Clinical Endocrinology News

A commercial for the continuous glucose monitor (CGM) Dexcom G6 shown during the Super Bowl has provoked strong reactions in the diabetes community, both positive and negative.

The 30-second ad, which aired between the first two quarters of the American football game yesterday, features singer-songwriter-actor Nick Jonas, who has type 1 diabetes. During the ad, Mr. Jonas asks – with so much technology available today, including drones that deliver packages and self-driving cars – why are people with diabetes still pricking their fingers to test their blood sugar?

Mr. Jonas goes on to demonstrate the Dexcom G6 smartphone glucose app as it displays three different glucose levels including two trending upward, explaining: “It shows your glucose right in your phone, and where it’s heading, without fingersticks. Finally, technology that makes it easier to manage our diabetes.”

Diabetes type or insulin treatment are not mentioned in the ad, despite the fact that most insurance plans typically only cover CGMs for people with type 1 diabetes and sometimes for those with type 2 diabetes who take multiple daily insulin doses (given the risk for hypoglycemia).
 

Ad prompts mixed reaction on social media

Reactions rolled in on Twitter after the ad debuted Feb. 2, and then again after it aired during the game.

Some people who have type 1 diabetes themselves or have children with the disease who use the product were thrilled.

“Thanks to @NickJonas for his advocacy on T1. My 11-year old has been on the Dexcom for 3 weeks. For a newly diagnosed kid, it removes a lot of anxiety (and for his parents, too!) Plus, he is thrilled his meter has a Super Bowl commercial!” tweeted @KatisJewell.

Another positive tweet, from @rturnerroy, read: “@nickjonas Thank you for bringing representation to #type1diabetes. And hey #Dexcom, you’re the best.”

But many others were critical, both of Jonas and Dexcom. @hb_herrick tweeted: “Diabetes awareness is fantastic. Dexcom being able to afford Nick Jonas for a #SuperBowl commercial is not. This is a health care product. Make it more affordable for those who need it.”

Another Twitter user, @universeofdust, tweeted: “Feeling ambivalent about the #Dexcom ad tbh. I love the awareness & representation. But also not a big fan of dexcom spending $5.5 mill+ to make the CGM seem like this ~cool & trendy~ thing when many type 1s can’t afford their insulin, let alone a CGM.”

And @andricheli wrote: “Only people lucky enough to have excellent insurance and be able to afford the out-of-pocket costs have access. Many others do not.”

And in another tweet the same user said, “The #Dexcom is an amazing device. It’s literally lifesaving and life extending. But it’s also very expensive and not available to everyone. Maybe instead of spending $5 mil on a Super Bowl ad, @dexcom should spend that on getting Dex into the handle of people who need it.”

Others, including @1hitwonderdate, criticized Mr. Jonas directly, asking him: “As someone who has struggled with diabetes and is trying to support themselves along with millions of others, why not use this platform to help those who can’t afford their supplies or are rationing them?!”


 

Dexcom and Jonas’ organization respond

This news organization reached out to both Dexcom and to Beyond Type 1, a nonprofit organization cofounded by Mr. Jonas, for comment. Both emailed responses.

Regarding the intended audience for the ad, Dexcom acknowledged that it hoped to reach a much wider group than just people with type 1 diabetes or even just insulin users.

“We believe our CGM technology has the ability to empower any person with diabetes and significantly improve their treatment and quality of life, whether they are using insulin or not,” the company said, adding that the ad was also aimed at “loved ones, caregivers, and even health care professionals who need to know about this technology.”

According to Dexcom, the G6 is covered by 99% of commercial insurance in the United States, in addition to Medicare, and by Medicaid in more than 40 states. Over 70% of Dexcom patients with pharmacy coverage in the United States pay under $60 per month for CGM, and a third pay $0 out-of-pocket.

“That said, we know there’s more to be done to improve access, and we are working with several partners to broaden access to Dexcom CGM, especially for people with type 2 diabetes not on mealtime insulin,” the company noted.

Beyond Type 1 responded to the criticisms about Mr. Jonas personally, noting that the celebrity is, in fact, heavily involved in advocacy.

“Nick was involved in the launch of GetInsulin.org this past October,” they said. “GetInsulin.org is a tool created by Beyond Type 1 to connect people with diabetes in the United States to the insulin access and affordability options that match their unique circumstances. ... Beyond Type 1 will continue driving awareness of short-term solutions related to insulin access and affordability while fighting for systemic change.”

The organization “is also advocating for systemic payment policies that will make devices less expensive and avoid the same pitfalls (and rising prices) as the drug pricing system in the U.S.”

Mr. Jonas himself appears aware of the concerns.

Is 2021’s most expensive Super Bowl ad justified?

Meanwhile, in a piece in Esquire, Dave Holmes, who has type 1 diabetes, weighs up the pros and cons of the ad.

He writes: “While Jonas makes it look fun and easy to use a Dexcom G6 – a program to just get with like you would a drone or LED eyelashes – the process of acquiring one is complicated and often very expensive, even for people with good insurance. Which makes the year’s most expensive ad buy, for a product that only a small percentage of the U.S. population needs, confusing to me and others.”

Mr. Holmes also spoke with Craig Stubing, founder of the Beta Cell Foundation, a nonprofit that aims to educate and empower those with type 1 diabetes.

“Spending all this money on an ad, when people’s lives are at stake. I don’t know if offensive is the right word, but it seems out of touch with the reality that their patients are facing,” Mr. Stubing told Mr. Holmes.

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

A commercial for the continuous glucose monitor (CGM) Dexcom G6 shown during the Super Bowl has provoked strong reactions in the diabetes community, both positive and negative.

The 30-second ad, which aired between the first two quarters of the American football game yesterday, features singer-songwriter-actor Nick Jonas, who has type 1 diabetes. During the ad, Mr. Jonas asks – with so much technology available today, including drones that deliver packages and self-driving cars – why are people with diabetes still pricking their fingers to test their blood sugar?

Mr. Jonas goes on to demonstrate the Dexcom G6 smartphone glucose app as it displays three different glucose levels including two trending upward, explaining: “It shows your glucose right in your phone, and where it’s heading, without fingersticks. Finally, technology that makes it easier to manage our diabetes.”

Diabetes type or insulin treatment are not mentioned in the ad, despite the fact that most insurance plans typically only cover CGMs for people with type 1 diabetes and sometimes for those with type 2 diabetes who take multiple daily insulin doses (given the risk for hypoglycemia).
 

Ad prompts mixed reaction on social media

Reactions rolled in on Twitter after the ad debuted Feb. 2, and then again after it aired during the game.

Some people who have type 1 diabetes themselves or have children with the disease who use the product were thrilled.

“Thanks to @NickJonas for his advocacy on T1. My 11-year old has been on the Dexcom for 3 weeks. For a newly diagnosed kid, it removes a lot of anxiety (and for his parents, too!) Plus, he is thrilled his meter has a Super Bowl commercial!” tweeted @KatisJewell.

