B-Cell Lymphoma ICYMI

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

U.K. researchers have established that hypertension is associated with a 22% greater risk of severe COVID-19, with the odds of severe COVID-19 unaffected by medication type.

Hypertension “appears to be one of the commonest comorbidities in COVID-19 patients”, explained the authors of a new study, published in PLOS ONE. The authors highlighted that previous research had shown that hypertension was more prevalent in severe and fatal cases compared with all cases of COVID-19.

They pointed out, however, that whether hypertensive individuals have a higher risk of severe COVID-19, compared with nonhypertensives, and whether the absolute level of systolic blood pressure or the type of antihypertensive medication is related to this risk, remained “unclear.”

To try to answer these questions, the research team, led by University of Cambridge researchers, analyzed data from 16,134 individuals who tested positive for COVID-19 (mean age 65.3 years, 47% male, 90% white), 40% were diagnosed with essential hypertension at the analysis baseline – 22% of whom had developed severe COVID-19.

Systolic blood pressure (SBP) was categorized by 10–mm Hg ranges, starting from < 120 mm Hg up to 180+ mm Hg, with the reference category defined as 120-129 mm Hg, based on data from the SPRINT study, which demonstrated that intensive SBP lowering to below 120 mm Hg, as compared with the traditional threshold of 140 mm Hg, was beneficial. Diastolic blood pressure was categorized by 10–mm Hg ranges, starting from < 60 mm Hg up to 100+ mm Hg with 80-90 mm Hg being the reference category.

In their analyses the researchers adjusted for age, sex, body mass index, ethnicity, smoking status, diabetes status, socioeconomic status, and inflammation (C-reactive protein [CRP]), as these were proposed as potential confounders. To assess the direct effect of hypertension on COVID-19, they also adjusted for intermediate variables, including cardiovascular comorbidities and stroke, on the causal pathway between hypertension and severe COVID-19.
 

Majority of effect of hypertension on severe COVID-19 was direct

The unadjusted odds ratio of the association between hypertension and severe COVID-19 was 2.33 (95% confidence interval, 2.16-2.51), the authors emphasized. They found that, after adjusting for all confounding variables, hypertension was associated with 22% higher odds of severe COVID-19 (OR, 1.22; 95% CI, 1.12-1.33), compared with normotension.

Individuals with severe COVID-19 were marginally older, more likely to be male, and more deprived, the authors said. “They were also more likely to be hypertensive, compared with individuals without severe COVID-19, and a greater proportion of individuals with severe COVID-19 had cardiovascular comorbidities.”

The majority of the effect of hypertension on development of severe COVID-19 was “direct,” they said. However, a modest proportion of the effect was mediated via cardiovascular comorbidities such as peripheral vascular disease, MI, coronary heart disease, arrhythmias, and stroke. Of note, those with a history of stroke had a 47% higher risk of severe COVID-19 and those with a history of other cardiovascular comorbidities had a 30% higher risk of severe COVID-19, the authors commented.
 

J-shaped relationship

Of the total of 6,517 (40%) individuals who had a diagnosis of essential hypertension at baseline, 67% were treated (41% with monotherapy, 59% with combination therapy), and 33% were untreated.

There were similar numbers of severe COVID-19 in each medication group: ACE inhibitors, 34%; angiotensin receptor blockers (ARBs), 36%; and “other” medications 34%.

In hypertensive individuals receiving antihypertensive medications, there was a “J-shaped relationship” between the level of blood pressure and risk of severe COVID-19 when using a systolic blood pressure level of 120-129 mm Hg as a reference – 150-159 mm Hg versus 120-129 mm Hg (OR 1.91; 95% CI, 1.44-2.53), > 180+ mm Hg versus 120-129 mm Hg (OR 1.93; 95% CI, 1.06-3.51).

The authors commented that there was no evidence of a higher risk of severe COVID-19 until systolic blood pressure “exceeded 150 mm Hg.”

They said it was an interesting finding that “very well-controlled” systolic blood pressure < 120 mm Hg was associated with a 40% (OR, 1.40; 95% CI, 1.11-1.78) greater odds of severe COVID-19. “This may be due to reverse causality, where low systolic blood pressure levels may indicate poorer health, such that the occurrence of severe COVID-19 may be related to underlying disease rather than the level of SBP per se,” they suggested.

The J-shaped association observed remained after multiple adjustments, including presence of known cardiovascular comorbidities, which suggested a possible “real effect” of low SBP on severe COVID-19, “at least in treated hypertensive individuals.”

Their analyses also identified that, compared with a “normal” diastolic blood pressure (80-90 mm Hg), having a diastolic blood pressure higher than 90 mm Hg was associated with higher odds of severe COVID-19.

The association between hypertension and COVID-19 was “amplified” if the individuals were treated and their BP remained uncontrolled, the authors pointed out.

There did not appear to be any difference in the risk of severe COVID-19 between individuals taking ACE inhibitors and those taking ARBs or other antihypertensive medications, the authors said.
 

Better understanding of underlying mechanisms needed

Individuals with hypertension who tested positive for COVID-19 had “over twice” the risk of developing severe COVID-19, compared with nonhypertensive individuals, the authors said.

They highlighted that their findings also suggest that there are “further effects” influencing the severity of COVID-19 beyond a “dichotomous” diagnosis of hypertension.

“Individuals with a higher-than-target systolic blood pressure may be less healthy, less active, suffering more severe hypertension, or have developed drug-resistant hypertension, all suggesting that the effects of hypertension have already had detrimental physiological effects on the cardiovascular system, which in turn may offer some explanation for the higher risk of severe COVID-19 with uncontrolled SBP,” they explained.

“Hypertension is an important risk factor for COVID-19,” reiterated the authors, who emphasized that a better understanding of the underlying mechanisms driving this increased risk is warranted in case of “more severe strains or other viruses” in the future.

The authors have declared no competing interests.

A version of this article first appeared on Medscape UK.

Roughly 7% of all adult Americans may currently have had long COVID, with symptoms that have lasted 3 months or longer, according to the latest U.S. government survey done in October. More than a quarter say their condition is severe enough to significantly limit their day-to-day activities – yet the problem is only barely starting to get the attention of employers, the health care system, and policymakers.

With no cure or treatment in sight, long COVID is already burdening not only the health care system, but also the economy – and that burden is set to grow. Many experts worry about the possible long-term ripple effects, from increased spending on medical care costs to lost wages due to not being able to work, as well as the policy implications that come with addressing these issues.

“At this point, anyone who’s looking at this seriously would say this is a huge deal,” says senior Brookings Institution fellow Katie Bach, the author of a study that analyzed long COVID’s impact on the labor market.

“We need a real concerted focus on treating these people, which means both research and the clinical side, and figuring out how to build a labor market that is more inclusive of people with disabilities,” she said.

It’s not only that many people are affected. It’s that they are often affected for months and possibly even years.

The U.S. government figures suggest more than 18 million people could have symptoms of long COVID right now. The latest Household Pulse Survey by the Census Bureau and the National Center for Health Statistics takes data from 41,415 people.

A preprint of a study by researchers from City University of New York, posted on medRxiv in September and based on a similar population survey done between June 30 and July 2, drew comparable results. The study has not been peer reviewed.

More than 7% of all those who answered said they had long COVID at the time of the survey, which the researchers said corresponded to approximately 18.5 million U.S. adults. The same study found that a quarter of those, or an estimated 4.7 million adults, said their daily activities were impacted “a lot.”

This can translate into pain not only for the patients, but for governments and employers, too.

In high-income countries around the world, government surveys and other studies are shedding light on the extent to which post-COVID-19 symptoms – commonly known as long COVID – are affecting populations. While results vary, they generally fall within similar ranges.

The World Health Organization estimates that between 10% and 20% of those with COVID-19 go on to have an array of medium- to long-term post-COVID-19 symptoms that range from mild to debilitating. The U.S. Government Accountability Office puts that estimate at 10% to 30%; one of the latest studies published at the end of October in The Journal of the American Medical Association found that 15% of U.S. adults who had tested positive for COVID-19 reported current long COVID symptoms. Elsewhere, a study from the Netherlands published in The Lancet in August found that one in eight COVID-19 cases, or 12.7%, were likely to become long COVID.

“It’s very clear that the condition is devastating people’s lives and livelihoods,” WHO Director-General Tedros Adhanom Ghebreyesus wrote in an article for The Guardian newspaper in October.

“The world has already lost a significant number of the workforce to illness, death, fatigue, unplanned retirement due to an increase in long-term disability, which not only impacts the health system, but is a hit to the overarching economy … the impact of long COVID for all countries is very serious and needs immediate and sustained action equivalent to its scale.”
 

Global snapshot: Lasting symptoms, impact on activities

Patients describe a spectrum of persistent issues, with extreme fatigue, brain fog or cognitive problems, and shortness of breath among the most common complaints. Many also have manageable symptoms that worsen significantly after even mild physical or mental exertion.

Women appear almost twice as likely as men to get long COVID. Many patients have other medical conditions and disabilities that make them more vulnerable to the condition. Those who face greater obstacles accessing health care due to discrimination or socioeconomic inequity are at higher risk as well. 

While many are older, a large number are also in their prime working age. The Census Bureau data show that people ages 40-49 are more likely than any other group to get long COVID, which has broader implications for labor markets and the global economy. Already, experts have estimated that long COVID is likely to cost the U.S. trillions of dollars and affect multiple industries.

“Whether they’re in the financial world, the medical system, lawyers, they’re telling me they’re sitting at the computer screen and they’re unable to process the data,” said Zachary Schwartz, MD, medical director for Vancouver General Hospital’s Post-COVID-19 Recovery Clinic.

