disputed bill arbitration process in its first year, filing about 70% of 657,040 cases against insurers in 2023, a new report finds. 

The findings, recently published in Health Affairs, suggest that private equity–owned organizations are forcefully challenging insurers about payments for certain kinds of out-of-network care. 

Their fighting stance has paid off: The percentage of resolved arbitration cases won by providers jumped from 72% in the first quarter of 2023 to 85% in the last quarter, and they were awarded a median of more than 300% the contracted in-network rates for the services in question.

With many more out-of-network bills disputed by providers than expected, “the system is not working exactly the way it was anticipated when this law was written,” lead author Jack Hoadley, PhD, a research professor emeritus at Georgetown University’s McCourt School of Public Policy, Washington, DC, told this news organization.

And, he said, the public and the federal government may end up paying a price. 

Congress passed the No Surprises Act in 2020 and then-President Donald Trump signed it. The landmark bill, which went into effect in 2022, was designed to protect patients from unexpected and often exorbitant “surprise” bills after they received some kinds of out-of-network care. 

Now, many types of providers are forbidden from billing patients beyond normal in-network costs. In these cases, health plans and out-of-network providers — who don’t have mutual agreements — must wrangle over payment amounts, which are intended to not exceed inflation-adjusted 2019 median levels. 

A binding arbitration process kicks in when a provider and a health plan fail to agree about how much the plan will pay for a service. Then, a third-party arbitrator is called in to make a ruling that’s binding. The process is controversial, and a flurry of lawsuits from providers have challenged it. 

The new report, which updates an earlier analysis, examines data about disputed cases from all of 2023.

Of the 657,040 new cases filed in 2023, about 70% came from four private equity-funded organizations: Team Health, SCP Health, Radiology Partners, and Envision, which each provide physician services.

About half of the 2023 cases were from just four states: Texas, Florida, Tennessee, and Georgia. The report says the four organizations are especially active in those states. In contrast, Connecticut, Maryland, Massachusetts, and Washington state each had just 1500 or fewer cases filed last year. 

Health plans challenged a third of cases as ineligible, and 22% of all resolved cases were deemed ineligible.

Providers won 80% of resolved challenges in 2023, although it’s not clear how much money they reaped. Still, it’s clear that “in the vast majority of the cases, insurers have to pay larger amounts to the provider,” Dr. Hoadley said.

Radiologists made a median of at least 500% of the in-network rate in their cases. Surgeons and neurologists made even more money — a median of at least 800% of the in-network rate. Overall, providers made 322%-350% of in-network rates, depending on the quarter.

Dr. Hoadley cautioned that only a small percentage of medical payments are disputed. In those cases, “the amount that the insurer offers is accepted, and that’s the end of the story.”

Why are the providers often reaping much more than typical payments for in-network services? It’s “really hard to know,” Dr. Hoadley said. But one factor, he said, may be the fact that providers are able to offer evidence challenging that amounts that insurers say they paid previously: “Hey, when we were in network, we were paid this much.”

It’s not clear whether the dispute-and-arbitration system will cost insurers — and patients — more in the long run. The Congressional Budget Office actually thought the No Surprises Act might lower the growth of premiums slightly and save the federal government money, Dr. Hoadley said, but that could potentially not happen. The flood of litigation also contributes to uncertainty, he said. 

Alan Sager, PhD, professor of Health Law, Policy, and Management at Boston University School of Public Health, told this news organization that premiums are bound to rise as insurers react to higher costs. He also expects that providers will question the value of being in-network. “If you’re out-of-network and can obtain much higher payments, why would any doctor or hospital remain in-network, especially since they don’t lose out on patient volume?”

Why are provider groups owned by private equity firms so aggressive at challenging health plans? Loren Adler, a fellow and associate director of the Brookings Institution’s Center on Health Policy, told this news organization that these companies play large roles in fields affected by the No Surprises Act. These include emergency medicine, radiology, and anesthesiology, said Mr. Adler, who’s also studied the No Surprises Act’s dispute/arbitration system.