Another positive tweet, from @rturnerroy, read: “@nickjonas Thank you for bringing representation to #type1diabetes. And hey #Dexcom, you’re the best.”

But many others were critical, both of Jonas and Dexcom. @hb_herrick tweeted: “Diabetes awareness is fantastic. Dexcom being able to afford Nick Jonas for a #SuperBowl commercial is not. This is a health care product. Make it more affordable for those who need it.”

Another Twitter user, @universeofdust, tweeted: “Feeling ambivalent about the #Dexcom ad tbh. I love the awareness & representation. But also not a big fan of dexcom spending $5.5 mill+ to make the CGM seem like this ~cool & trendy~ thing when many type 1s can’t afford their insulin, let alone a CGM.”

And @andricheli wrote: “Only people lucky enough to have excellent insurance and be able to afford the out-of-pocket costs have access. Many others do not.”

And in another tweet the same user said, “The #Dexcom is an amazing device. It’s literally lifesaving and life extending. But it’s also very expensive and not available to everyone. Maybe instead of spending $5 mil on a Super Bowl ad, @dexcom should spend that on getting Dex into the handle of people who need it.”

Others, including @1hitwonderdate, criticized Mr. Jonas directly, asking him: “As someone who has struggled with diabetes and is trying to support themselves along with millions of others, why not use this platform to help those who can’t afford their supplies or are rationing them?!”


 

Dexcom and Jonas’ organization respond

This news organization reached out to both Dexcom and to Beyond Type 1, a nonprofit organization cofounded by Mr. Jonas, for comment. Both emailed responses.

Regarding the intended audience for the ad, Dexcom acknowledged that it hoped to reach a much wider group than just people with type 1 diabetes or even just insulin users.

“We believe our CGM technology has the ability to empower any person with diabetes and significantly improve their treatment and quality of life, whether they are using insulin or not,” the company said, adding that the ad was also aimed at “loved ones, caregivers, and even health care professionals who need to know about this technology.”

According to Dexcom, the G6 is covered by 99% of commercial insurance in the United States, in addition to Medicare, and by Medicaid in more than 40 states. Over 70% of Dexcom patients with pharmacy coverage in the United States pay under $60 per month for CGM, and a third pay $0 out-of-pocket.

“That said, we know there’s more to be done to improve access, and we are working with several partners to broaden access to Dexcom CGM, especially for people with type 2 diabetes not on mealtime insulin,” the company noted.

Beyond Type 1 responded to the criticisms about Mr. Jonas personally, noting that the celebrity is, in fact, heavily involved in advocacy.

“Nick was involved in the launch of GetInsulin.org this past October,” they said. “GetInsulin.org is a tool created by Beyond Type 1 to connect people with diabetes in the United States to the insulin access and affordability options that match their unique circumstances. ... Beyond Type 1 will continue driving awareness of short-term solutions related to insulin access and affordability while fighting for systemic change.”

The organization “is also advocating for systemic payment policies that will make devices less expensive and avoid the same pitfalls (and rising prices) as the drug pricing system in the U.S.”

Mr. Jonas himself appears aware of the concerns.

Is 2021’s most expensive Super Bowl ad justified?

Meanwhile, in a piece in Esquire, Dave Holmes, who has type 1 diabetes, weighs up the pros and cons of the ad.

He writes: “While Jonas makes it look fun and easy to use a Dexcom G6 – a program to just get with like you would a drone or LED eyelashes – the process of acquiring one is complicated and often very expensive, even for people with good insurance. Which makes the year’s most expensive ad buy, for a product that only a small percentage of the U.S. population needs, confusing to me and others.”

Mr. Holmes also spoke with Craig Stubing, founder of the Beta Cell Foundation, a nonprofit that aims to educate and empower those with type 1 diabetes.

“Spending all this money on an ad, when people’s lives are at stake. I don’t know if offensive is the right word, but it seems out of touch with the reality that their patients are facing,” Mr. Stubing told Mr. Holmes.

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

A commercial for the continuous glucose monitor (CGM) Dexcom G6 shown during the Super Bowl has provoked strong reactions in the diabetes community, both positive and negative.

The 30-second ad, which aired between the first two quarters of the American football game yesterday, features singer-songwriter-actor Nick Jonas, who has type 1 diabetes. During the ad, Mr. Jonas asks – with so much technology available today, including drones that deliver packages and self-driving cars – why are people with diabetes still pricking their fingers to test their blood sugar?

Mr. Jonas goes on to demonstrate the Dexcom G6 smartphone glucose app as it displays three different glucose levels including two trending upward, explaining: “It shows your glucose right in your phone, and where it’s heading, without fingersticks. Finally, technology that makes it easier to manage our diabetes.”

Diabetes type or insulin treatment are not mentioned in the ad, despite the fact that most insurance plans typically only cover CGMs for people with type 1 diabetes and sometimes for those with type 2 diabetes who take multiple daily insulin doses (given the risk for hypoglycemia).
 

Ad prompts mixed reaction on social media

Reactions rolled in on Twitter after the ad debuted Feb. 2, and then again after it aired during the game.

Some people who have type 1 diabetes themselves or have children with the disease who use the product were thrilled.

“Thanks to @NickJonas for his advocacy on T1. My 11-year old has been on the Dexcom for 3 weeks. For a newly diagnosed kid, it removes a lot of anxiety (and for his parents, too!) Plus, he is thrilled his meter has a Super Bowl commercial!” tweeted @KatisJewell.

Another positive tweet, from @rturnerroy, read: “@nickjonas Thank you for bringing representation to #type1diabetes. And hey #Dexcom, you’re the best.”

But many others were critical, both of Jonas and Dexcom. @hb_herrick tweeted: “Diabetes awareness is fantastic. Dexcom being able to afford Nick Jonas for a #SuperBowl commercial is not. This is a health care product. Make it more affordable for those who need it.”

Another Twitter user, @universeofdust, tweeted: “Feeling ambivalent about the #Dexcom ad tbh. I love the awareness & representation. But also not a big fan of dexcom spending $5.5 mill+ to make the CGM seem like this ~cool & trendy~ thing when many type 1s can’t afford their insulin, let alone a CGM.”

And @andricheli wrote: “Only people lucky enough to have excellent insurance and be able to afford the out-of-pocket costs have access. Many others do not.”

And in another tweet the same user said, “The #Dexcom is an amazing device. It’s literally lifesaving and life extending. But it’s also very expensive and not available to everyone. Maybe instead of spending $5 mil on a Super Bowl ad, @dexcom should spend that on getting Dex into the handle of people who need it.”

Others, including @1hitwonderdate, criticized Mr. Jonas directly, asking him: “As someone who has struggled with diabetes and is trying to support themselves along with millions of others, why not use this platform to help those who can’t afford their supplies or are rationing them?!”


 

Dexcom and Jonas’ organization respond

This news organization reached out to both Dexcom and to Beyond Type 1, a nonprofit organization cofounded by Mr. Jonas, for comment. Both emailed responses.