“That is what’s most distressing for people, in that they’re not working, they’re not making money, and they don’t know when, or if, they’re going to get better.”

Nearly a third of respondents in the Census Bureau’s Household Pulse Survey who said they have had COVID-19 reported symptoms that lasted 3 months or longer. People between the ages of 30 and 59 were the most affected, with about 32% reporting symptoms. Across the entire adult U.S. population, the survey found that 1 in 7 adults have had long COVID at some point during the pandemic, with about 1 in 18 saying it limited their activity to some degree, and 1 in 50 saying they have faced “a lot” of limits on their activities. Any way these numbers are dissected, long COVID has impacted a large swath of the population.

Yet research into the causes and possible treatments of long COVID is just getting underway.

“The amount of energy and time devoted to it is way, way less than it should, given how many people are likely affected,” said David Cutler, PhD, professor of economics at Harvard University, Cambridge, Mass., who has written about the economic cost of long COVID. “We’re way, way underdoing it here. And I think that’s really a terrible thing.”

Population surveys and studies from around the world show that long COVID lives up to its name, with people reporting serious symptoms for months on end.

In October, Statistics Canada and the Public Health Agency of Canada published early results from a questionnaire done between spring and summer 2022 that found just under 15% of adults who had a confirmed or suspected case of COVID-19 went on to have new or continuing symptoms 3 or more months later. Nearly half, or 47.3%, dealt with symptoms that lasted a year or more. More than one in five said their symptoms “often or always” limited their day-to-day activities, which included routine tasks such as preparing meals, doing errands and chores, and basic functions such as personal care and moving around in their homes.

Nearly three-quarters of workers or students said they missed an average of 20 days of work or school. 

“We haven’t yet been able to determine exactly when symptoms resolve,” said Rainu Kaushal, MD, the senior associate dean for clinical research at Weill Cornell Medicine in New York. She is co-leading a national study on long COVID in adults and children, funded by the National Institutes of Health RECOVER Initiative.

“But there does seem to be, for many of the milder symptoms, resolution at about 4-6 weeks. There seems to be a second point of resolution around 6 months for certain symptoms, and then some symptoms do seem to be permanent, and those tend to be patients who have underlying conditions,” she said.
 

Reducing the risk

Given all the data so far, experts recommend urgent policy changes to help people with long COVID.

“The population needs to be prepared, that understanding long COVID is going to be a very long and difficult process,” said Alexander Charney, MD, PhD, associate professor and the lead principal investigator of the RECOVER adult cohort at Icahn School of Medicine at Mount Sinai in New York. He said the government can do a great deal to help, including setting up a network of connected clinics treating long COVID, standardizing best practices, and sharing information.

“That would go a long way towards making sure that every person feels like they’re not too far away from a clinic where they can get treated for this particular condition,” he said.

But the only known way to prevent long COVID is to prevent COVID-19 infections in the first place, experts say. That means equitable access to tests, therapeutics, and vaccines.

“I will say that avoiding COVID remains the best treatment in the arsenal right now,” said Dr. Kaushal. This means masking, avoiding crowded places with poor ventilation and high exposure risk, and being up to date on vaccinations, she said.

A number of papers – including a large U.K. study published in May 2022, another one from July, and the JAMA study from October – all suggest that vaccinations can help reduce the risk of long COVID.

“I am absolutely of the belief that vaccination has reduced the incidence and overall amount of long COVID … [and is] still by far the best thing the public can do,” said Dr. Schwartz.

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

Roughly 7% of all adult Americans may currently have had long COVID, with symptoms that have lasted 3 months or longer, according to the latest U.S. government survey done in October. More than a quarter say their condition is severe enough to significantly limit their day-to-day activities – yet the problem is only barely starting to get the attention of employers, the health care system, and policymakers.

With no cure or treatment in sight, long COVID is already burdening not only the health care system, but also the economy – and that burden is set to grow. Many experts worry about the possible long-term ripple effects, from increased spending on medical care costs to lost wages due to not being able to work, as well as the policy implications that come with addressing these issues.

“At this point, anyone who’s looking at this seriously would say this is a huge deal,” says senior Brookings Institution fellow Katie Bach, the author of a study that analyzed long COVID’s impact on the labor market.

“We need a real concerted focus on treating these people, which means both research and the clinical side, and figuring out how to build a labor market that is more inclusive of people with disabilities,” she said.

It’s not only that many people are affected. It’s that they are often affected for months and possibly even years.

The U.S. government figures suggest more than 18 million people could have symptoms of long COVID right now. The latest Household Pulse Survey by the Census Bureau and the National Center for Health Statistics takes data from 41,415 people.

A preprint of a study by researchers from City University of New York, posted on medRxiv in September and based on a similar population survey done between June 30 and July 2, drew comparable results. The study has not been peer reviewed.

More than 7% of all those who answered said they had long COVID at the time of the survey, which the researchers said corresponded to approximately 18.5 million U.S. adults. The same study found that a quarter of those, or an estimated 4.7 million adults, said their daily activities were impacted “a lot.”

This can translate into pain not only for the patients, but for governments and employers, too.

In high-income countries around the world, government surveys and other studies are shedding light on the extent to which post-COVID-19 symptoms – commonly known as long COVID – are affecting populations. While results vary, they generally fall within similar ranges.

The World Health Organization estimates that between 10% and 20% of those with COVID-19 go on to have an array of medium- to long-term post-COVID-19 symptoms that range from mild to debilitating. The U.S. Government Accountability Office puts that estimate at 10% to 30%; one of the latest studies published at the end of October in The Journal of the American Medical Association found that 15% of U.S. adults who had tested positive for COVID-19 reported current long COVID symptoms. Elsewhere, a study from the Netherlands published in The Lancet in August found that one in eight COVID-19 cases, or 12.7%, were likely to become long COVID.

“It’s very clear that the condition is devastating people’s lives and livelihoods,” WHO Director-General Tedros Adhanom Ghebreyesus wrote in an article for The Guardian newspaper in October.

“The world has already lost a significant number of the workforce to illness, death, fatigue, unplanned retirement due to an increase in long-term disability, which not only impacts the health system, but is a hit to the overarching economy … the impact of long COVID for all countries is very serious and needs immediate and sustained action equivalent to its scale.”
 

Global snapshot: Lasting symptoms, impact on activities

Patients describe a spectrum of persistent issues, with extreme fatigue, brain fog or cognitive problems, and shortness of breath among the most common complaints. Many also have manageable symptoms that worsen significantly after even mild physical or mental exertion.

Women appear almost twice as likely as men to get long COVID. Many patients have other medical conditions and disabilities that make them more vulnerable to the condition. Those who face greater obstacles accessing health care due to discrimination or socioeconomic inequity are at higher risk as well. 

While many are older, a large number are also in their prime working age. The Census Bureau data show that people ages 40-49 are more likely than any other group to get long COVID, which has broader implications for labor markets and the global economy. Already, experts have estimated that long COVID is likely to cost the U.S. trillions of dollars and affect multiple industries.

“Whether they’re in the financial world, the medical system, lawyers, they’re telling me they’re sitting at the computer screen and they’re unable to process the data,” said Zachary Schwartz, MD, medical director for Vancouver General Hospital’s Post-COVID-19 Recovery Clinic.

“That is what’s most distressing for people, in that they’re not working, they’re not making money, and they don’t know when, or if, they’re going to get better.”

Nearly a third of respondents in the Census Bureau’s Household Pulse Survey who said they have had COVID-19 reported symptoms that lasted 3 months or longer. People between the ages of 30 and 59 were the most affected, with about 32% reporting symptoms. Across the entire adult U.S. population, the survey found that 1 in 7 adults have had long COVID at some point during the pandemic, with about 1 in 18 saying it limited their activity to some degree, and 1 in 50 saying they have faced “a lot” of limits on their activities. Any way these numbers are dissected, long COVID has impacted a large swath of the population.

Yet research into the causes and possible treatments of long COVID is just getting underway.

“The amount of energy and time devoted to it is way, way less than it should, given how many people are likely affected,” said David Cutler, PhD, professor of economics at Harvard University, Cambridge, Mass., who has written about the economic cost of long COVID. “We’re way, way underdoing it here. And I think that’s really a terrible thing.”

Population surveys and studies from around the world show that long COVID lives up to its name, with people reporting serious symptoms for months on end.

In October, Statistics Canada and the Public Health Agency of Canada published early results from a questionnaire done between spring and summer 2022 that found just under 15% of adults who had a confirmed or suspected case of COVID-19 went on to have new or continuing symptoms 3 or more months later. Nearly half, or 47.3%, dealt with symptoms that lasted a year or more. More than one in five said their symptoms “often or always” limited their day-to-day activities, which included routine tasks such as preparing meals, doing errands and chores, and basic functions such as personal care and moving around in their homes.

Nearly three-quarters of workers or students said they missed an average of 20 days of work or school. 

“We haven’t yet been able to determine exactly when symptoms resolve,” said Rainu Kaushal, MD, the senior associate dean for clinical research at Weill Cornell Medicine in New York. She is co-leading a national study on long COVID in adults and children, funded by the National Institutes of Health RECOVER Initiative.

“But there does seem to be, for many of the milder symptoms, resolution at about 4-6 weeks. There seems to be a second point of resolution around 6 months for certain symptoms, and then some symptoms do seem to be permanent, and those tend to be patients who have underlying conditions,” she said.
 

Reducing the risk

Given all the data so far, experts recommend urgent policy changes to help people with long COVID.

“The population needs to be prepared, that understanding long COVID is going to be a very long and difficult process,” said Alexander Charney, MD, PhD, associate professor and the lead principal investigator of the RECOVER adult cohort at Icahn School of Medicine at Mount Sinai in New York. He said the government can do a great deal to help, including setting up a network of connected clinics treating long COVID, standardizing best practices, and sharing information.

