Clinician Reviews

This transcript has been edited for clarity.

I’m Dr. Neil Skolnik. Today we’re going to talk about the consensus report by the American Diabetes Association and the European Association for the Study of Diabetes on the management of hyperglycemia.

A lot has changed in this consensus statement. It covers a lot of ground. We’re going to focus today on pharmacologic management.

After lifestyle modifications, metformin is no longer the go-to drug for every patient in the management of hyperglycemia. It is recommended that we assess each patient’s personal characteristics in deciding what medication to prescribe. For patients at high cardiorenal risk, refer to the left side of the algorithm and to the right side for all other patients.

American Diabetes Association

• Very high efficacy for glucose lowering: dulaglutide at a high dose, semaglutide, tirzepatide, insulin, or combination injectable agents (GLP-1 receptor agonist/insulin combinations).
• High glucose-lowering efficacy: a GLP-1 receptor agonist not already mentioned, metformin, SGLT-2 inhibitors, sulfonylureas, thiazolidinediones.
• Intermediate glucose lowering efficacy: dipeptidyl peptidase 4 (DPP-4) inhibitors.

Weight management. For weight management, lifestyle modification (diet and exercise) is important. If lifestyle modification alone is insufficient, consider either a medication that specifically helps with weight management or metabolic surgery.

We particularly want to focus on weight management in patients who have complications from obesity. What would those complications be? Sleep apnea, hip or knee pain from arthritis, back pain – that is, biomechanical complications of obesity or nonalcoholic fatty liver disease. Medications for weight loss are listed by degree of efficacy:

• Very high efficacy for weight loss: semaglutide, tirzepatide.
• High efficacy for weight loss: dulaglutide and liraglutide.
• Intermediate for weight loss: GLP-1 receptor agonist (not listed above), SGLT-2 inhibitor.
• Neutral for weight loss: DPP-4 inhibitors and metformin.

Where does insulin fit in? If patients present with a very high A1c, if they are on other medications and their A1c is still not to goal, or if they are catabolic and losing weight because of their diabetes, then insulin has an important place in management.

These are incredibly important guidelines that provide a clear algorithm for a personalized approach to diabetes management.
 

Dr. Skolnik is professor, department of family medicine, Sidney Kimmel Medical College, Philadelphia, and associate director, department of family medicine, Abington (Pa.) Jefferson Health. He reported conflicts of interest with AstraZeneca, Teva, Eli Lilly, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

I’m Dr. Neil Skolnik. Today we’re going to talk about the consensus report by the American Diabetes Association and the European Association for the Study of Diabetes on the management of hyperglycemia.

A lot has changed in this consensus statement. It covers a lot of ground. We’re going to focus today on pharmacologic management.

After lifestyle modifications, metformin is no longer the go-to drug for every patient in the management of hyperglycemia. It is recommended that we assess each patient’s personal characteristics in deciding what medication to prescribe. For patients at high cardiorenal risk, refer to the left side of the algorithm and to the right side for all other patients.

American Diabetes Association

• Very high efficacy for glucose lowering: dulaglutide at a high dose, semaglutide, tirzepatide, insulin, or combination injectable agents (GLP-1 receptor agonist/insulin combinations).
• High glucose-lowering efficacy: a GLP-1 receptor agonist not already mentioned, metformin, SGLT-2 inhibitors, sulfonylureas, thiazolidinediones.
• Intermediate glucose lowering efficacy: dipeptidyl peptidase 4 (DPP-4) inhibitors.

Weight management. For weight management, lifestyle modification (diet and exercise) is important. If lifestyle modification alone is insufficient, consider either a medication that specifically helps with weight management or metabolic surgery.

We particularly want to focus on weight management in patients who have complications from obesity. What would those complications be? Sleep apnea, hip or knee pain from arthritis, back pain – that is, biomechanical complications of obesity or nonalcoholic fatty liver disease. Medications for weight loss are listed by degree of efficacy:

• Very high efficacy for weight loss: semaglutide, tirzepatide.
• High efficacy for weight loss: dulaglutide and liraglutide.
• Intermediate for weight loss: GLP-1 receptor agonist (not listed above), SGLT-2 inhibitor.
• Neutral for weight loss: DPP-4 inhibitors and metformin.