Regarding the intended audience for the ad, Dexcom acknowledged that it hoped to reach a much wider group than just people with type 1 diabetes or even just insulin users.

“We believe our CGM technology has the ability to empower any person with diabetes and significantly improve their treatment and quality of life, whether they are using insulin or not,” the company said, adding that the ad was also aimed at “loved ones, caregivers, and even health care professionals who need to know about this technology.”

According to Dexcom, the G6 is covered by 99% of commercial insurance in the United States, in addition to Medicare, and by Medicaid in more than 40 states. Over 70% of Dexcom patients with pharmacy coverage in the United States pay under $60 per month for CGM, and a third pay $0 out-of-pocket.

“That said, we know there’s more to be done to improve access, and we are working with several partners to broaden access to Dexcom CGM, especially for people with type 2 diabetes not on mealtime insulin,” the company noted.

Beyond Type 1 responded to the criticisms about Mr. Jonas personally, noting that the celebrity is, in fact, heavily involved in advocacy.

“Nick was involved in the launch of GetInsulin.org this past October,” they said. “GetInsulin.org is a tool created by Beyond Type 1 to connect people with diabetes in the United States to the insulin access and affordability options that match their unique circumstances. ... Beyond Type 1 will continue driving awareness of short-term solutions related to insulin access and affordability while fighting for systemic change.”

The organization “is also advocating for systemic payment policies that will make devices less expensive and avoid the same pitfalls (and rising prices) as the drug pricing system in the U.S.”

Mr. Jonas himself appears aware of the concerns.

Is 2021’s most expensive Super Bowl ad justified?

Meanwhile, in a piece in Esquire, Dave Holmes, who has type 1 diabetes, weighs up the pros and cons of the ad.

He writes: “While Jonas makes it look fun and easy to use a Dexcom G6 – a program to just get with like you would a drone or LED eyelashes – the process of acquiring one is complicated and often very expensive, even for people with good insurance. Which makes the year’s most expensive ad buy, for a product that only a small percentage of the U.S. population needs, confusing to me and others.”

Mr. Holmes also spoke with Craig Stubing, founder of the Beta Cell Foundation, a nonprofit that aims to educate and empower those with type 1 diabetes.

“Spending all this money on an ad, when people’s lives are at stake. I don’t know if offensive is the right word, but it seems out of touch with the reality that their patients are facing,” Mr. Stubing told Mr. Holmes.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

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

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has updated its recommended immunization schedule for adults for 2021.

A summary of the annual update was published online Feb. 11 in the CDC’s Morbidity and Mortality Weekly Report and is available in Annals of Internal Medicine and on the CDC website.

It features a special section on vaccination during the pandemic as well as interim recommendations on administering the Pfizer-BioNtech and Moderna COVID-19 vaccines.

The authors, led by Mark S. Freedman, DVM, MPH, DACVPM, of the CDC’s National Center for Immunization and Respiratory Diseases, in Atlanta, note that this year’s recommendations for adults – persons aged 19 years and older – are largely the same as last year’s. “There have been very few changes,” Dr. Freedman said in an interview. “Changes to the schedule tables and notes were made to harmonize to the greatest extent possible the adult and child/adolescent schedules.”

Changes in the schedule include new or updated ACIP recommendations for influenza, hepatitis A, hepatitis B (Hep B), and human papillomavirus (HPV) as well as for meningococcal serogroups A, C, W, and Y (MenACYW) vaccines, meningococcal B (MenB) vaccines, and the zoster vaccine.

Vaccine-specific changes

Influenza

The schedule highlights updates to the composition of several influenza vaccines, which apply to components in both trivalent and quadrivalent formulations.

The cover page abbreviation for live attenuated influenza vaccine (LAIV) was changed to LAIV4. The abbreviation for live recombinant influenza vaccine (RIV) was changed to RIV4.

For individuals with a history of egg allergy who experience reactions other than hives, the following procedural warning has been added: “If using an influenza vaccine other than RIV4 or ccIIV4, administer in medical setting under supervision of health care provider who can recognize and manage severe allergic reactions.”

Zoster

The zoster vaccine live (Zostavax) has been removed from the schedule because it is no longer available in the United States. The recombinant zoster vaccine Shingrix remains available as a 2-dose regimen for adults aged 50 years or older.

HPV

As in previous years, HPV vaccination is routinely recommended for persons aged 11-12 years, with catch-up vaccination for those aged 26 or younger. Catch-up vaccination can be considered with shared decision making for those aged 27 through 45. In this year’s schedule, in the pregnancy column, the color pink, which formerly indicated “delay until after pregnancy,” has been replaced with red and an asterisk, indicating “vaccinate after pregnancy.”

HepB

ACIP continues to recommend vaccination of adults at risk for HepB; however, the text overlay has been changed to read, “2, 3, or 4 doses, depending on vaccine or condition.” Additionally, HepB vaccination is now routinely recommended for adults younger than 60 years with diabetes. For those with diabetes who are older than 60, shared decision making is recommended.

Meningococcal vaccine

ACIP continues to recommend routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for persons at increased risk for meningococcal disease caused by serogroups A, C, W, or Y. The MenQuadfi (MenACWY-TT) vaccine, which was first licensed in 2020, has been added to all relevant sections of MenACWY vaccines. For MenACWY booster doses, new text addresses special situations, including outbreaks.

Improvements have been made to text and layout, Dr. Freedman said. An example is the minimizing of specialized text. Other changes were made to ensure more consistent text structure and language. Various fine-tunings of color and positioning were made to the cover page and tables, and the wording of the notes sections was improved.

Vaccination in the pandemic

The updated schedule outlines guidance on the use of COVID-19 vaccines approved by the Food and Drug Administration under emergency use authorization, with interim recommendations for the Pfizer-BioNTech COVID-19 vaccine for people aged 16 and older and the Moderna COVID-19 vaccine for people aged 18 and older.

The authors stress the importance of receiving the recommended routine and catch-up immunizations notwithstanding widespread anxiety about visiting medical offices. Last spring, the CDC reported a dramatic drop in child vaccinations after the declaration of the national emergency in mid-March, a drop attributed to fear of COVID-19 exposure.

“ACIP continued to meet and make recommendations during the pandemic,” Dr. Freedman said. “Our recommendation remains that despite challenges caused by the COVID-19 pandemic, adults and their healthcare providers should follow the recommended vaccine schedule to protect against serious and sometimes deadly diseases.”

Regular vaccines can be safely administered even as COVID-19 retains its grasp on the United States. “Healthcare providers should follow the CDC’s interim guidance for the safe delivery of vaccines during the pandemic, which includes the use of personal protective equipment and physical distancing,” Dr. Freedman said.

Dr. Freedman has disclosed no relevant financial relationships. Coauthor Henry Bernstein, DO, is the editor of the Current Opinion in Pediatrics Office Pediatrics Series, is a Harvard School of Public Health faculty member, and is a member of the data safety and monitoring board for a Takeda study on intrathecal enzymes for Hunter and San Filippo syndromes. Coauthor Kevin Ault, MD, has served on the data safety and monitoring committee for ACI Clinical.
 