“That would go a long way towards making sure that every person feels like they’re not too far away from a clinic where they can get treated for this particular condition,” he said.

But the only known way to prevent long COVID is to prevent COVID-19 infections in the first place, experts say. That means equitable access to tests, therapeutics, and vaccines.

“I will say that avoiding COVID remains the best treatment in the arsenal right now,” said Dr. Kaushal. This means masking, avoiding crowded places with poor ventilation and high exposure risk, and being up to date on vaccinations, she said.

A number of papers – including a large U.K. study published in May 2022, another one from July, and the JAMA study from October – all suggest that vaccinations can help reduce the risk of long COVID.

“I am absolutely of the belief that vaccination has reduced the incidence and overall amount of long COVID … [and is] still by far the best thing the public can do,” said Dr. Schwartz.

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

Roughly 7% of all adult Americans may currently have had long COVID, with symptoms that have lasted 3 months or longer, according to the latest U.S. government survey done in October. More than a quarter say their condition is severe enough to significantly limit their day-to-day activities – yet the problem is only barely starting to get the attention of employers, the health care system, and policymakers.

With no cure or treatment in sight, long COVID is already burdening not only the health care system, but also the economy – and that burden is set to grow. Many experts worry about the possible long-term ripple effects, from increased spending on medical care costs to lost wages due to not being able to work, as well as the policy implications that come with addressing these issues.

“At this point, anyone who’s looking at this seriously would say this is a huge deal,” says senior Brookings Institution fellow Katie Bach, the author of a study that analyzed long COVID’s impact on the labor market.

“We need a real concerted focus on treating these people, which means both research and the clinical side, and figuring out how to build a labor market that is more inclusive of people with disabilities,” she said.

It’s not only that many people are affected. It’s that they are often affected for months and possibly even years.

The U.S. government figures suggest more than 18 million people could have symptoms of long COVID right now. The latest Household Pulse Survey by the Census Bureau and the National Center for Health Statistics takes data from 41,415 people.

A preprint of a study by researchers from City University of New York, posted on medRxiv in September and based on a similar population survey done between June 30 and July 2, drew comparable results. The study has not been peer reviewed.

More than 7% of all those who answered said they had long COVID at the time of the survey, which the researchers said corresponded to approximately 18.5 million U.S. adults. The same study found that a quarter of those, or an estimated 4.7 million adults, said their daily activities were impacted “a lot.”

This can translate into pain not only for the patients, but for governments and employers, too.

In high-income countries around the world, government surveys and other studies are shedding light on the extent to which post-COVID-19 symptoms – commonly known as long COVID – are affecting populations. While results vary, they generally fall within similar ranges.

The World Health Organization estimates that between 10% and 20% of those with COVID-19 go on to have an array of medium- to long-term post-COVID-19 symptoms that range from mild to debilitating. The U.S. Government Accountability Office puts that estimate at 10% to 30%; one of the latest studies published at the end of October in The Journal of the American Medical Association found that 15% of U.S. adults who had tested positive for COVID-19 reported current long COVID symptoms. Elsewhere, a study from the Netherlands published in The Lancet in August found that one in eight COVID-19 cases, or 12.7%, were likely to become long COVID.

“It’s very clear that the condition is devastating people’s lives and livelihoods,” WHO Director-General Tedros Adhanom Ghebreyesus wrote in an article for The Guardian newspaper in October.

“The world has already lost a significant number of the workforce to illness, death, fatigue, unplanned retirement due to an increase in long-term disability, which not only impacts the health system, but is a hit to the overarching economy … the impact of long COVID for all countries is very serious and needs immediate and sustained action equivalent to its scale.”
 

Global snapshot: Lasting symptoms, impact on activities

Patients describe a spectrum of persistent issues, with extreme fatigue, brain fog or cognitive problems, and shortness of breath among the most common complaints. Many also have manageable symptoms that worsen significantly after even mild physical or mental exertion.

Women appear almost twice as likely as men to get long COVID. Many patients have other medical conditions and disabilities that make them more vulnerable to the condition. Those who face greater obstacles accessing health care due to discrimination or socioeconomic inequity are at higher risk as well. 

While many are older, a large number are also in their prime working age. The Census Bureau data show that people ages 40-49 are more likely than any other group to get long COVID, which has broader implications for labor markets and the global economy. Already, experts have estimated that long COVID is likely to cost the U.S. trillions of dollars and affect multiple industries.

“Whether they’re in the financial world, the medical system, lawyers, they’re telling me they’re sitting at the computer screen and they’re unable to process the data,” said Zachary Schwartz, MD, medical director for Vancouver General Hospital’s Post-COVID-19 Recovery Clinic.

“That is what’s most distressing for people, in that they’re not working, they’re not making money, and they don’t know when, or if, they’re going to get better.”

Nearly a third of respondents in the Census Bureau’s Household Pulse Survey who said they have had COVID-19 reported symptoms that lasted 3 months or longer. People between the ages of 30 and 59 were the most affected, with about 32% reporting symptoms. Across the entire adult U.S. population, the survey found that 1 in 7 adults have had long COVID at some point during the pandemic, with about 1 in 18 saying it limited their activity to some degree, and 1 in 50 saying they have faced “a lot” of limits on their activities. Any way these numbers are dissected, long COVID has impacted a large swath of the population.

Yet research into the causes and possible treatments of long COVID is just getting underway.

“The amount of energy and time devoted to it is way, way less than it should, given how many people are likely affected,” said David Cutler, PhD, professor of economics at Harvard University, Cambridge, Mass., who has written about the economic cost of long COVID. “We’re way, way underdoing it here. And I think that’s really a terrible thing.”

Population surveys and studies from around the world show that long COVID lives up to its name, with people reporting serious symptoms for months on end.

In October, Statistics Canada and the Public Health Agency of Canada published early results from a questionnaire done between spring and summer 2022 that found just under 15% of adults who had a confirmed or suspected case of COVID-19 went on to have new or continuing symptoms 3 or more months later. Nearly half, or 47.3%, dealt with symptoms that lasted a year or more. More than one in five said their symptoms “often or always” limited their day-to-day activities, which included routine tasks such as preparing meals, doing errands and chores, and basic functions such as personal care and moving around in their homes.

Nearly three-quarters of workers or students said they missed an average of 20 days of work or school. 

“We haven’t yet been able to determine exactly when symptoms resolve,” said Rainu Kaushal, MD, the senior associate dean for clinical research at Weill Cornell Medicine in New York. She is co-leading a national study on long COVID in adults and children, funded by the National Institutes of Health RECOVER Initiative.

“But there does seem to be, for many of the milder symptoms, resolution at about 4-6 weeks. There seems to be a second point of resolution around 6 months for certain symptoms, and then some symptoms do seem to be permanent, and those tend to be patients who have underlying conditions,” she said.
 

Reducing the risk

Given all the data so far, experts recommend urgent policy changes to help people with long COVID.

“The population needs to be prepared, that understanding long COVID is going to be a very long and difficult process,” said Alexander Charney, MD, PhD, associate professor and the lead principal investigator of the RECOVER adult cohort at Icahn School of Medicine at Mount Sinai in New York. He said the government can do a great deal to help, including setting up a network of connected clinics treating long COVID, standardizing best practices, and sharing information.

“That would go a long way towards making sure that every person feels like they’re not too far away from a clinic where they can get treated for this particular condition,” he said.

But the only known way to prevent long COVID is to prevent COVID-19 infections in the first place, experts say. That means equitable access to tests, therapeutics, and vaccines.

“I will say that avoiding COVID remains the best treatment in the arsenal right now,” said Dr. Kaushal. This means masking, avoiding crowded places with poor ventilation and high exposure risk, and being up to date on vaccinations, she said.

A number of papers – including a large U.K. study published in May 2022, another one from July, and the JAMA study from October – all suggest that vaccinations can help reduce the risk of long COVID.

“I am absolutely of the belief that vaccination has reduced the incidence and overall amount of long COVID … [and is] still by far the best thing the public can do,” said Dr. Schwartz.

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

Dementia prevalence is dropping in the United States, new research shows. New data from the Health and Retirement Study, a nationally representative survey, show that the prevalence of dementia among individuals aged 65 and older dropped from 12.2% in 2000 to 8.5% in 2016 – a 30.1% decrease. In men, the prevalence of dementia fell from 10.2% to 7.0%, while for women, it declined from 13.6% to 9.7%, researchers reported. Their finding were published online in PNAS.

The study also revealed that the proportion of college-educated men in the sample increased from 21.5% in 2000 to 33.7% in 2016, while the proportion of college-educated women increased from 12.3% in 2000 to 23% in 2016.

The findings also show a decline in the dementia prevalence in non-Hispanic Black men, which dropped from 17.2% to 9.9%, a decrease of 42.6%. In non-Hispanic White men, dementia declined 9.3% to 6.6%, or 29.0%.

The investigators also found a substantial increase in the level of education between 2000 and 2016. In addition, they found that, among 74- to 84-year-old women in 2000, 29.5% had worked for more than 30 years during their lifetime versus 59.0% in 2016.

The investigators speculated that the decline in dementia prevalence reflects larger socioeconomic changes in the United States as well as prevention strategies to reduce cardiovascular disease.

A person born around 1920, for example, would have had greater exposure to the Great Depression, while someone born in 1936 would have benefited more from the changes in living standards in the years following World War II, they noted.