Where does insulin fit in? If patients present with a very high A1c, if they are on other medications and their A1c is still not to goal, or if they are catabolic and losing weight because of their diabetes, then insulin has an important place in management.

These are incredibly important guidelines that provide a clear algorithm for a personalized approach to diabetes management.
 

Dr. Skolnik is professor, department of family medicine, Sidney Kimmel Medical College, Philadelphia, and associate director, department of family medicine, Abington (Pa.) Jefferson Health. He reported conflicts of interest with AstraZeneca, Teva, Eli Lilly, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

I’m Dr. Neil Skolnik. Today we’re going to talk about the consensus report by the American Diabetes Association and the European Association for the Study of Diabetes on the management of hyperglycemia.

A lot has changed in this consensus statement. It covers a lot of ground. We’re going to focus today on pharmacologic management.

After lifestyle modifications, metformin is no longer the go-to drug for every patient in the management of hyperglycemia. It is recommended that we assess each patient’s personal characteristics in deciding what medication to prescribe. For patients at high cardiorenal risk, refer to the left side of the algorithm and to the right side for all other patients.

American Diabetes Association

• Very high efficacy for glucose lowering: dulaglutide at a high dose, semaglutide, tirzepatide, insulin, or combination injectable agents (GLP-1 receptor agonist/insulin combinations).
• High glucose-lowering efficacy: a GLP-1 receptor agonist not already mentioned, metformin, SGLT-2 inhibitors, sulfonylureas, thiazolidinediones.
• Intermediate glucose lowering efficacy: dipeptidyl peptidase 4 (DPP-4) inhibitors.

Weight management. For weight management, lifestyle modification (diet and exercise) is important. If lifestyle modification alone is insufficient, consider either a medication that specifically helps with weight management or metabolic surgery.

We particularly want to focus on weight management in patients who have complications from obesity. What would those complications be? Sleep apnea, hip or knee pain from arthritis, back pain – that is, biomechanical complications of obesity or nonalcoholic fatty liver disease. Medications for weight loss are listed by degree of efficacy:

• Very high efficacy for weight loss: semaglutide, tirzepatide.
• High efficacy for weight loss: dulaglutide and liraglutide.
• Intermediate for weight loss: GLP-1 receptor agonist (not listed above), SGLT-2 inhibitor.
• Neutral for weight loss: DPP-4 inhibitors and metformin.

Where does insulin fit in? If patients present with a very high A1c, if they are on other medications and their A1c is still not to goal, or if they are catabolic and losing weight because of their diabetes, then insulin has an important place in management.

These are incredibly important guidelines that provide a clear algorithm for a personalized approach to diabetes management.
 

Dr. Skolnik is professor, department of family medicine, Sidney Kimmel Medical College, Philadelphia, and associate director, department of family medicine, Abington (Pa.) Jefferson Health. He reported conflicts of interest with AstraZeneca, Teva, Eli Lilly, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer. A version of this article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

The incidence of new COVID-19 cases in children seems to have stabilized as the national count remained under 30,000 for the fifth consecutive week, but hospitalization data may indicate some possible turbulence.

Just over 28,000 pediatric cases were reported during the week of Nov. 4-10, a drop of 5.4% from the previous week, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID-19 report involving data from state and territorial health departments, several of which are no longer updating their websites.

The stability in weekly cases, however, comes in contrast to a very recent and considerable increase in new hospital admissions of children aged 0-17 years with confirmed COVID-19. That rate, which was 0.18 hospitalizations per 100,000 population on Nov. 7 and 0.19 per 100,000 on Nov. 8 and 9, jumped all the way to 0.34 on Nov. 10 and 0.48 on Nov. 11, according to data from the Centers for Disease Control and Prevention. That is the highest rate since the closing days of the Omicron surge in February.

The rate for Nov. 12, the most recent one available, was down slightly to 0.47 admissions per 100,000. There doesn’t seem to be any evidence in the CDC’s data of a similar sudden increase in new hospitalizations among any other age group, and no age group, including children, shows any sign of a recent increase in emergency department visits with diagnosed COVID. (The CDC has not yet responded to our inquiry about this development.)