Mr. Adler added that larger companies “are better suited to deal with technical complexities of this process and spend the sort of upfront money to go through it.”

In the big picture, Mr. Adler said, the new study “raises question of whether Congress at some point wants to try to basically bring prices from the arbitration process back in line with average in-network prices.”

The study was funded by the Commonwealth Fund and Arnold Ventures. Dr. Hoadley, Dr. Sager, and Mr. Adler had no disclosures.

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

Four organizations owned by private equity firms — including two provider groups — dominated the No Surprises Act’s disputed bill arbitration process in its first year, filing about 70% of 657,040 cases against insurers in 2023, a new report finds. 

The findings, recently published in Health Affairs, suggest that private equity–owned organizations are forcefully challenging insurers about payments for certain kinds of out-of-network care. 

Their fighting stance has paid off: The percentage of resolved arbitration cases won by providers jumped from 72% in the first quarter of 2023 to 85% in the last quarter, and they were awarded a median of more than 300% the contracted in-network rates for the services in question.

With many more out-of-network bills disputed by providers than expected, “the system is not working exactly the way it was anticipated when this law was written,” lead author Jack Hoadley, PhD, a research professor emeritus at Georgetown University’s McCourt School of Public Policy, Washington, DC, told this news organization.

And, he said, the public and the federal government may end up paying a price. 

Congress passed the No Surprises Act in 2020 and then-President Donald Trump signed it. The landmark bill, which went into effect in 2022, was designed to protect patients from unexpected and often exorbitant “surprise” bills after they received some kinds of out-of-network care. 

Now, many types of providers are forbidden from billing patients beyond normal in-network costs. In these cases, health plans and out-of-network providers — who don’t have mutual agreements — must wrangle over payment amounts, which are intended to not exceed inflation-adjusted 2019 median levels. 

A binding arbitration process kicks in when a provider and a health plan fail to agree about how much the plan will pay for a service. Then, a third-party arbitrator is called in to make a ruling that’s binding. The process is controversial, and a flurry of lawsuits from providers have challenged it. 

The new report, which updates an earlier analysis, examines data about disputed cases from all of 2023.

Of the 657,040 new cases filed in 2023, about 70% came from four private equity-funded organizations: Team Health, SCP Health, Radiology Partners, and Envision, which each provide physician services.

About half of the 2023 cases were from just four states: Texas, Florida, Tennessee, and Georgia. The report says the four organizations are especially active in those states. In contrast, Connecticut, Maryland, Massachusetts, and Washington state each had just 1500 or fewer cases filed last year. 

Health plans challenged a third of cases as ineligible, and 22% of all resolved cases were deemed ineligible.

Providers won 80% of resolved challenges in 2023, although it’s not clear how much money they reaped. Still, it’s clear that “in the vast majority of the cases, insurers have to pay larger amounts to the provider,” Dr. Hoadley said.

Radiologists made a median of at least 500% of the in-network rate in their cases. Surgeons and neurologists made even more money — a median of at least 800% of the in-network rate. Overall, providers made 322%-350% of in-network rates, depending on the quarter.

Dr. Hoadley cautioned that only a small percentage of medical payments are disputed. In those cases, “the amount that the insurer offers is accepted, and that’s the end of the story.”

Why are the providers often reaping much more than typical payments for in-network services? It’s “really hard to know,” Dr. Hoadley said. But one factor, he said, may be the fact that providers are able to offer evidence challenging that amounts that insurers say they paid previously: “Hey, when we were in network, we were paid this much.”

It’s not clear whether the dispute-and-arbitration system will cost insurers — and patients — more in the long run. The Congressional Budget Office actually thought the No Surprises Act might lower the growth of premiums slightly and save the federal government money, Dr. Hoadley said, but that could potentially not happen. The flood of litigation also contributes to uncertainty, he said. 