“There’s a need for more research on the effect of employment on cognitive reserve. It’s plausible that working is good for your mental cognitive abilities,” said study investigator Péter Hudomiet, PhD, from the RAND Corporation, adding that there may also be benefits that extend beyond working years. It’s possible that women’s greater participation in the workforce gives them more chances to establish relationships that in some cases last well into retirement and provide essential social connection. It’s well known that social isolation has a negative impact on cognition.

“It’s plausible that working is good for your mental cognitive abilities,” he added.

The investigators noted that it is beyond the scope of their study to draw definitive conclusions about the causes of the decline, but they observed that positive trends in employment and standard of living make sense. “They would suggest that as schooling levels continue to rise in the U.S. population in younger generations, the prevalence of dementia would continue to decrease.

The investigators report no relevant financial relationships.

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

Dementia prevalence is dropping in the United States, new research shows. New data from the Health and Retirement Study, a nationally representative survey, show that the prevalence of dementia among individuals aged 65 and older dropped from 12.2% in 2000 to 8.5% in 2016 – a 30.1% decrease. In men, the prevalence of dementia fell from 10.2% to 7.0%, while for women, it declined from 13.6% to 9.7%, researchers reported. Their finding were published online in PNAS.

The study also revealed that the proportion of college-educated men in the sample increased from 21.5% in 2000 to 33.7% in 2016, while the proportion of college-educated women increased from 12.3% in 2000 to 23% in 2016.

The findings also show a decline in the dementia prevalence in non-Hispanic Black men, which dropped from 17.2% to 9.9%, a decrease of 42.6%. In non-Hispanic White men, dementia declined 9.3% to 6.6%, or 29.0%.

The investigators also found a substantial increase in the level of education between 2000 and 2016. In addition, they found that, among 74- to 84-year-old women in 2000, 29.5% had worked for more than 30 years during their lifetime versus 59.0% in 2016.

The investigators speculated that the decline in dementia prevalence reflects larger socioeconomic changes in the United States as well as prevention strategies to reduce cardiovascular disease.

A person born around 1920, for example, would have had greater exposure to the Great Depression, while someone born in 1936 would have benefited more from the changes in living standards in the years following World War II, they noted.

“There’s a need for more research on the effect of employment on cognitive reserve. It’s plausible that working is good for your mental cognitive abilities,” said study investigator Péter Hudomiet, PhD, from the RAND Corporation, adding that there may also be benefits that extend beyond working years. It’s possible that women’s greater participation in the workforce gives them more chances to establish relationships that in some cases last well into retirement and provide essential social connection. It’s well known that social isolation has a negative impact on cognition.

“It’s plausible that working is good for your mental cognitive abilities,” he added.

The investigators noted that it is beyond the scope of their study to draw definitive conclusions about the causes of the decline, but they observed that positive trends in employment and standard of living make sense. “They would suggest that as schooling levels continue to rise in the U.S. population in younger generations, the prevalence of dementia would continue to decrease.

The investigators report no relevant financial relationships.

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

Dementia prevalence is dropping in the United States, new research shows. New data from the Health and Retirement Study, a nationally representative survey, show that the prevalence of dementia among individuals aged 65 and older dropped from 12.2% in 2000 to 8.5% in 2016 – a 30.1% decrease. In men, the prevalence of dementia fell from 10.2% to 7.0%, while for women, it declined from 13.6% to 9.7%, researchers reported. Their finding were published online in PNAS.

The study also revealed that the proportion of college-educated men in the sample increased from 21.5% in 2000 to 33.7% in 2016, while the proportion of college-educated women increased from 12.3% in 2000 to 23% in 2016.

The findings also show a decline in the dementia prevalence in non-Hispanic Black men, which dropped from 17.2% to 9.9%, a decrease of 42.6%. In non-Hispanic White men, dementia declined 9.3% to 6.6%, or 29.0%.

The investigators also found a substantial increase in the level of education between 2000 and 2016. In addition, they found that, among 74- to 84-year-old women in 2000, 29.5% had worked for more than 30 years during their lifetime versus 59.0% in 2016.

The investigators speculated that the decline in dementia prevalence reflects larger socioeconomic changes in the United States as well as prevention strategies to reduce cardiovascular disease.

A person born around 1920, for example, would have had greater exposure to the Great Depression, while someone born in 1936 would have benefited more from the changes in living standards in the years following World War II, they noted.

“There’s a need for more research on the effect of employment on cognitive reserve. It’s plausible that working is good for your mental cognitive abilities,” said study investigator Péter Hudomiet, PhD, from the RAND Corporation, adding that there may also be benefits that extend beyond working years. It’s possible that women’s greater participation in the workforce gives them more chances to establish relationships that in some cases last well into retirement and provide essential social connection. It’s well known that social isolation has a negative impact on cognition.

“It’s plausible that working is good for your mental cognitive abilities,” he added.

The investigators noted that it is beyond the scope of their study to draw definitive conclusions about the causes of the decline, but they observed that positive trends in employment and standard of living make sense. “They would suggest that as schooling levels continue to rise in the U.S. population in younger generations, the prevalence of dementia would continue to decrease.

The investigators report no relevant financial relationships.

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

Many Americans turn to the latest big idea to lose weight – fad diets, fitness crazes, dodgy herbs and pills, bariatric surgery, just to name a few. They’re rarely the magic solution people dream of.

Now a wave of startups offer access to a new category of drugs coupled with intensive behavioral coaching online. But already concerns are emerging.

These startups, spurred by hundreds of millions of dollars in funding from blue-chip venture capital firms, have signed up well over 100,000 patients and could reach millions more. These patients pay hundreds, if not thousands, of dollars to access new drugs, called glucagonlike peptide–1 (GLP-1) agonists, along with online coaching to encourage healthy habits.

The startups initially positioned themselves in lofty terms. “This is the last weight-loss program you’ll try,” said a 2020 marketing analysis by startup Calibrate Health, in messaging designed to reach one of its target demographics, the “working mom.” (Company spokesperson Michelle Wellington said the document does not reflect Calibrate’s current marketing strategy.)

But while doctors and patients are intrigued by the new model, some customers complain online that reality is short of the buildup: They say they got canned advice and unresponsive clinicians – and some report they couldn’t get the newest drugs.

Calibrate Health, a New York City–based startup, reported earlier in 2022 it had served 20,000 people. Another startup, Found, headquartered in San Francisco, has served 135,000 patients since July 2020, CEO Sarah Jones Simmer said in an interview. Calibrate costs patients nearly $1,600 a year, not counting the price of drugs, which can hit nearly $1,500 monthly without insurance, according to drug price savings site GoodRx. (Insurers reimburse for GLP-1agonists in limited circumstances, patients said.) Found offers a 6-month plan for nearly $600, a company spokesperson said. (That price includes generic drugs, but not the newer GLP-1 agonists, like Wegovy.)

The two companies are beneficiaries of over $200 million in combined venture funding, according to tracking by Crunchbase, a repository of venture capital investments. The firms say they’re on the vanguard of weight care, both citing the influence of biology and other scientific factors as key ingredients to their approaches.

There’s potentially a big market for these startups. Just over 4 in 10 Americans are obese, according to the Centers for Disease Control and Prevention, driving up their risk for cardiovascular conditions and type 2 diabetes. Effective medical treatments are elusive and hard to access.

Centers that provide this specialty care “are overwhelmed,” said Fatima Stanford, MD, an obesity medicine specialist at Massachusetts General in Boston, a teaching hospital affiliated with Harvard. Her own clinic has a wait list of 3,000.

Dr. Stanford, who said she has advised several of these telemedicine startups, is bullish on their potential.

Scott Butsch, MD, director of obesity medicine at the Cleveland Clinic, said the startups can offer care with less judgment and stigma than in-person peers. They’re also more convenient.

Dr. Butsch, who learned about the model through consultancies, patients, and colleagues, wonders whether the startups are operating “to strategically find which patients respond to which drug.” He said they should coordinate well with behavioral specialists, as antidepressants or other medications may be driving weight gain. “Obesity is a complex disease and requires treatments that match its complexity. I think programs that do not have a multidisciplinary team are less comprehensive and, in the long term, less effective.”

The startups market a two-pronged product: first, the new class of GLP-1 agonists. While these medications are effective at provoking weight loss, Wegovy, one of two in this class specifically approved for this purpose, is in short supply because of manufacturing difficulties, according to its maker, Novo Nordisk. Others in the category can be prescribed off label. But doctors generally aren’t familiar with the medications, Stanford said. In theory, the startups can bridge some of those gaps: They offer more specialized, knowledgeable clinicians.

Then there’s the other prong: behavioral changes. The companies use televisits and online messaging with nutritionists or coaches to help patients incorporate new diet and exercise habits. The weight loss figures achieved by participants in clinical trials for the new drugs – up to 15% of body mass – were tied to such changes, according to Novo Nordisk.

Social media sites are bursting with these startups’ ads, everywhere from podcasts to Instagram. A search of Meta’s ad library finds 40,000 ads on Facebook and Instagram between the two firms.

The ads complement people’s own postings on social media: Numerous Facebook groups are devoted to the new type of drugs – some even focused on helping patients manage side effects, like changes in their bowel movements. The buzz is quantifiable: On TikTok, mentions of the new GLP-1 agonists tripled from last June to this June, according to an analysis by investment bankers at Morgan Stanley.

There’s now a feverish, expectant appetite for these medications among the startups’ clientele. Patients often complained that their friends had obtained a drug they weren’t offered, recalled Alexandra Coults, a former pharmacist consultant for Found. Ms. Coults said patients may have perceived some sort of bait-and-switch when in reality clinical reasons – like drug contraindications – guide prescribing decisions.

Patient expectations influence care, Ms. Coults said. Customers came in with ideas shaped by the culture of fad diets and New Year’s resolutions. “Quite a few people would sign up for 1 month and not continue.”