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

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has updated its recommended immunization schedule for adults for 2021.

A summary of the annual update was published online Feb. 11 in the CDC’s Morbidity and Mortality Weekly Report and is available in Annals of Internal Medicine and on the CDC website.

It features a special section on vaccination during the pandemic as well as interim recommendations on administering the Pfizer-BioNtech and Moderna COVID-19 vaccines.

The authors, led by Mark S. Freedman, DVM, MPH, DACVPM, of the CDC’s National Center for Immunization and Respiratory Diseases, in Atlanta, note that this year’s recommendations for adults – persons aged 19 years and older – are largely the same as last year’s. “There have been very few changes,” Dr. Freedman said in an interview. “Changes to the schedule tables and notes were made to harmonize to the greatest extent possible the adult and child/adolescent schedules.”

Changes in the schedule include new or updated ACIP recommendations for influenza, hepatitis A, hepatitis B (Hep B), and human papillomavirus (HPV) as well as for meningococcal serogroups A, C, W, and Y (MenACYW) vaccines, meningococcal B (MenB) vaccines, and the zoster vaccine.

Vaccine-specific changes

Influenza

The schedule highlights updates to the composition of several influenza vaccines, which apply to components in both trivalent and quadrivalent formulations.

The cover page abbreviation for live attenuated influenza vaccine (LAIV) was changed to LAIV4. The abbreviation for live recombinant influenza vaccine (RIV) was changed to RIV4.

For individuals with a history of egg allergy who experience reactions other than hives, the following procedural warning has been added: “If using an influenza vaccine other than RIV4 or ccIIV4, administer in medical setting under supervision of health care provider who can recognize and manage severe allergic reactions.”

Zoster

The zoster vaccine live (Zostavax) has been removed from the schedule because it is no longer available in the United States. The recombinant zoster vaccine Shingrix remains available as a 2-dose regimen for adults aged 50 years or older.

HPV

As in previous years, HPV vaccination is routinely recommended for persons aged 11-12 years, with catch-up vaccination for those aged 26 or younger. Catch-up vaccination can be considered with shared decision making for those aged 27 through 45. In this year’s schedule, in the pregnancy column, the color pink, which formerly indicated “delay until after pregnancy,” has been replaced with red and an asterisk, indicating “vaccinate after pregnancy.”

HepB

ACIP continues to recommend vaccination of adults at risk for HepB; however, the text overlay has been changed to read, “2, 3, or 4 doses, depending on vaccine or condition.” Additionally, HepB vaccination is now routinely recommended for adults younger than 60 years with diabetes. For those with diabetes who are older than 60, shared decision making is recommended.

Meningococcal vaccine

ACIP continues to recommend routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for persons at increased risk for meningococcal disease caused by serogroups A, C, W, or Y. The MenQuadfi (MenACWY-TT) vaccine, which was first licensed in 2020, has been added to all relevant sections of MenACWY vaccines. For MenACWY booster doses, new text addresses special situations, including outbreaks.

Improvements have been made to text and layout, Dr. Freedman said. An example is the minimizing of specialized text. Other changes were made to ensure more consistent text structure and language. Various fine-tunings of color and positioning were made to the cover page and tables, and the wording of the notes sections was improved.

Vaccination in the pandemic

The updated schedule outlines guidance on the use of COVID-19 vaccines approved by the Food and Drug Administration under emergency use authorization, with interim recommendations for the Pfizer-BioNTech COVID-19 vaccine for people aged 16 and older and the Moderna COVID-19 vaccine for people aged 18 and older.

The authors stress the importance of receiving the recommended routine and catch-up immunizations notwithstanding widespread anxiety about visiting medical offices. Last spring, the CDC reported a dramatic drop in child vaccinations after the declaration of the national emergency in mid-March, a drop attributed to fear of COVID-19 exposure.

“ACIP continued to meet and make recommendations during the pandemic,” Dr. Freedman said. “Our recommendation remains that despite challenges caused by the COVID-19 pandemic, adults and their healthcare providers should follow the recommended vaccine schedule to protect against serious and sometimes deadly diseases.”

Regular vaccines can be safely administered even as COVID-19 retains its grasp on the United States. “Healthcare providers should follow the CDC’s interim guidance for the safe delivery of vaccines during the pandemic, which includes the use of personal protective equipment and physical distancing,” Dr. Freedman said.

Dr. Freedman has disclosed no relevant financial relationships. Coauthor Henry Bernstein, DO, is the editor of the Current Opinion in Pediatrics Office Pediatrics Series, is a Harvard School of Public Health faculty member, and is a member of the data safety and monitoring board for a Takeda study on intrathecal enzymes for Hunter and San Filippo syndromes. Coauthor Kevin Ault, MD, has served on the data safety and monitoring committee for ACI Clinical.
 

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

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has updated its recommended immunization schedule for adults for 2021.

A summary of the annual update was published online Feb. 11 in the CDC’s Morbidity and Mortality Weekly Report and is available in Annals of Internal Medicine and on the CDC website.

It features a special section on vaccination during the pandemic as well as interim recommendations on administering the Pfizer-BioNtech and Moderna COVID-19 vaccines.

The authors, led by Mark S. Freedman, DVM, MPH, DACVPM, of the CDC’s National Center for Immunization and Respiratory Diseases, in Atlanta, note that this year’s recommendations for adults – persons aged 19 years and older – are largely the same as last year’s. “There have been very few changes,” Dr. Freedman said in an interview. “Changes to the schedule tables and notes were made to harmonize to the greatest extent possible the adult and child/adolescent schedules.”

Changes in the schedule include new or updated ACIP recommendations for influenza, hepatitis A, hepatitis B (Hep B), and human papillomavirus (HPV) as well as for meningococcal serogroups A, C, W, and Y (MenACYW) vaccines, meningococcal B (MenB) vaccines, and the zoster vaccine.

Vaccine-specific changes

Influenza

The schedule highlights updates to the composition of several influenza vaccines, which apply to components in both trivalent and quadrivalent formulations.

The cover page abbreviation for live attenuated influenza vaccine (LAIV) was changed to LAIV4. The abbreviation for live recombinant influenza vaccine (RIV) was changed to RIV4.

For individuals with a history of egg allergy who experience reactions other than hives, the following procedural warning has been added: “If using an influenza vaccine other than RIV4 or ccIIV4, administer in medical setting under supervision of health care provider who can recognize and manage severe allergic reactions.”

Zoster

The zoster vaccine live (Zostavax) has been removed from the schedule because it is no longer available in the United States. The recombinant zoster vaccine Shingrix remains available as a 2-dose regimen for adults aged 50 years or older.