Centers for Disease Control and Prevention

The two most recent 7-day averages for new admissions in children aged 0-17 show a small increase, but they cover the periods of Oct. 15 to Oct. 31, when there were 126 admissions per day, and Nov. 1 to Nov. 7, when the average went up to 133 per day, the CDC said on its COVID Data Tracker.

The CDC does not publish a weekly count of new COVID cases, but its latest data on the rate of incident cases seem to agree with the AAP/CHA figures: A gradual decline in all age groups, including children, since the beginning of September.

Vaccinations, on the other hand, bucked their recent trend and increased in the last week. About 43,000 children under age 5 years received their initial dose of COVID vaccine during Nov. 3-9, compared with 30,000 and 33,000 the 2 previous weeks, while 5- to 11-year-olds hit their highest weekly mark (31,000) since late August and 12- to 17-year-olds had their biggest week (27,000) since mid-August, the AAP reported based on CDC data.


 

The incidence of new COVID-19 cases in children seems to have stabilized as the national count remained under 30,000 for the fifth consecutive week, but hospitalization data may indicate some possible turbulence.

Just over 28,000 pediatric cases were reported during the week of Nov. 4-10, a drop of 5.4% from the previous week, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID-19 report involving data from state and territorial health departments, several of which are no longer updating their websites.

The stability in weekly cases, however, comes in contrast to a very recent and considerable increase in new hospital admissions of children aged 0-17 years with confirmed COVID-19. That rate, which was 0.18 hospitalizations per 100,000 population on Nov. 7 and 0.19 per 100,000 on Nov. 8 and 9, jumped all the way to 0.34 on Nov. 10 and 0.48 on Nov. 11, according to data from the Centers for Disease Control and Prevention. That is the highest rate since the closing days of the Omicron surge in February.

The rate for Nov. 12, the most recent one available, was down slightly to 0.47 admissions per 100,000. There doesn’t seem to be any evidence in the CDC’s data of a similar sudden increase in new hospitalizations among any other age group, and no age group, including children, shows any sign of a recent increase in emergency department visits with diagnosed COVID. (The CDC has not yet responded to our inquiry about this development.)

Centers for Disease Control and Prevention

The two most recent 7-day averages for new admissions in children aged 0-17 show a small increase, but they cover the periods of Oct. 15 to Oct. 31, when there were 126 admissions per day, and Nov. 1 to Nov. 7, when the average went up to 133 per day, the CDC said on its COVID Data Tracker.

The CDC does not publish a weekly count of new COVID cases, but its latest data on the rate of incident cases seem to agree with the AAP/CHA figures: A gradual decline in all age groups, including children, since the beginning of September.

Vaccinations, on the other hand, bucked their recent trend and increased in the last week. About 43,000 children under age 5 years received their initial dose of COVID vaccine during Nov. 3-9, compared with 30,000 and 33,000 the 2 previous weeks, while 5- to 11-year-olds hit their highest weekly mark (31,000) since late August and 12- to 17-year-olds had their biggest week (27,000) since mid-August, the AAP reported based on CDC data.


 

The incidence of new COVID-19 cases in children seems to have stabilized as the national count remained under 30,000 for the fifth consecutive week, but hospitalization data may indicate some possible turbulence.

Just over 28,000 pediatric cases were reported during the week of Nov. 4-10, a drop of 5.4% from the previous week, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID-19 report involving data from state and territorial health departments, several of which are no longer updating their websites.

The stability in weekly cases, however, comes in contrast to a very recent and considerable increase in new hospital admissions of children aged 0-17 years with confirmed COVID-19. That rate, which was 0.18 hospitalizations per 100,000 population on Nov. 7 and 0.19 per 100,000 on Nov. 8 and 9, jumped all the way to 0.34 on Nov. 10 and 0.48 on Nov. 11, according to data from the Centers for Disease Control and Prevention. That is the highest rate since the closing days of the Omicron surge in February.