Alan Sager, PhD, professor of Health Law, Policy, and Management at Boston University School of Public Health, told this news organization that premiums are bound to rise as insurers react to higher costs. He also expects that providers will question the value of being in-network. “If you’re out-of-network and can obtain much higher payments, why would any doctor or hospital remain in-network, especially since they don’t lose out on patient volume?”

Why are provider groups owned by private equity firms so aggressive at challenging health plans? Loren Adler, a fellow and associate director of the Brookings Institution’s Center on Health Policy, told this news organization that these companies play large roles in fields affected by the No Surprises Act. These include emergency medicine, radiology, and anesthesiology, said Mr. Adler, who’s also studied the No Surprises Act’s dispute/arbitration system.

Mr. Adler added that larger companies “are better suited to deal with technical complexities of this process and spend the sort of upfront money to go through it.”

In the big picture, Mr. Adler said, the new study “raises question of whether Congress at some point wants to try to basically bring prices from the arbitration process back in line with average in-network prices.”

The study was funded by the Commonwealth Fund and Arnold Ventures. Dr. Hoadley, Dr. Sager, and Mr. Adler had no disclosures.

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

Vaccines work pretty well. But with a little help, they could work better.

Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.

In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.

“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”

The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.

The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.

Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)

The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects. 

Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak. 

“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
 

100 Years of Adjuvants

The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.

But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants. 

TLR agonists have recently become research hotspots in vaccine science. 

“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.

Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”

TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis. 
 

Combining Forces

In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells. 

“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.

Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.

“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”

According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.

Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists. 

The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
 

Tailoring Vaccines

The customizable aspect of TLR agonists is important too, Dr. Burkhart said. 

“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”

That’s what the Stanford researchers hope for.

They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.

But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said. 

“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”

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

Vaccines work pretty well. But with a little help, they could work better.

Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.

In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.

“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”

The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.

The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.

Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)

The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects. 

Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak. 

“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
 

100 Years of Adjuvants

The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.

But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants. 

TLR agonists have recently become research hotspots in vaccine science. 

“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.

Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”

TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis. 
 

Combining Forces

In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells. 

“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.

Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.

“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”

According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.

Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists. 

The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
 

Tailoring Vaccines

The customizable aspect of TLR agonists is important too, Dr. Burkhart said. 

“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”

That’s what the Stanford researchers hope for.

They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.

But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said. 

“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”

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

Vaccines work pretty well. But with a little help, they could work better.

Stanford researchers have developed a new vaccine helper that combines two kinds of adjuvants, ingredients that improve a vaccine’s efficacy, in a novel, customizable system.

In lab tests, the experimental additive improved the effectiveness of COVID-19 and HIV vaccine candidates, though it could be adapted to stimulate immune responses to a variety of pathogens, the researchers said. It could also be used one day to fine-tune vaccines for vulnerable groups like young children, older adults, and those with compromised immune systems.

“Current vaccines are not perfect,” said lead study author Ben Ou, a PhD candidate and researcher in the lab of Eric Appel, PhD, an associate professor of materials science and engineering, at Stanford University in California. “Many fail to generate long-lasting immunity or immunity against closely related strains [such as] flu or COVID vaccines. One way to improve them is to design more potent vaccine adjuvants.”

The study marks an advance in an area of growing scientific interest: Combining different adjuvants to enhance the immune-stimulating effect.

The Stanford scientists developed sphere-shaped nanoparticles, like tiny round cages, made of saponins, immune-stimulating molecules common in adjuvant development. To these nanoparticles, they attached Toll-like receptor (TLR) agonists, molecules that have become a focus in vaccine research because they stimulate a variety of immune responses.

Dr. Ou and the team tested the new adjuvant platform in COVID and HIV vaccines, comparing it to vaccines containing alum, a widely used adjuvant. (Alum is not used in COVID vaccines available in the United States.)

The nanoparticle-adjuvanted vaccines triggered stronger, longer-lasting effects. 

Notably, the combination of the new adjuvant system with a SARS-CoV-2 virus vaccine was effective in mice against the original SARS-CoV-2 virus and against Delta, Omicron, and other variants that emerged in the months and years after the initial outbreak. 