HPV

As in previous years, HPV vaccination is routinely recommended for persons aged 11-12 years, with catch-up vaccination for those aged 26 or younger. Catch-up vaccination can be considered with shared decision making for those aged 27 through 45. In this year’s schedule, in the pregnancy column, the color pink, which formerly indicated “delay until after pregnancy,” has been replaced with red and an asterisk, indicating “vaccinate after pregnancy.”

HepB

ACIP continues to recommend vaccination of adults at risk for HepB; however, the text overlay has been changed to read, “2, 3, or 4 doses, depending on vaccine or condition.” Additionally, HepB vaccination is now routinely recommended for adults younger than 60 years with diabetes. For those with diabetes who are older than 60, shared decision making is recommended.

Meningococcal vaccine

ACIP continues to recommend routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for persons at increased risk for meningococcal disease caused by serogroups A, C, W, or Y. The MenQuadfi (MenACWY-TT) vaccine, which was first licensed in 2020, has been added to all relevant sections of MenACWY vaccines. For MenACWY booster doses, new text addresses special situations, including outbreaks.

Improvements have been made to text and layout, Dr. Freedman said. An example is the minimizing of specialized text. Other changes were made to ensure more consistent text structure and language. Various fine-tunings of color and positioning were made to the cover page and tables, and the wording of the notes sections was improved.

Vaccination in the pandemic

The updated schedule outlines guidance on the use of COVID-19 vaccines approved by the Food and Drug Administration under emergency use authorization, with interim recommendations for the Pfizer-BioNTech COVID-19 vaccine for people aged 16 and older and the Moderna COVID-19 vaccine for people aged 18 and older.

The authors stress the importance of receiving the recommended routine and catch-up immunizations notwithstanding widespread anxiety about visiting medical offices. Last spring, the CDC reported a dramatic drop in child vaccinations after the declaration of the national emergency in mid-March, a drop attributed to fear of COVID-19 exposure.

“ACIP continued to meet and make recommendations during the pandemic,” Dr. Freedman said. “Our recommendation remains that despite challenges caused by the COVID-19 pandemic, adults and their healthcare providers should follow the recommended vaccine schedule to protect against serious and sometimes deadly diseases.”

Regular vaccines can be safely administered even as COVID-19 retains its grasp on the United States. “Healthcare providers should follow the CDC’s interim guidance for the safe delivery of vaccines during the pandemic, which includes the use of personal protective equipment and physical distancing,” Dr. Freedman said.

Dr. Freedman has disclosed no relevant financial relationships. Coauthor Henry Bernstein, DO, is the editor of the Current Opinion in Pediatrics Office Pediatrics Series, is a Harvard School of Public Health faculty member, and is a member of the data safety and monitoring board for a Takeda study on intrathecal enzymes for Hunter and San Filippo syndromes. Coauthor Kevin Ault, MD, has served on the data safety and monitoring committee for ACI Clinical.
 

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

Patients who received intensive lifestyle training by coaches in the primary care setting experienced improvement in several indicators of cardiometabolic health in a 2-year trial.

The 803 trial participants comprised a racially diverse, low-income population with obesity. In this study, primary care clinics were randomly assigned to provide weight-loss coaching or usual care. Patients at the intensive training clinics lost significantly more weight than the other patients, as reported in a paper published in September in the New England Journal of Medicine on the PROmoting Successful Weight Loss in Primary CarE in Louisiana (PROPEL) trial. The patients who received weight loss coaching also had significantly more improvement in HDL cholesterol levels, total to HDL cholesterol ratios, and metabolic syndrome severity score, said researchers in the new paper on the PROPEL trial, which was published in Circulation on February 8 .

“We believe that one reason for success of the program was the use of a health coach [who] was embedded in the primary care office,” said lead author Peter Katzmarzyk, PhD, associate executive director for population and public health sciences at the Pennington Biomedical Research Center, Baton Rouge, La. “This way, the patients could get their counseling in a familiar environment and did not have to go to a different setting. The coaches developed close relationships with the patients over the 2 years, and this helped develop a sense of responsibility in the patients as the coaches were helping the patients to set goals and kept them accountable.”

In the PROPEL study, 67% of patients were Black and had low health literacy scores that corresponded with less than a ninth-grade education level. The intensive lifestyle intervention program included weekly sessions with the trained health coaches over the first 6 months — 16 face-to-face and 6 over the phone — and then at least monthly for the last 18 months. The coaches had higher education degrees in nutrition, physical activity, or behavioral medicine. Before the program started, the coaches also received training in the management of obesity and related health issues, health literacy, and patient communication and education. The goal of the program was 10% weight loss, using personalized action plans on eating, dieting, and physical activity.

Those in the usual-care clinics continued receiving normal care and received newsletters on health topics, such as the importance of sleep and tips for limiting time spent sitting. The primary care physicians at those clinics also were given a presentation with Centers for Medicare & Medicaid Services (CMS) information on intensive lifestyle interventions for obesity.
 

Cholesterol changes in intervention vs. control group

HDL cholesterol improved significantly among the coached patients, compared with the other patients, with a mean difference of 4.1 mg/dL at 1 year and 4.6 mg/dL at 2 years (P less than .01 for both). The total cholesterol to HDL cholesterol ratio showed a similarly significant difference in decline, with a between-group difference of –0.29 at 1 year and –0.31 at 2 years (P less than .01 for both). Also, the difference in the change in metabolic severity scores were –0.40 at 1 year and –0.21 at 2 years (P less than .01 for both).

Fasting blood glucose had declined after the 1st year by a significantly greater degree in the clinics with coaching, compared with the others, but not after the second year, researchers found.

There were no significant differences seen in total cholesterol, LDL cholesterol, non-HDL cholesterol, or blood pressure. Dr. Katzmarzyk said the likely reason for no change in blood pressure was that it was already relatively well-controlled at baseline for all the patients.
 

Funding barriers to obesity treatment

The CMS currently cover intensive training for obesity if delivered directly by a primary care physician, according to the authors of the new paper. Dr. Katzmarzyk said he hopes that will change.

“We are hoping that the evidence provided in this study may change the way that CMS funds obesity treatment in the future by allowing an expansion of the care team,” he said.

John Flack, MD, chair of internal medicine at Southern Illinois University, Springfield, said that the main achievement of the study was that it showed that intensive weight-loss training in the primary-care setting could be accomplished in a racially diverse population with low health literacy.

“You can’t just automatically assume just because you’ve seen it in some other populations that you can replicate this in every population, so they’ve done a really good job,” he said.

That programs are eligible for reimbursement only if they’re run by primary-care physicians is an ongoing problem, he said.

“You don’t necessarily need to be a physician to do this,” Dr. Flack said.

For best results, payment for coaching should not be tied to office visits, Dr. Flack noted.

“If they’re de-tethered from the office visits and you’re paid for quality ... you’re going to build out your infrastructure differently to care for people,” he said.

Andrew Freeman, MD, associate professor of medicine at the University of Colorado, Denver, and cochair of the American College of Cardiology’s nutrition and lifestyle work group, said the findings dovetail with his experience.