The rate for Nov. 12, the most recent one available, was down slightly to 0.47 admissions per 100,000. There doesn’t seem to be any evidence in the CDC’s data of a similar sudden increase in new hospitalizations among any other age group, and no age group, including children, shows any sign of a recent increase in emergency department visits with diagnosed COVID. (The CDC has not yet responded to our inquiry about this development.)

Centers for Disease Control and Prevention

The two most recent 7-day averages for new admissions in children aged 0-17 show a small increase, but they cover the periods of Oct. 15 to Oct. 31, when there were 126 admissions per day, and Nov. 1 to Nov. 7, when the average went up to 133 per day, the CDC said on its COVID Data Tracker.

The CDC does not publish a weekly count of new COVID cases, but its latest data on the rate of incident cases seem to agree with the AAP/CHA figures: A gradual decline in all age groups, including children, since the beginning of September.

Vaccinations, on the other hand, bucked their recent trend and increased in the last week. About 43,000 children under age 5 years received their initial dose of COVID vaccine during Nov. 3-9, compared with 30,000 and 33,000 the 2 previous weeks, while 5- to 11-year-olds hit their highest weekly mark (31,000) since late August and 12- to 17-year-olds had their biggest week (27,000) since mid-August, the AAP reported based on CDC data.


 

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

On March 26, 2022, Hawaii became the last state in the United States to lift its indoor mask mandate. By the time the current school year started, there were essentially no public school mask mandates either.

Whether you viewed the mask as an emblem of stalwart defiance against a rampaging virus, or a scarlet letter emblematic of the overreaches of public policy, you probably aren’t seeing them much anymore.

And yet, the debate about masks still rages. Who was right, who was wrong? Who trusted science, and what does the science even say? If we brought our country into marriage counseling, would we be told it is time to move on?  To look forward, not backward? To plan for our bright future together?

Perhaps. But this question isn’t really moot just because masks have largely disappeared in the United States. Variants may emerge that lead to more infection waves – and other pandemics may occur in the future. And so I think it is important to discuss a study that, with quite rigorous analysis, attempts to answer the following question: Did masking in schools lower students’ and teachers’ risk of COVID?

We are talking about this study, appearing in the New England Journal of Medicine. The short version goes like this.

Researchers had access to two important sources of data. One – an accounting of all the teachers and students (more than 300,000 of them) in 79 public, noncharter school districts in Eastern Massachusetts who tested positive for COVID every week. Two – the date that each of those school districts lifted their mask mandates or (in the case of two districts) didn’t.

Right away, I’m sure you’re thinking of potential issues. Districts that kept masks even when the statewide ban was lifted are likely quite a bit different from districts that dropped masks right away. You’re right, of course – hold on to that thought; we’ll get there.

But first – the big question – would districts that kept their masks on longer do better when it comes to the rate of COVID infection?

When everyone was masking, COVID case rates were pretty similar. Statewide mandates are lifted in late February – and most school districts remove their mandates within a few weeks – the black line are the two districts (Boston and Chelsea) where mask mandates remained in place.

As time marched on, the case rates in the various districts spread out – with districts that kept masks on longer doing better than those that took them off, and districts that kept masks on the whole time doing best of all.

Prior to the mask mandate lifting, you see very similar COVID rates in districts that would eventually remove the mandate and those that would not, with a bit of noise around the initial Omicron wave which saw just a huge amount of people get infected.

And then, after the mandate was lifted, separation. Districts that held on to masks longer had lower rates of COVID infection.

In all, over the 15-weeks of the study, there were roughly 12,000 extra cases of COVID in the mask-free school districts, which corresponds to about 35% of the total COVID burden during that time. And, yes, kids do well with COVID – on average. But 12,000 extra cases is enough to translate into a significant number of important clinical outcomes – think hospitalizations and post-COVID syndromes. And of course, maybe most importantly, missed school days. Positive kids were not allowed in class no matter what district they were in.

Okay – I promised we’d address confounders. This was not a cluster-randomized trial, where some school districts had their mandates removed based on the vicissitudes of a virtual coin flip, as much as many of us would have been interested to see that. The decision to remove masks was up to the various school boards – and they had a lot of pressure on them from many different directions. But all we need to worry about is whether any of those things that pressure a school board to keep masks on would ALSO lead to fewer COVID cases. That’s how confounders work, and how you can get false results in a study like this.