“Since our nanoparticle adjuvant platform is more potent than traditional/clinical vaccine adjuvants,” Dr. Ou said, “we expected mice to produce broadly neutralizing antibodies and better breadth responses.”
 

100 Years of Adjuvants

The first vaccine adjuvants were aluminum salts mixed into shots against pertussis, diphtheria, and tetanus in the 1920s. Today, alum is still used in many vaccines, including shots for diphtheria, tetanus, and pertussis; hepatitis A and B; human papillomavirus; and pneumococcal disease.

But since the 1990s, new adjuvants have come on the scene. Saponin-based compounds, harvested from the soapbark tree, are used in the Novavax COVID-19 Vaccine, Adjuvanted; a synthetic DNA adjuvant in the Heplisav-B vaccine against hepatitis B; and oil in water adjuvants using squalene in the Fluad and Fluad Quadrivalent influenza vaccines. Other vaccines, including those for chickenpox, cholera, measles, mumps, rubella, and mRNA-based COVID vaccines from Pfizer-BioNTech and Moderna, don’t contain adjuvants. 

TLR agonists have recently become research hotspots in vaccine science. 

“TLR agonists activate the innate immune system, putting it on a heightened alert state that can result in a higher antibody production and longer-lasting protection,” said David Burkhart, PhD, a research professor in biomedical and pharmaceutical sciences at the University of Montana in Missoula. He is also the chief operating officer of Inimmune, a biotech company developing vaccines and immunotherapies.

Dr. Burkhart studies TLR agonists in vaccines and other applications. “Different combinations activate different parts of the immune system,” he said. “TLR4 might activate the army, while TLR7 might activate the air force. You might need both in one vaccine.”

TLR agonists have also shown promise against Alzheimer’s disease, allergies, cancer, and even addiction. In immune’s experimental immunotherapy using TLR agonists for advanced solid tumors has just entered human trials, and the company is looking at a TLR agonist therapy for allergic rhinitis. 
 

Combining Forces

In the new study, researchers tested five different combinations of TLR agonists hooked to the saponin nanoparticle framework. Each elicited a slightly different response from the immune cells. 

“Our immune systems generate different downstream immune responses based on which TLRs are activated,” Dr. Ou said.

Ultimately, the advance could spur the development of vaccines tuned for stronger immune protection.

“We need different immune responses to fight different types of pathogens,” Dr. Ou said. “Depending on what specific virus/disease the vaccine is formulated for, activation of one specific TLR may confer better protection than another TLR.”

According to Dr. Burkhart, combining a saponin with a TLR agonist has found success before.

Biopharma company GSK (formerly GlaxoSmithKline) used the combination in its AS01 adjuvant, in the vaccine Shingrix against herpes zoster. The live-attenuated yellow fever vaccine, given to more than 600 million people around the world and considered one of the most powerful vaccines ever developed, uses several TLR agonists. 

The Stanford paper, Dr. Burkhart said, “is a nice demonstration of the enhanced efficacy [that] adjuvants can provide to vaccines by exploiting the synergy different adjuvants and TLR agonists can provide when used in combination.”
 

Tailoring Vaccines

The customizable aspect of TLR agonists is important too, Dr. Burkhart said. 

“The human immune system changes dramatically from birth to childhood into adulthood into older maturity,” he said. “It’s not a one-size-fits-all. Vaccines need to be tailored to these populations for maximum effectiveness and safety. TLRAs [TLR agonists] are a highly valuable tool in the vaccine toolbox. I think it’s inevitable we’ll have more in the future.”

That’s what the Stanford researchers hope for.

They noted in the study that the nanoparticle platform could easily be used to test different TLR agonist adjuvant combinations in vaccines.

But human studies are still a ways off. Tests in larger animals would likely come next, Dr. Ou said. 

“We now have a single nanoparticle adjuvant platform with formulations containing different TLRs,” Dr. Ou said. “Scientists can pick which specific formulation is the most suitable for their needs.”

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

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

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

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.