“I’m a huge believer that when people need to make lifestyle changes, having someone hold their hand and guide them through the effort is incredibly rewarding and incredibly powerful,” said Dr. Freeman, who also oversees the intensive cardiac rehab program at National Jewish Health in Denver.

A program like this needs proper funding in order to work, Dr, Freeman noted. He added that, even with coaches being paid well, “if you are able to prevent just one readmission for, say, heart failure a month . . . you could be saving millions of dollars over just a couple of years.”

Dr. Katzmarzyk, Dr. Flack, and Dr. Freeman reported no relevant disclosures. Louisiana State University, Pennington Biomedical Research Center, and Montclair State University have interest in the intellectual property surrounding a weight graph used in the study. The other researchers reported grants and/or fees from Bayer, Boehringer Ingelheim, Gilead, Takeda, Novo Nordisk, and other companies.
 

Patients who received intensive lifestyle training by coaches in the primary care setting experienced improvement in several indicators of cardiometabolic health in a 2-year trial.

The 803 trial participants comprised a racially diverse, low-income population with obesity. In this study, primary care clinics were randomly assigned to provide weight-loss coaching or usual care. Patients at the intensive training clinics lost significantly more weight than the other patients, as reported in a paper published in September in the New England Journal of Medicine on the PROmoting Successful Weight Loss in Primary CarE in Louisiana (PROPEL) trial. The patients who received weight loss coaching also had significantly more improvement in HDL cholesterol levels, total to HDL cholesterol ratios, and metabolic syndrome severity score, said researchers in the new paper on the PROPEL trial, which was published in Circulation on February 8 .

“We believe that one reason for success of the program was the use of a health coach [who] was embedded in the primary care office,” said lead author Peter Katzmarzyk, PhD, associate executive director for population and public health sciences at the Pennington Biomedical Research Center, Baton Rouge, La. “This way, the patients could get their counseling in a familiar environment and did not have to go to a different setting. The coaches developed close relationships with the patients over the 2 years, and this helped develop a sense of responsibility in the patients as the coaches were helping the patients to set goals and kept them accountable.”

In the PROPEL study, 67% of patients were Black and had low health literacy scores that corresponded with less than a ninth-grade education level. The intensive lifestyle intervention program included weekly sessions with the trained health coaches over the first 6 months — 16 face-to-face and 6 over the phone — and then at least monthly for the last 18 months. The coaches had higher education degrees in nutrition, physical activity, or behavioral medicine. Before the program started, the coaches also received training in the management of obesity and related health issues, health literacy, and patient communication and education. The goal of the program was 10% weight loss, using personalized action plans on eating, dieting, and physical activity.

Those in the usual-care clinics continued receiving normal care and received newsletters on health topics, such as the importance of sleep and tips for limiting time spent sitting. The primary care physicians at those clinics also were given a presentation with Centers for Medicare & Medicaid Services (CMS) information on intensive lifestyle interventions for obesity.
 

Cholesterol changes in intervention vs. control group

HDL cholesterol improved significantly among the coached patients, compared with the other patients, with a mean difference of 4.1 mg/dL at 1 year and 4.6 mg/dL at 2 years (P less than .01 for both). The total cholesterol to HDL cholesterol ratio showed a similarly significant difference in decline, with a between-group difference of –0.29 at 1 year and –0.31 at 2 years (P less than .01 for both). Also, the difference in the change in metabolic severity scores were –0.40 at 1 year and –0.21 at 2 years (P less than .01 for both).

Fasting blood glucose had declined after the 1st year by a significantly greater degree in the clinics with coaching, compared with the others, but not after the second year, researchers found.

There were no significant differences seen in total cholesterol, LDL cholesterol, non-HDL cholesterol, or blood pressure. Dr. Katzmarzyk said the likely reason for no change in blood pressure was that it was already relatively well-controlled at baseline for all the patients.
 

Funding barriers to obesity treatment

The CMS currently cover intensive training for obesity if delivered directly by a primary care physician, according to the authors of the new paper. Dr. Katzmarzyk said he hopes that will change.

“We are hoping that the evidence provided in this study may change the way that CMS funds obesity treatment in the future by allowing an expansion of the care team,” he said.

John Flack, MD, chair of internal medicine at Southern Illinois University, Springfield, said that the main achievement of the study was that it showed that intensive weight-loss training in the primary-care setting could be accomplished in a racially diverse population with low health literacy.

“You can’t just automatically assume just because you’ve seen it in some other populations that you can replicate this in every population, so they’ve done a really good job,” he said.

That programs are eligible for reimbursement only if they’re run by primary-care physicians is an ongoing problem, he said.

“You don’t necessarily need to be a physician to do this,” Dr. Flack said.

For best results, payment for coaching should not be tied to office visits, Dr. Flack noted.

“If they’re de-tethered from the office visits and you’re paid for quality ... you’re going to build out your infrastructure differently to care for people,” he said.

Andrew Freeman, MD, associate professor of medicine at the University of Colorado, Denver, and cochair of the American College of Cardiology’s nutrition and lifestyle work group, said the findings dovetail with his experience.

“I’m a huge believer that when people need to make lifestyle changes, having someone hold their hand and guide them through the effort is incredibly rewarding and incredibly powerful,” said Dr. Freeman, who also oversees the intensive cardiac rehab program at National Jewish Health in Denver.

A program like this needs proper funding in order to work, Dr, Freeman noted. He added that, even with coaches being paid well, “if you are able to prevent just one readmission for, say, heart failure a month . . . you could be saving millions of dollars over just a couple of years.”

Dr. Katzmarzyk, Dr. Flack, and Dr. Freeman reported no relevant disclosures. Louisiana State University, Pennington Biomedical Research Center, and Montclair State University have interest in the intellectual property surrounding a weight graph used in the study. The other researchers reported grants and/or fees from Bayer, Boehringer Ingelheim, Gilead, Takeda, Novo Nordisk, and other companies.
 

Patients who received intensive lifestyle training by coaches in the primary care setting experienced improvement in several indicators of cardiometabolic health in a 2-year trial.

The 803 trial participants comprised a racially diverse, low-income population with obesity. In this study, primary care clinics were randomly assigned to provide weight-loss coaching or usual care. Patients at the intensive training clinics lost significantly more weight than the other patients, as reported in a paper published in September in the New England Journal of Medicine on the PROmoting Successful Weight Loss in Primary CarE in Louisiana (PROPEL) trial. The patients who received weight loss coaching also had significantly more improvement in HDL cholesterol levels, total to HDL cholesterol ratios, and metabolic syndrome severity score, said researchers in the new paper on the PROPEL trial, which was published in Circulation on February 8 .

“We believe that one reason for success of the program was the use of a health coach [who] was embedded in the primary care office,” said lead author Peter Katzmarzyk, PhD, associate executive director for population and public health sciences at the Pennington Biomedical Research Center, Baton Rouge, La. “This way, the patients could get their counseling in a familiar environment and did not have to go to a different setting. The coaches developed close relationships with the patients over the 2 years, and this helped develop a sense of responsibility in the patients as the coaches were helping the patients to set goals and kept them accountable.”