And yes – districts that kept the masks on longer were different than those who took them right off. But check out how they were different.

The districts that kept masks on longer had more low-income students. More Black and Latino students. More students per classroom. These are all risk factors that increase the risk of COVID infection. In other words, the confounding here goes in the opposite direction of the results. If anything, these factors should make you more certain that masking works.

The authors also adjusted for other factors – the community transmission of COVID-19, vaccination rates, school district sizes, and so on. No major change in the results.

One concern I addressed to Dr. Ellie Murray, the biostatistician on the study – could districts that removed masks simply have been testing more to compensate, leading to increased capturing of cases?

If anything, the schools that kept masks on were testing more than the schools that took them off – again that would tend to imply that the results are even stronger than what was reported.

Is this a perfect study? Of course not – it’s one study, it’s from one state. And the relatively large effects from keeping masks on for one or 2 weeks require us to really embrace the concept of exponential growth of infections, but, if COVID has taught us anything, it is that small changes in initial conditions can have pretty big effects.

My daughter, who goes to a public school here in Connecticut, unmasked, was home with COVID this past week. She’s fine. But you know what? She missed a week of school. I worked from home to be with her – though I didn’t test positive. And that is a real cost to both of us that I think we need to consider when we consider the value of masks. Yes, they’re annoying – but if they keep kids in school, might they be worth it? Perhaps not for now, as cases aren’t surging. But in the future, be it a particularly concerning variant, or a whole new pandemic, we should not discount the simple, cheap, and apparently beneficial act of wearing masks to decrease transmission.

Dr. Perry Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He disclosed no relevant conflicts of interest.

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

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

On March 26, 2022, Hawaii became the last state in the United States to lift its indoor mask mandate. By the time the current school year started, there were essentially no public school mask mandates either.

Whether you viewed the mask as an emblem of stalwart defiance against a rampaging virus, or a scarlet letter emblematic of the overreaches of public policy, you probably aren’t seeing them much anymore.

And yet, the debate about masks still rages. Who was right, who was wrong? Who trusted science, and what does the science even say? If we brought our country into marriage counseling, would we be told it is time to move on?  To look forward, not backward? To plan for our bright future together?

Perhaps. But this question isn’t really moot just because masks have largely disappeared in the United States. Variants may emerge that lead to more infection waves – and other pandemics may occur in the future. And so I think it is important to discuss a study that, with quite rigorous analysis, attempts to answer the following question: Did masking in schools lower students’ and teachers’ risk of COVID?

We are talking about this study, appearing in the New England Journal of Medicine. The short version goes like this.

Researchers had access to two important sources of data. One – an accounting of all the teachers and students (more than 300,000 of them) in 79 public, noncharter school districts in Eastern Massachusetts who tested positive for COVID every week. Two – the date that each of those school districts lifted their mask mandates or (in the case of two districts) didn’t.

Right away, I’m sure you’re thinking of potential issues. Districts that kept masks even when the statewide ban was lifted are likely quite a bit different from districts that dropped masks right away. You’re right, of course – hold on to that thought; we’ll get there.

But first – the big question – would districts that kept their masks on longer do better when it comes to the rate of COVID infection?

When everyone was masking, COVID case rates were pretty similar. Statewide mandates are lifted in late February – and most school districts remove their mandates within a few weeks – the black line are the two districts (Boston and Chelsea) where mask mandates remained in place.

As time marched on, the case rates in the various districts spread out – with districts that kept masks on longer doing better than those that took them off, and districts that kept masks on the whole time doing best of all.

Prior to the mask mandate lifting, you see very similar COVID rates in districts that would eventually remove the mandate and those that would not, with a bit of noise around the initial Omicron wave which saw just a huge amount of people get infected.

And then, after the mandate was lifted, separation. Districts that held on to masks longer had lower rates of COVID infection.