In interviews with KHN and in online complaints, patients also questioned the quality of care they received. Some said intake – which began by filling out a form and proceeded to an online visit with a doctor – was perfunctory. Once medication began, they said, requests for counseling about side effects were slow to be answered.

Jess Garrant, a Found patient, recalled that after she was prescribed zonisamide, a generic anticonvulsant that has shown some ability to help with weight loss, she felt “absolutely weird.”

“I was up all night and my thoughts were racing,” she wrote in a blog post. She developed sores in her mouth.

She sought advice and help from Found physicians, but their replies “weren’t quick.” Nonemergency communications are routed through the company’s portal.

It took a week to complete a switch of medications and have a new prescription arrive at her home, she said. Meanwhile, she said, she went to an urgent care clinic for the mouth sores.

Found frequently prescribes generic medications – often off label – rather than just the new GLP-1 agonists, company executives said in an interview. Found said older generics like zonisamide are more accessible than the GLP-1 agonists advertised on social media and their own website. Both Dr. Butsch and Dr. Stanford said they’ve prescribed zonisamide successfully. Dr. Butsch said ramping up dosage rapidly can increase the risk of side effects.

But Kim Boyd, MD, chief medical officer of competitor Calibrate, said the older drugs “just haven’t worked.”

Patients of both companies have critiqued online and in interviews the startups’ behavioral care – which experts across the board maintain is integral to successful weight loss treatment. But some patients felt they simply had canned advice.

Other patients said they had ups and downs with their coaches. Dana Crom, an attorney, said she had gone through many coaches with Calibrate. Some were good, effective cheerleaders; others, not so good. But when kinks in the program arose, she said, the coach wasn’t able to help her navigate them. While the coach can report trouble with medications or the app, it appears those reports are no more effective than messages sent through the portal, Ms. Crom said.

And what about when her yearlong subscription ends? Ms. Crom said she’d consider continuing with Calibrate.

Relationships with coaches, given the need to change behavior, are a critical element of the business models. Patients’ results depend “on how adherent they are to lifestyle changes,” said Found’s chief medical officer, Rehka Kumar, MD.

While the startups offer care to a larger geographic footprint, it’s not clear whether the demographics of their patient populations are different from those of the traditional bricks-and-mortar model. Calibrate’s patients are overwhelmingly White; over 8 in 10 have at least an undergraduate degree; and over 8 in 10 are women, according to the company.

And its earlier marketing strategies reflected that. The September 2020 “segmentation” document laid out three types of customers the company could hope to attract: perimenopausal or menopausal women, with income ranging from $75,000 to $150,000 a year; working mothers, with a similar income; and “men.”

Isabelle Kenyon, Calibrate’s CEO, said the company now hopes to expand its reach to partner with large employers, and that will help diversify its patients.

Patients will need to be convinced that the model – more affordable, more accessible – works for them. For her part, Ms. Garrant, who no longer is using Found, reflected on her experience, writing in her blog post that she was hoping for more follow-up and a more personal approach. “I don’t think it’s a helpful way to lose weight,” she said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Many Americans turn to the latest big idea to lose weight – fad diets, fitness crazes, dodgy herbs and pills, bariatric surgery, just to name a few. They’re rarely the magic solution people dream of.

Now a wave of startups offer access to a new category of drugs coupled with intensive behavioral coaching online. But already concerns are emerging.

These startups, spurred by hundreds of millions of dollars in funding from blue-chip venture capital firms, have signed up well over 100,000 patients and could reach millions more. These patients pay hundreds, if not thousands, of dollars to access new drugs, called glucagonlike peptide–1 (GLP-1) agonists, along with online coaching to encourage healthy habits.

The startups initially positioned themselves in lofty terms. “This is the last weight-loss program you’ll try,” said a 2020 marketing analysis by startup Calibrate Health, in messaging designed to reach one of its target demographics, the “working mom.” (Company spokesperson Michelle Wellington said the document does not reflect Calibrate’s current marketing strategy.)

But while doctors and patients are intrigued by the new model, some customers complain online that reality is short of the buildup: They say they got canned advice and unresponsive clinicians – and some report they couldn’t get the newest drugs.

Calibrate Health, a New York City–based startup, reported earlier in 2022 it had served 20,000 people. Another startup, Found, headquartered in San Francisco, has served 135,000 patients since July 2020, CEO Sarah Jones Simmer said in an interview. Calibrate costs patients nearly $1,600 a year, not counting the price of drugs, which can hit nearly $1,500 monthly without insurance, according to drug price savings site GoodRx. (Insurers reimburse for GLP-1agonists in limited circumstances, patients said.) Found offers a 6-month plan for nearly $600, a company spokesperson said. (That price includes generic drugs, but not the newer GLP-1 agonists, like Wegovy.)

The two companies are beneficiaries of over $200 million in combined venture funding, according to tracking by Crunchbase, a repository of venture capital investments. The firms say they’re on the vanguard of weight care, both citing the influence of biology and other scientific factors as key ingredients to their approaches.

There’s potentially a big market for these startups. Just over 4 in 10 Americans are obese, according to the Centers for Disease Control and Prevention, driving up their risk for cardiovascular conditions and type 2 diabetes. Effective medical treatments are elusive and hard to access.

Centers that provide this specialty care “are overwhelmed,” said Fatima Stanford, MD, an obesity medicine specialist at Massachusetts General in Boston, a teaching hospital affiliated with Harvard. Her own clinic has a wait list of 3,000.

Dr. Stanford, who said she has advised several of these telemedicine startups, is bullish on their potential.

Scott Butsch, MD, director of obesity medicine at the Cleveland Clinic, said the startups can offer care with less judgment and stigma than in-person peers. They’re also more convenient.

Dr. Butsch, who learned about the model through consultancies, patients, and colleagues, wonders whether the startups are operating “to strategically find which patients respond to which drug.” He said they should coordinate well with behavioral specialists, as antidepressants or other medications may be driving weight gain. “Obesity is a complex disease and requires treatments that match its complexity. I think programs that do not have a multidisciplinary team are less comprehensive and, in the long term, less effective.”

The startups market a two-pronged product: first, the new class of GLP-1 agonists. While these medications are effective at provoking weight loss, Wegovy, one of two in this class specifically approved for this purpose, is in short supply because of manufacturing difficulties, according to its maker, Novo Nordisk. Others in the category can be prescribed off label. But doctors generally aren’t familiar with the medications, Stanford said. In theory, the startups can bridge some of those gaps: They offer more specialized, knowledgeable clinicians.

Then there’s the other prong: behavioral changes. The companies use televisits and online messaging with nutritionists or coaches to help patients incorporate new diet and exercise habits. The weight loss figures achieved by participants in clinical trials for the new drugs – up to 15% of body mass – were tied to such changes, according to Novo Nordisk.

Social media sites are bursting with these startups’ ads, everywhere from podcasts to Instagram. A search of Meta’s ad library finds 40,000 ads on Facebook and Instagram between the two firms.

The ads complement people’s own postings on social media: Numerous Facebook groups are devoted to the new type of drugs – some even focused on helping patients manage side effects, like changes in their bowel movements. The buzz is quantifiable: On TikTok, mentions of the new GLP-1 agonists tripled from last June to this June, according to an analysis by investment bankers at Morgan Stanley.

There’s now a feverish, expectant appetite for these medications among the startups’ clientele. Patients often complained that their friends had obtained a drug they weren’t offered, recalled Alexandra Coults, a former pharmacist consultant for Found. Ms. Coults said patients may have perceived some sort of bait-and-switch when in reality clinical reasons – like drug contraindications – guide prescribing decisions.

Patient expectations influence care, Ms. Coults said. Customers came in with ideas shaped by the culture of fad diets and New Year’s resolutions. “Quite a few people would sign up for 1 month and not continue.”

In interviews with KHN and in online complaints, patients also questioned the quality of care they received. Some said intake – which began by filling out a form and proceeded to an online visit with a doctor – was perfunctory. Once medication began, they said, requests for counseling about side effects were slow to be answered.

Jess Garrant, a Found patient, recalled that after she was prescribed zonisamide, a generic anticonvulsant that has shown some ability to help with weight loss, she felt “absolutely weird.”

“I was up all night and my thoughts were racing,” she wrote in a blog post. She developed sores in her mouth.

She sought advice and help from Found physicians, but their replies “weren’t quick.” Nonemergency communications are routed through the company’s portal.

It took a week to complete a switch of medications and have a new prescription arrive at her home, she said. Meanwhile, she said, she went to an urgent care clinic for the mouth sores.

Found frequently prescribes generic medications – often off label – rather than just the new GLP-1 agonists, company executives said in an interview. Found said older generics like zonisamide are more accessible than the GLP-1 agonists advertised on social media and their own website. Both Dr. Butsch and Dr. Stanford said they’ve prescribed zonisamide successfully. Dr. Butsch said ramping up dosage rapidly can increase the risk of side effects.

But Kim Boyd, MD, chief medical officer of competitor Calibrate, said the older drugs “just haven’t worked.”

Patients of both companies have critiqued online and in interviews the startups’ behavioral care – which experts across the board maintain is integral to successful weight loss treatment. But some patients felt they simply had canned advice.

Other patients said they had ups and downs with their coaches. Dana Crom, an attorney, said she had gone through many coaches with Calibrate. Some were good, effective cheerleaders; others, not so good. But when kinks in the program arose, she said, the coach wasn’t able to help her navigate them. While the coach can report trouble with medications or the app, it appears those reports are no more effective than messages sent through the portal, Ms. Crom said.

And what about when her yearlong subscription ends? Ms. Crom said she’d consider continuing with Calibrate.