In the PROPEL study, 67% of patients were Black and had low health literacy scores that corresponded with less than a ninth-grade education level. The intensive lifestyle intervention program included weekly sessions with the trained health coaches over the first 6 months — 16 face-to-face and 6 over the phone — and then at least monthly for the last 18 months. The coaches had higher education degrees in nutrition, physical activity, or behavioral medicine. Before the program started, the coaches also received training in the management of obesity and related health issues, health literacy, and patient communication and education. The goal of the program was 10% weight loss, using personalized action plans on eating, dieting, and physical activity.

Those in the usual-care clinics continued receiving normal care and received newsletters on health topics, such as the importance of sleep and tips for limiting time spent sitting. The primary care physicians at those clinics also were given a presentation with Centers for Medicare & Medicaid Services (CMS) information on intensive lifestyle interventions for obesity.
 

Cholesterol changes in intervention vs. control group

HDL cholesterol improved significantly among the coached patients, compared with the other patients, with a mean difference of 4.1 mg/dL at 1 year and 4.6 mg/dL at 2 years (P less than .01 for both). The total cholesterol to HDL cholesterol ratio showed a similarly significant difference in decline, with a between-group difference of –0.29 at 1 year and –0.31 at 2 years (P less than .01 for both). Also, the difference in the change in metabolic severity scores were –0.40 at 1 year and –0.21 at 2 years (P less than .01 for both).

Fasting blood glucose had declined after the 1st year by a significantly greater degree in the clinics with coaching, compared with the others, but not after the second year, researchers found.

There were no significant differences seen in total cholesterol, LDL cholesterol, non-HDL cholesterol, or blood pressure. Dr. Katzmarzyk said the likely reason for no change in blood pressure was that it was already relatively well-controlled at baseline for all the patients.
 

Funding barriers to obesity treatment

The CMS currently cover intensive training for obesity if delivered directly by a primary care physician, according to the authors of the new paper. Dr. Katzmarzyk said he hopes that will change.

“We are hoping that the evidence provided in this study may change the way that CMS funds obesity treatment in the future by allowing an expansion of the care team,” he said.

John Flack, MD, chair of internal medicine at Southern Illinois University, Springfield, said that the main achievement of the study was that it showed that intensive weight-loss training in the primary-care setting could be accomplished in a racially diverse population with low health literacy.

“You can’t just automatically assume just because you’ve seen it in some other populations that you can replicate this in every population, so they’ve done a really good job,” he said.

That programs are eligible for reimbursement only if they’re run by primary-care physicians is an ongoing problem, he said.

“You don’t necessarily need to be a physician to do this,” Dr. Flack said.

For best results, payment for coaching should not be tied to office visits, Dr. Flack noted.

“If they’re de-tethered from the office visits and you’re paid for quality ... you’re going to build out your infrastructure differently to care for people,” he said.

Andrew Freeman, MD, associate professor of medicine at the University of Colorado, Denver, and cochair of the American College of Cardiology’s nutrition and lifestyle work group, said the findings dovetail with his experience.

“I’m a huge believer that when people need to make lifestyle changes, having someone hold their hand and guide them through the effort is incredibly rewarding and incredibly powerful,” said Dr. Freeman, who also oversees the intensive cardiac rehab program at National Jewish Health in Denver.

A program like this needs proper funding in order to work, Dr, Freeman noted. He added that, even with coaches being paid well, “if you are able to prevent just one readmission for, say, heart failure a month . . . you could be saving millions of dollars over just a couple of years.”

Dr. Katzmarzyk, Dr. Flack, and Dr. Freeman reported no relevant disclosures. Louisiana State University, Pennington Biomedical Research Center, and Montclair State University have interest in the intellectual property surrounding a weight graph used in the study. The other researchers reported grants and/or fees from Bayer, Boehringer Ingelheim, Gilead, Takeda, Novo Nordisk, and other companies.
 

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.

In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.

Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.

“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.

Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.

The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.

In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.

“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”

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

Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.

In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.

Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.

“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.

Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.

The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.

In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.

“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”

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

Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.

In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.

Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.

“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.

Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.

The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.

In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.

“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”

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

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

While 34 million adults in the United States have received a COVID-19 vaccine, children and teenagers are waiting at the back of the line, mostly ineligible for the authorized vaccines. That secondary status is rapidly changing though, as experts expect vaccinations of adolescents to begin by this summer.

The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.

Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”

She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.

“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”

Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.

Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.

Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
 

Easing the burden

Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”

The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”

As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.

Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.

Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.

“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.

Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.

She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
 

Teen trials underway

Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.

The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.

Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.

Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.

“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.

Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.

Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.

He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.

“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”

Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.

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

While 34 million adults in the United States have received a COVID-19 vaccine, children and teenagers are waiting at the back of the line, mostly ineligible for the authorized vaccines. That secondary status is rapidly changing though, as experts expect vaccinations of adolescents to begin by this summer.

The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.

Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”

She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.

“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”

Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.

Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.

Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
 

Easing the burden

Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”

The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”

As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.

Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.

Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.

“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.

Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.

She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
 

Teen trials underway

Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.

The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.

Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.

Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.

“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.

Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.

Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.

He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.

“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”

Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.

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

While 34 million adults in the United States have received a COVID-19 vaccine, children and teenagers are waiting at the back of the line, mostly ineligible for the authorized vaccines. That secondary status is rapidly changing though, as experts expect vaccinations of adolescents to begin by this summer.

The vaccinations can’t come soon enough for parents like Stacy Hillenburg, a developmental therapist in Aurora, Ill., whose 9-year-old son takes immunosuppressants because he had a heart transplant when he was 7 weeks old. Although school-age children aren’t yet included in clinical trials, if her 12- and 13-year-old daughters could get vaccinated, along with both parents, then the family could relax some of the protocols they currently follow to prevent infection.

Whenever they are around other people, even masked and socially distanced, they come home and immediately shower and change their clothes. So far, no one in the family has been infected with COVID, but the anxiety is ever-present. “I can’t wait for it to come out,” Ms. Hillenburg said of a pediatric COVID vaccine. “It will ease my mind so much.”

She isn’t alone in that anticipation. In the fall, the American Academy of Pediatrics and other pediatric vaccine experts urged faster action on pediatric vaccine trials and worried that children would be left behind as adults gained protection from COVID. But recent developments have eased those concerns.

“Over the next couple of months, we will be doing trials in an age-deescalation manner,” with studies moving gradually to younger children, Anthony S. Fauci, MD, chief medical adviser on COVID-19 to the president, said in a coronavirus response team briefing on Jan. 29. “So that hopefully, as we get to the late spring and summer, we will have children being able to be vaccinated.”

Pfizer completed enrollment of 2,259 teens aged 12-15 years in late January and expects to move forward with a separate pediatric trial of children aged 5-11 years by this spring, Keanna Ghazvini, senior associate for global media relations at Pfizer, said in an interview.