Relationships with coaches, given the need to change behavior, are a critical element of the business models. Patients’ results depend “on how adherent they are to lifestyle changes,” said Found’s chief medical officer, Rehka Kumar, MD.

While the startups offer care to a larger geographic footprint, it’s not clear whether the demographics of their patient populations are different from those of the traditional bricks-and-mortar model. Calibrate’s patients are overwhelmingly White; over 8 in 10 have at least an undergraduate degree; and over 8 in 10 are women, according to the company.

And its earlier marketing strategies reflected that. The September 2020 “segmentation” document laid out three types of customers the company could hope to attract: perimenopausal or menopausal women, with income ranging from $75,000 to $150,000 a year; working mothers, with a similar income; and “men.”

Isabelle Kenyon, Calibrate’s CEO, said the company now hopes to expand its reach to partner with large employers, and that will help diversify its patients.

Patients will need to be convinced that the model – more affordable, more accessible – works for them. For her part, Ms. Garrant, who no longer is using Found, reflected on her experience, writing in her blog post that she was hoping for more follow-up and a more personal approach. “I don’t think it’s a helpful way to lose weight,” she said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Many Americans turn to the latest big idea to lose weight – fad diets, fitness crazes, dodgy herbs and pills, bariatric surgery, just to name a few. They’re rarely the magic solution people dream of.

Now a wave of startups offer access to a new category of drugs coupled with intensive behavioral coaching online. But already concerns are emerging.

These startups, spurred by hundreds of millions of dollars in funding from blue-chip venture capital firms, have signed up well over 100,000 patients and could reach millions more. These patients pay hundreds, if not thousands, of dollars to access new drugs, called glucagonlike peptide–1 (GLP-1) agonists, along with online coaching to encourage healthy habits.

The startups initially positioned themselves in lofty terms. “This is the last weight-loss program you’ll try,” said a 2020 marketing analysis by startup Calibrate Health, in messaging designed to reach one of its target demographics, the “working mom.” (Company spokesperson Michelle Wellington said the document does not reflect Calibrate’s current marketing strategy.)

But while doctors and patients are intrigued by the new model, some customers complain online that reality is short of the buildup: They say they got canned advice and unresponsive clinicians – and some report they couldn’t get the newest drugs.

Calibrate Health, a New York City–based startup, reported earlier in 2022 it had served 20,000 people. Another startup, Found, headquartered in San Francisco, has served 135,000 patients since July 2020, CEO Sarah Jones Simmer said in an interview. Calibrate costs patients nearly $1,600 a year, not counting the price of drugs, which can hit nearly $1,500 monthly without insurance, according to drug price savings site GoodRx. (Insurers reimburse for GLP-1agonists in limited circumstances, patients said.) Found offers a 6-month plan for nearly $600, a company spokesperson said. (That price includes generic drugs, but not the newer GLP-1 agonists, like Wegovy.)

The two companies are beneficiaries of over $200 million in combined venture funding, according to tracking by Crunchbase, a repository of venture capital investments. The firms say they’re on the vanguard of weight care, both citing the influence of biology and other scientific factors as key ingredients to their approaches.

There’s potentially a big market for these startups. Just over 4 in 10 Americans are obese, according to the Centers for Disease Control and Prevention, driving up their risk for cardiovascular conditions and type 2 diabetes. Effective medical treatments are elusive and hard to access.

Centers that provide this specialty care “are overwhelmed,” said Fatima Stanford, MD, an obesity medicine specialist at Massachusetts General in Boston, a teaching hospital affiliated with Harvard. Her own clinic has a wait list of 3,000.

Dr. Stanford, who said she has advised several of these telemedicine startups, is bullish on their potential.

Scott Butsch, MD, director of obesity medicine at the Cleveland Clinic, said the startups can offer care with less judgment and stigma than in-person peers. They’re also more convenient.

Dr. Butsch, who learned about the model through consultancies, patients, and colleagues, wonders whether the startups are operating “to strategically find which patients respond to which drug.” He said they should coordinate well with behavioral specialists, as antidepressants or other medications may be driving weight gain. “Obesity is a complex disease and requires treatments that match its complexity. I think programs that do not have a multidisciplinary team are less comprehensive and, in the long term, less effective.”

The startups market a two-pronged product: first, the new class of GLP-1 agonists. While these medications are effective at provoking weight loss, Wegovy, one of two in this class specifically approved for this purpose, is in short supply because of manufacturing difficulties, according to its maker, Novo Nordisk. Others in the category can be prescribed off label. But doctors generally aren’t familiar with the medications, Stanford said. In theory, the startups can bridge some of those gaps: They offer more specialized, knowledgeable clinicians.

Then there’s the other prong: behavioral changes. The companies use televisits and online messaging with nutritionists or coaches to help patients incorporate new diet and exercise habits. The weight loss figures achieved by participants in clinical trials for the new drugs – up to 15% of body mass – were tied to such changes, according to Novo Nordisk.

Social media sites are bursting with these startups’ ads, everywhere from podcasts to Instagram. A search of Meta’s ad library finds 40,000 ads on Facebook and Instagram between the two firms.

The ads complement people’s own postings on social media: Numerous Facebook groups are devoted to the new type of drugs – some even focused on helping patients manage side effects, like changes in their bowel movements. The buzz is quantifiable: On TikTok, mentions of the new GLP-1 agonists tripled from last June to this June, according to an analysis by investment bankers at Morgan Stanley.

There’s now a feverish, expectant appetite for these medications among the startups’ clientele. Patients often complained that their friends had obtained a drug they weren’t offered, recalled Alexandra Coults, a former pharmacist consultant for Found. Ms. Coults said patients may have perceived some sort of bait-and-switch when in reality clinical reasons – like drug contraindications – guide prescribing decisions.

Patient expectations influence care, Ms. Coults said. Customers came in with ideas shaped by the culture of fad diets and New Year’s resolutions. “Quite a few people would sign up for 1 month and not continue.”

In interviews with KHN and in online complaints, patients also questioned the quality of care they received. Some said intake – which began by filling out a form and proceeded to an online visit with a doctor – was perfunctory. Once medication began, they said, requests for counseling about side effects were slow to be answered.

Jess Garrant, a Found patient, recalled that after she was prescribed zonisamide, a generic anticonvulsant that has shown some ability to help with weight loss, she felt “absolutely weird.”

“I was up all night and my thoughts were racing,” she wrote in a blog post. She developed sores in her mouth.

She sought advice and help from Found physicians, but their replies “weren’t quick.” Nonemergency communications are routed through the company’s portal.

It took a week to complete a switch of medications and have a new prescription arrive at her home, she said. Meanwhile, she said, she went to an urgent care clinic for the mouth sores.

Found frequently prescribes generic medications – often off label – rather than just the new GLP-1 agonists, company executives said in an interview. Found said older generics like zonisamide are more accessible than the GLP-1 agonists advertised on social media and their own website. Both Dr. Butsch and Dr. Stanford said they’ve prescribed zonisamide successfully. Dr. Butsch said ramping up dosage rapidly can increase the risk of side effects.

But Kim Boyd, MD, chief medical officer of competitor Calibrate, said the older drugs “just haven’t worked.”

Patients of both companies have critiqued online and in interviews the startups’ behavioral care – which experts across the board maintain is integral to successful weight loss treatment. But some patients felt they simply had canned advice.

Other patients said they had ups and downs with their coaches. Dana Crom, an attorney, said she had gone through many coaches with Calibrate. Some were good, effective cheerleaders; others, not so good. But when kinks in the program arose, she said, the coach wasn’t able to help her navigate them. While the coach can report trouble with medications or the app, it appears those reports are no more effective than messages sent through the portal, Ms. Crom said.

And what about when her yearlong subscription ends? Ms. Crom said she’d consider continuing with Calibrate.

Relationships with coaches, given the need to change behavior, are a critical element of the business models. Patients’ results depend “on how adherent they are to lifestyle changes,” said Found’s chief medical officer, Rehka Kumar, MD.

While the startups offer care to a larger geographic footprint, it’s not clear whether the demographics of their patient populations are different from those of the traditional bricks-and-mortar model. Calibrate’s patients are overwhelmingly White; over 8 in 10 have at least an undergraduate degree; and over 8 in 10 are women, according to the company.

And its earlier marketing strategies reflected that. The September 2020 “segmentation” document laid out three types of customers the company could hope to attract: perimenopausal or menopausal women, with income ranging from $75,000 to $150,000 a year; working mothers, with a similar income; and “men.”

Isabelle Kenyon, Calibrate’s CEO, said the company now hopes to expand its reach to partner with large employers, and that will help diversify its patients.

Patients will need to be convinced that the model – more affordable, more accessible – works for them. For her part, Ms. Garrant, who no longer is using Found, reflected on her experience, writing in her blog post that she was hoping for more follow-up and a more personal approach. “I don’t think it’s a helpful way to lose weight,” she said.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.

The study in mice elucidated a “key cause” of T2D by showing that high blood glucose reprograms the metabolism of pancreatic beta-cells, helping to explain the progressive decline in their function in diabetes.

Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.

In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
 

Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin

The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes. 

Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”

Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired. 
 

Vicious spiral of hyperglycemia and beta-cell damage

Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained. 

Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”

In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure. 

“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
 

Blocking metabolic enzyme could maintain insulin secretion

The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.

“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.

Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results. 

“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D. 

“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”

This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.

A version of this article first appeared on Medscape UK.

Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.

The study in mice elucidated a “key cause” of T2D by showing that high blood glucose reprograms the metabolism of pancreatic beta-cells, helping to explain the progressive decline in their function in diabetes.

Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.

In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
 

Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin

The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes. 

Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”

Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired. 
 

Vicious spiral of hyperglycemia and beta-cell damage

Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained. 

Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”

In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure. 

“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
 

Blocking metabolic enzyme could maintain insulin secretion

The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.

“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.

Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results. 

“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D. 

“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”

This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.

A version of this article first appeared on Medscape UK.

Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.

The study in mice elucidated a “key cause” of T2D by showing that high blood glucose reprograms the metabolism of pancreatic beta-cells, helping to explain the progressive decline in their function in diabetes.

Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.

In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
 

Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin

The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes. 

Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”

Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired. 
 

Vicious spiral of hyperglycemia and beta-cell damage

Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained. 

Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”

In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure. 

“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
 

Blocking metabolic enzyme could maintain insulin secretion

The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.

“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.

Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results. 

“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D. 

“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”

This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.

A version of this article first appeared on Medscape UK.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

Use of continuous glucose monitoring (CGM) by people without diabetes is becoming increasingly popular despite little evidence of benefit thus far, prompting discussion in the diabetes technology community about best practices.

Emerging uses for CGM outside of diabetes include improving glucose patterns to avoid diabetes, improving mental or physical performance, and promoting motivation for healthy behavior change. Such uses are not approved by the Food and Drug Administration and not covered by health insurance, yet a growing number of people are paying digital health companies for the devices as part of wellness packages.

Click_and_Photo/Thinkstock

‘An idea whose time has come?’

Dr. Espinoza was a co-author on a review published online in the Journal of Diabetes Science and Technology, entitled, “Use of Continuous Glucose Monitors by People Without Diabetes: An Idea Whose Time Has Come?”

The review examines several aspects of the issue, beginning with studies that used CGM to investigate glucose concentrations in people with normal fasting glucose and glucose tolerance tests. Nearly all those individuals – from populations around the world – fell in the blood glucose range of 70-140 mg/dL.

Also reviewed are studies using CGM to study effects of diet, exercise, and stress on glucose levels in people without diabetes. Subsequent sections summarize the limited data that are available suggesting potential benefit for use of CGM in metabolic disease including prediabetes and obesity, non-metabolic conditions such as steroid treatment or parenteral nutrition, health and wellness, and among elite athletes. In that last group, glucose levels in both the hypoglycemic and hyperglycemic ranges during intensive activity have been documented.

Currently, there are four CGM devices that are FDA-approved for use in people with diabetes: FreeStyle Libre (Abbott), the implantable Eversense (Senseonics), and devices from Dexcom and Medtronic.

As Dr. Espinoza and colleagues explain in their review, most of the commercial health and wellness CGM programs, such as Nutrisense, Signos, and Supersapiens, actually use sensors made by those same manufacturers. Nutrisense and Supersapiens use the Libre, and Signos uses the Dexcom.

But, rather than the manufacturer’s apps meant for use by people with diabetes, the wellness companies pair the sensors with their own specially designed apps and typically offer additional services such as health coaching or nutrition counseling “to improve general health.”

Subscribers pay a monthly fee. Signos, for example, charges $399 for 1 month, $199/month for 3 months, or $159/month for 6 months. A prescription is required, but the company’s website says, “rest assured, an independent physician will handle the prescription for you, so you won’t need to arrange for a doctor visit. It is included in the cost of membership.”

Several consumer health product companies are now developing non-invasive glucose monitors, most often as a wristwatch, for people without diabetes to measure glucose optically from the skin in the wrist.

“It remains to be determined how accurate these new devices will be and how they will be regulated,” the researchers write.
 

What to do with the data?

The dedicated health and wellness apps typically provide average glucose and trend data but not the GMI. However, in theory users could access that metric by downloading the manufacturers’ viewing apps – for example, Clarity for Dexcom or LibreView for Libre.

Moreover, a person without diabetes could always obtain an off-label prescription from their physician for a FreeStyle Libre and purchase it at a pharmacy. At Walmart, for example, the cost for two boxes of two glucose meters with 14 days of wear each is $136.77. In that situation as well, users could download the viewing app that contains the summary data including the GMI that could potentially mislead in the setting of consistent normoglycemia.  

Dr. Espinoza said: “I think there’s certainly value in glucose levels. We know the summary metrics are useful in type 1 diabetes. We don’t know which summary metrics are going to be useful in any other disease states. We may need brand new summary metrics for other disease states where it’s not about time in range. Maybe the thing that matters is the frequency or height of spikes. We don’t have a measure for that.”

He added that despite the availability of normative data, “even people without diabetes are a fairly heterogenous group. They can still have insulin resistance, so it’s tricky. From a science standpoint, we probably need studies with hundreds of patients with well-established A1c and [insulin resistance measures], weight, and body mass index. Then and only then will we be able to give an accurate glucose profile.”

In the meantime, “more data is always a good thing, but the hard thing is figuring out what do we do with it. Maybe it’s biofeedback for behavioral modification. We don’t know yet. But these are powerful tools and maybe we should learn how to use them better.”

Dr. Shah has reported receiving research grants and participating in advisory boards for Dexcom and Sanofi US. Dr. Espinoza has reported receiving research funding from the National Institutes of Health and FDA.

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

Use of continuous glucose monitoring (CGM) by people without diabetes is becoming increasingly popular despite little evidence of benefit thus far, prompting discussion in the diabetes technology community about best practices.

Emerging uses for CGM outside of diabetes include improving glucose patterns to avoid diabetes, improving mental or physical performance, and promoting motivation for healthy behavior change. Such uses are not approved by the Food and Drug Administration and not covered by health insurance, yet a growing number of people are paying digital health companies for the devices as part of wellness packages.

Click_and_Photo/Thinkstock

‘An idea whose time has come?’

Dr. Espinoza was a co-author on a review published online in the Journal of Diabetes Science and Technology, entitled, “Use of Continuous Glucose Monitors by People Without Diabetes: An Idea Whose Time Has Come?”

The review examines several aspects of the issue, beginning with studies that used CGM to investigate glucose concentrations in people with normal fasting glucose and glucose tolerance tests. Nearly all those individuals – from populations around the world – fell in the blood glucose range of 70-140 mg/dL.

Also reviewed are studies using CGM to study effects of diet, exercise, and stress on glucose levels in people without diabetes. Subsequent sections summarize the limited data that are available suggesting potential benefit for use of CGM in metabolic disease including prediabetes and obesity, non-metabolic conditions such as steroid treatment or parenteral nutrition, health and wellness, and among elite athletes. In that last group, glucose levels in both the hypoglycemic and hyperglycemic ranges during intensive activity have been documented.

Currently, there are four CGM devices that are FDA-approved for use in people with diabetes: FreeStyle Libre (Abbott), the implantable Eversense (Senseonics), and devices from Dexcom and Medtronic.

As Dr. Espinoza and colleagues explain in their review, most of the commercial health and wellness CGM programs, such as Nutrisense, Signos, and Supersapiens, actually use sensors made by those same manufacturers. Nutrisense and Supersapiens use the Libre, and Signos uses the Dexcom.

But, rather than the manufacturer’s apps meant for use by people with diabetes, the wellness companies pair the sensors with their own specially designed apps and typically offer additional services such as health coaching or nutrition counseling “to improve general health.”

Subscribers pay a monthly fee. Signos, for example, charges $399 for 1 month, $199/month for 3 months, or $159/month for 6 months. A prescription is required, but the company’s website says, “rest assured, an independent physician will handle the prescription for you, so you won’t need to arrange for a doctor visit. It is included in the cost of membership.”

Several consumer health product companies are now developing non-invasive glucose monitors, most often as a wristwatch, for people without diabetes to measure glucose optically from the skin in the wrist.

“It remains to be determined how accurate these new devices will be and how they will be regulated,” the researchers write.
 

What to do with the data?

The dedicated health and wellness apps typically provide average glucose and trend data but not the GMI. However, in theory users could access that metric by downloading the manufacturers’ viewing apps – for example, Clarity for Dexcom or LibreView for Libre.

Moreover, a person without diabetes could always obtain an off-label prescription from their physician for a FreeStyle Libre and purchase it at a pharmacy. At Walmart, for example, the cost for two boxes of two glucose meters with 14 days of wear each is $136.77. In that situation as well, users could download the viewing app that contains the summary data including the GMI that could potentially mislead in the setting of consistent normoglycemia.  

Dr. Espinoza said: “I think there’s certainly value in glucose levels. We know the summary metrics are useful in type 1 diabetes. We don’t know which summary metrics are going to be useful in any other disease states. We may need brand new summary metrics for other disease states where it’s not about time in range. Maybe the thing that matters is the frequency or height of spikes. We don’t have a measure for that.”

He added that despite the availability of normative data, “even people without diabetes are a fairly heterogenous group. They can still have insulin resistance, so it’s tricky. From a science standpoint, we probably need studies with hundreds of patients with well-established A1c and [insulin resistance measures], weight, and body mass index. Then and only then will we be able to give an accurate glucose profile.”

In the meantime, “more data is always a good thing, but the hard thing is figuring out what do we do with it. Maybe it’s biofeedback for behavioral modification. We don’t know yet. But these are powerful tools and maybe we should learn how to use them better.”

Dr. Shah has reported receiving research grants and participating in advisory boards for Dexcom and Sanofi US. Dr. Espinoza has reported receiving research funding from the National Institutes of Health and FDA.

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

Use of continuous glucose monitoring (CGM) by people without diabetes is becoming increasingly popular despite little evidence of benefit thus far, prompting discussion in the diabetes technology community about best practices.

Emerging uses for CGM outside of diabetes include improving glucose patterns to avoid diabetes, improving mental or physical performance, and promoting motivation for healthy behavior change. Such uses are not approved by the Food and Drug Administration and not covered by health insurance, yet a growing number of people are paying digital health companies for the devices as part of wellness packages.

Click_and_Photo/Thinkstock

‘An idea whose time has come?’

Dr. Espinoza was a co-author on a review published online in the Journal of Diabetes Science and Technology, entitled, “Use of Continuous Glucose Monitors by People Without Diabetes: An Idea Whose Time Has Come?”

The review examines several aspects of the issue, beginning with studies that used CGM to investigate glucose concentrations in people with normal fasting glucose and glucose tolerance tests. Nearly all those individuals – from populations around the world – fell in the blood glucose range of 70-140 mg/dL.

Also reviewed are studies using CGM to study effects of diet, exercise, and stress on glucose levels in people without diabetes. Subsequent sections summarize the limited data that are available suggesting potential benefit for use of CGM in metabolic disease including prediabetes and obesity, non-metabolic conditions such as steroid treatment or parenteral nutrition, health and wellness, and among elite athletes. In that last group, glucose levels in both the hypoglycemic and hyperglycemic ranges during intensive activity have been documented.

Currently, there are four CGM devices that are FDA-approved for use in people with diabetes: FreeStyle Libre (Abbott), the implantable Eversense (Senseonics), and devices from Dexcom and Medtronic.

As Dr. Espinoza and colleagues explain in their review, most of the commercial health and wellness CGM programs, such as Nutrisense, Signos, and Supersapiens, actually use sensors made by those same manufacturers. Nutrisense and Supersapiens use the Libre, and Signos uses the Dexcom.

But, rather than the manufacturer’s apps meant for use by people with diabetes, the wellness companies pair the sensors with their own specially designed apps and typically offer additional services such as health coaching or nutrition counseling “to improve general health.”

Subscribers pay a monthly fee. Signos, for example, charges $399 for 1 month, $199/month for 3 months, or $159/month for 6 months. A prescription is required, but the company’s website says, “rest assured, an independent physician will handle the prescription for you, so you won’t need to arrange for a doctor visit. It is included in the cost of membership.”

Several consumer health product companies are now developing non-invasive glucose monitors, most often as a wristwatch, for people without diabetes to measure glucose optically from the skin in the wrist.

“It remains to be determined how accurate these new devices will be and how they will be regulated,” the researchers write.
 

What to do with the data?

The dedicated health and wellness apps typically provide average glucose and trend data but not the GMI. However, in theory users could access that metric by downloading the manufacturers’ viewing apps – for example, Clarity for Dexcom or LibreView for Libre.

Moreover, a person without diabetes could always obtain an off-label prescription from their physician for a FreeStyle Libre and purchase it at a pharmacy. At Walmart, for example, the cost for two boxes of two glucose meters with 14 days of wear each is $136.77. In that situation as well, users could download the viewing app that contains the summary data including the GMI that could potentially mislead in the setting of consistent normoglycemia.  

Dr. Espinoza said: “I think there’s certainly value in glucose levels. We know the summary metrics are useful in type 1 diabetes. We don’t know which summary metrics are going to be useful in any other disease states. We may need brand new summary metrics for other disease states where it’s not about time in range. Maybe the thing that matters is the frequency or height of spikes. We don’t have a measure for that.”

He added that despite the availability of normative data, “even people without diabetes are a fairly heterogenous group. They can still have insulin resistance, so it’s tricky. From a science standpoint, we probably need studies with hundreds of patients with well-established A1c and [insulin resistance measures], weight, and body mass index. Then and only then will we be able to give an accurate glucose profile.”

In the meantime, “more data is always a good thing, but the hard thing is figuring out what do we do with it. Maybe it’s biofeedback for behavioral modification. We don’t know yet. But these are powerful tools and maybe we should learn how to use them better.”

Dr. Shah has reported receiving research grants and participating in advisory boards for Dexcom and Sanofi US. Dr. Espinoza has reported receiving research funding from the National Institutes of Health and FDA.

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

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – A novel glucagonlike peptide-1 (GLP-1)/glucagon dual-receptor agonist, BI 456906, being developed by Boehringer Ingelheim and Zealand Pharma, led to “impressive” weight loss in a phase 2 dosing study of patients with overweight/obesity and type 2 diabetes – but this is early research.

Julio Rosenstock, MD, presented the study results, including weight loss and adverse events, at the annual meeting of the Obesity Society.

At the highest tested dose (1.8 mg twice weekly subcutaneous injections), 57% of patients lost at least 5% of their initial body weight and 35% lost at least 10% of their initial body weight at 16 weeks.

In contrast, among the patients who received a 1-mg semaglutide dose as a comparator, 38% lost at least 5% of their initial body weight and 16% lost at least 10% of their initial body weight at study end.

Sara Freeman/MDedge News

This is “very promising data as an anti-obesity compound,” said Dr. Rosenstock, professor of medicine, University of Texas Southwestern Medical Center in Dallas.

The researchers enrolled 411 adults and randomized them into eight groups of roughly 50 patients each.

They compared six doses of BI 456906 (from 0.3 mg/week to 1.8 mg twice weekly) versus 1 mg/week of the GLP-1 agonist semaglutide (Wegovy, Novo Nordisk) versus placebo.

Patients had a mean initial weight of 97 kg (214 pounds).

After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight or roughly 8.7 kg (19 pounds).

Patients who received semaglutide lost 5.4% of their initial weight or roughly 5.2 kg (11.5 pounds), and patients who received placebo lost only 1.2% of their initial weight

The main adverse events were gastrointestinal.
 

‘Exciting data,’ but still early days

“This is very exciting data. It comes from another experienced company with a track record of successful products with a new compound in a class where other related compounds have shown efficacy and safety,” Dan Bessesen, MD, president of The Obesity Society, who was not involved with this research, told this news organization in an email.

“The degree of weight loss is impressive for a 16-week study,” Dr. Bessesen, professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado at Denver, Aurora, added. “The longer-term weight loss will likely be more.”

The side-effect profile is not particularly concerning and is like other drugs in this general class, he said.

However, he also noted a few caveats. This was only a phase 2 study, “so we should not make firm conclusions about efficacy from a study like this, as the number of subjects studied at each dose is relatively small and the follow-up not long.”

In addition, “the dose of semaglutide is the old ‘diabetes’ dose (1 mg) not the weight-loss dose of 2.4 mg or the new diabetes dose of 2 mg. It is not a real comparison with the maximal approved dose of semaglutide. So, we cannot say that it will be better than semaglutide.”

The next hurdle is the “need to see phase 3 studies in a larger group of patients studied for a longer time. Then [the company] will need FDA approval, so it may be a bit of time” before this drug potentially enters the marketplace.

The “bottom line” is that this potential new antiobesity/diabetes drug is “very promising, but [it is] still a little early to say where it ultimately will go.”
 

A1c results presented at EASD

To be included in this study, patients had to be 18-75 years old, have type 2 diabetes, a body mass index of 25-50 kg/m², and hemoglobin A1c of 7%-10%, and be stable on metformin therapy.

The patients had a mean age of 57 years, and 57% were men. They had a mean A1c of 8.1%, a mean BMI of 34 kg/m², and a mean waist circumference of 110 cm (43 inches).

“We just recently reported at the EASD conference last month, the effect of BI 456906 on A1c lowering,” Dr. Rosenstock said.

“It looks like the [drop in] A1c plateaus at 1.9%, which is pretty good when you consider the baseline A1c is around 8%. You get down to around 6%, which is what we regard as a very robust reduction in people with type 2 diabetes on metformin.”

The current analysis showed that patients who received doses of 0.3, 0.9, 1.8, and 2.7 mg/week of the novel drug lost 1.9%, 4.4%, 6.6%, and 6.7% of their initial body weight, respectively, after 16 weeks.

The patients who received 1.2 mg and 1.8 mg twice weekly lost even more weight, 7.2% and 9% of their initial weight, respectively.

At the highest dose, on average, patients lost 13 cm (5 inches) around their waist.

Adverse events were reported by 78% of the patients, most commonly nausea (34% of patients), vomiting (18%), and diarrhea (16%).

Only 1.3% of patients had a drug-related serious adverse event. A total of 16% of patients discontinued the therapy.

Most of the “gastrointestinal adverse events leading the treatment discontinuation were possibly dose and titration related,” Dr. Rosenstock said, “and it’s highly conceivable that for future studies a slower dose escalation may mitigate the occurrence of the gastrointestinal adverse events.”

BI 456906 was coinvented with Zealand Pharma. Under the licensing agreement, Boehringer Ingelheim funds all research, development, and commercialization.

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

SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


SAN DIEGO – Weight loss with tirzepatide was fairly uniform across different body mass index ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide – the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist – for obesity, presented at the annual meeting of the Obesity Society.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

In early October, the FDA granted fast track status (expedited review) to tirzepatide for use as an antiobesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [antiobesity] medications,” added Dr. O’Neil, professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, Charleston.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he said in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [antiobesity] medications to be making any permanent physiological changes,” Dr. O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.

“Clearly the medications are having a significant impact,” he emphasized.
 

BMI, age, comorbidity subgroups, and overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age subgroups

Robert F. Kushner, MD, of Northwestern University, Chicago, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post hoc analysis in patients who had dual-energy x-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Dr. Kushner reported.
 

BMI subgroups

Louis J. Aronne, MD, Weill Cornell Medicine, New York, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29-30 pounds
• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33-43 pounds
• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34-56 pounds
• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44-64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15-mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Dr. Aronne.

In addition, overall, 73%-90% of patients receiving the 5- to 15-mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50%-78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Dr. Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27- to 30-kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.
 

Number of comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, nonalcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina at Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of at least two obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• Zero comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men
• One comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men
• Two or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.
 

Quality of life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life–Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form–36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

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


Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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

Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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

Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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