Enrollment in Moderna’s TeenCove study of adolescents ages 12-17 years began slowly in late December, but the pace has since picked up, said company spokesperson Colleen Hussey. “We continue to bring clinical trial sites online, and we are on track to provide updated data around mid-year 2021.” A trial extension in children 11 years and younger is expected to begin later in 2021.

Johnson & Johnson and AstraZeneca said they expect to begin adolescent trials in early 2021, according to data shared by the Advisory Committee on Immunization Practices. An interim analysis of J&J’s Janssen COVID-19 vaccine trial data, released on Jan. 29, showed it was 72% effective in US participants aged 18 years or older. AstraZeneca’s U.S. trial in adults is ongoing.
 

Easing the burden

Vaccination could lessen children’s risk of severe disease as well as the social and emotional burdens of the pandemic, says James Campbell, MD, a pediatric infectious disease specialist at the University of Maryland’s Center for Vaccine Development in Baltimore, which was involved in the Moderna and early-phase Pfizer trials. He coauthored a September 2020 article in Clinical Infectious Diseases titled: “Warp Speed for COVID-19 vaccines: Why are children stuck in neutral?”

The adolescent trials are a vital step to ensure timely vaccine access for teens and younger children. “It is reasonable, when you have limited vaccine, that your rollout goes to the highest priority and then moves to lower and lower priorities. In adults, we’re just saying: ‘Wait your turn,’ ” he said of the current vaccination effort. “If we didn’t have the [vaccine trial] data in children, we’d be saying: ‘You don’t have a turn.’ ”

As the pandemic has worn on, the burden on children has grown. As of Tuesday, 269 children had died of COVID-19. That is well above the highest annual death toll recorded during a regular flu season – 188 flu deaths among children and adolescents under 18 in the 2019-2020 and 2017-2018 flu seasons.

Children are less likely to transmit COVID-19 in their household than adults, according to a meta-analysis of 54 studies published in JAMA Network Open. But that does not necessarily mean children are less infectious, the authors said, noting that unmeasured factors could have affected the spread of infection among adults.

Moreover, children and adolescents need protection from COVID infection – and from the potential for severe disease or lingering effects – and, given that there are 74 million children and teens in the United States, their vaccination is an important part of stopping the pandemic, said Grace Lee, MD, professor of pediatrics at Stanford (Calif.) University, and cochair of ACIP’s COVID-19 Vaccine Safety Technical Subgroup.

“In order to interrupt transmission, I don’t see how we’re going to do that without vaccinating children and adolescents,” she said.

Dr. Lee said her 16-year-old daughter misses the normal teenage social life and is excited about getting the vaccine when she is eligible. (Adolescents without high-risk conditions are in the lowest vaccination tier, according to ACIP recommendations.) “There is truly individual protection to be gained,” Dr. Lee said.

She noted that researchers continue to assess the immune responses to the adult vaccines – even looking at immune characteristics of the small percentage of people who aren’t protected from infection – and that information helps in the evaluation of the pediatric immune responses. As the trials expand to younger children and infants, dosing will be a major focus. “How many doses do they need they need to receive the same immunity? Safety considerations will be critically important,” she said.
 

Teen trials underway

Pfizer/BioNTech extended its adult trial to 16- and 17-year-olds in October, which enabled older teens to be included in its emergency-use authorization. They and younger teens, ages 12-15, receive the same dose as adults.

The ongoing trials with Pfizer and Moderna vaccines are immunobridging trials, designed to study safety and immunogenicity. Investigators will compare the teens’ immune response with the findings from the larger adult trials. When the trials expand to school-age children (6-12 years), protocols call for testing the safety and immunogenicity of a half-dose vaccine as well as the full dose.

Children ages 2-5 years and infants and toddlers will be enrolled in future trials, studying safety and immunogenicity of full, half, or even quarter dosages. The Pediatric Research Equity Act of 2003 requires licensed vaccines to be tested for safety and efficacy in children, unless they are not appropriate for a pediatric population.

Demand for the teen trials has been strong. At Cincinnati Children’s Hospital Medical Center, 259 teenagers joined the Pfizer/BioNTech trial, but some teenagers were turned away when the trial’s national enrollment closed in late January.

“Many of the children are having no side effects, and if they are, they’re having the same [effects] as the young adults – local redness or pain, fatigue, and headaches,” said Robert Frenck, MD, director of the Cincinnati Children’s Gamble Program for Clinical Studies.

Parents may share some of the vaccine hesitancy that has affected adult vaccination. But that is balanced by the hope that vaccines will end the pandemic and usher in a new normal. “If it looks like [vaccines] will increase the likelihood of children returning to school safely, that may be a motivating factor,” Dr. Frenck said.

Cody Meissner, MD, chief of the pediatric infectious disease service at Tufts Medical Center, Boston, was initially cautious about the extension of vaccination to adolescents. A member of the Vaccine and Related Biological Products Advisory Committee, which evaluates data and makes recommendations to the Food and Drug Administration, Dr. Meissner initially abstained in the vote on the Pfizer/BioNTech emergency-use authorization for people 16 and older.

He noted that, at the time the committee reviewed the Pfizer vaccine, the company had data available for just 134 teenagers, half of whom received a placebo. But the vaccination of 34 million adults has provided robust data about the vaccine’s safety, and the trial expansion into adolescents is important.

“I’m comfortable with the way these trials are going now,” he said. “This is the way I was hoping they would go.”

Ms. Hillenburg is on the parent advisory board of Voices for Vaccines, an organization of parents supporting vaccination that is affiliated with the Task Force for Global Health, an Atlanta-based independent public health organization. Dr. Campbell’s institution has received funds to conduct clinical trials from the National Institutes of Health and several companies, including Merck, GlaxoSmithKline, Sanofi, Pfizer, and Moderna. He has served pro bono on many safety and data monitoring committees. Dr. Frenck’s institution is receiving funds to conduct the Pfizer trial. In the past 5 years, he has also participated in clinical trials for GlaxoSmithKline, Merck, and Meissa vaccines. Dr. Lee and Dr. Meissner disclosed no relevant financial relationships.

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

Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.

“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”

The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.

“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said

The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
 

Mathematics, not hypotheses

To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.

The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.

Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
 

Heart failure and risk reduced

In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.

When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).

While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”

She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
 

Machine learning mines observational trials

Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”

He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.

“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”

He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”

The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.

*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.

Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.

“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”

The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.

“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said

The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
 

Mathematics, not hypotheses

To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.

The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.

Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
 

Heart failure and risk reduced

In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.

When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).

While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”

She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
 

Machine learning mines observational trials

Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”

He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.

“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”

He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”

The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.

*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.

Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.

“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”

The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.

“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said

The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
 

Mathematics, not hypotheses

To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.

The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.

Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
 

Heart failure and risk reduced

In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.

When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).

While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”

She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
 

Machine learning mines observational trials

Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”

He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.

“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”

He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”

The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.

*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.