In all, over the 15-weeks of the study, there were roughly 12,000 extra cases of COVID in the mask-free school districts, which corresponds to about 35% of the total COVID burden during that time. And, yes, kids do well with COVID – on average. But 12,000 extra cases is enough to translate into a significant number of important clinical outcomes – think hospitalizations and post-COVID syndromes. And of course, maybe most importantly, missed school days. Positive kids were not allowed in class no matter what district they were in.

Okay – I promised we’d address confounders. This was not a cluster-randomized trial, where some school districts had their mandates removed based on the vicissitudes of a virtual coin flip, as much as many of us would have been interested to see that. The decision to remove masks was up to the various school boards – and they had a lot of pressure on them from many different directions. But all we need to worry about is whether any of those things that pressure a school board to keep masks on would ALSO lead to fewer COVID cases. That’s how confounders work, and how you can get false results in a study like this.

And yes – districts that kept the masks on longer were different than those who took them right off. But check out how they were different.

The districts that kept masks on longer had more low-income students. More Black and Latino students. More students per classroom. These are all risk factors that increase the risk of COVID infection. In other words, the confounding here goes in the opposite direction of the results. If anything, these factors should make you more certain that masking works.

The authors also adjusted for other factors – the community transmission of COVID-19, vaccination rates, school district sizes, and so on. No major change in the results.

One concern I addressed to Dr. Ellie Murray, the biostatistician on the study – could districts that removed masks simply have been testing more to compensate, leading to increased capturing of cases?

If anything, the schools that kept masks on were testing more than the schools that took them off – again that would tend to imply that the results are even stronger than what was reported.

Is this a perfect study? Of course not – it’s one study, it’s from one state. And the relatively large effects from keeping masks on for one or 2 weeks require us to really embrace the concept of exponential growth of infections, but, if COVID has taught us anything, it is that small changes in initial conditions can have pretty big effects.

My daughter, who goes to a public school here in Connecticut, unmasked, was home with COVID this past week. She’s fine. But you know what? She missed a week of school. I worked from home to be with her – though I didn’t test positive. And that is a real cost to both of us that I think we need to consider when we consider the value of masks. Yes, they’re annoying – but if they keep kids in school, might they be worth it? Perhaps not for now, as cases aren’t surging. But in the future, be it a particularly concerning variant, or a whole new pandemic, we should not discount the simple, cheap, and apparently beneficial act of wearing masks to decrease transmission.

Dr. Perry Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He disclosed no relevant conflicts of interest.

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

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

On March 26, 2022, Hawaii became the last state in the United States to lift its indoor mask mandate. By the time the current school year started, there were essentially no public school mask mandates either.

Whether you viewed the mask as an emblem of stalwart defiance against a rampaging virus, or a scarlet letter emblematic of the overreaches of public policy, you probably aren’t seeing them much anymore.

And yet, the debate about masks still rages. Who was right, who was wrong? Who trusted science, and what does the science even say? If we brought our country into marriage counseling, would we be told it is time to move on?  To look forward, not backward? To plan for our bright future together?

Perhaps. But this question isn’t really moot just because masks have largely disappeared in the United States. Variants may emerge that lead to more infection waves – and other pandemics may occur in the future. And so I think it is important to discuss a study that, with quite rigorous analysis, attempts to answer the following question: Did masking in schools lower students’ and teachers’ risk of COVID?

We are talking about this study, appearing in the New England Journal of Medicine. The short version goes like this.

Researchers had access to two important sources of data. One – an accounting of all the teachers and students (more than 300,000 of them) in 79 public, noncharter school districts in Eastern Massachusetts who tested positive for COVID every week. Two – the date that each of those school districts lifted their mask mandates or (in the case of two districts) didn’t.

Right away, I’m sure you’re thinking of potential issues. Districts that kept masks even when the statewide ban was lifted are likely quite a bit different from districts that dropped masks right away. You’re right, of course – hold on to that thought; we’ll get there.

But first – the big question – would districts that kept their masks on longer do better when it comes to the rate of COVID infection?

When everyone was masking, COVID case rates were pretty similar. Statewide mandates are lifted in late February – and most school districts remove their mandates within a few weeks – the black line are the two districts (Boston and Chelsea) where mask mandates remained in place.

As time marched on, the case rates in the various districts spread out – with districts that kept masks on longer doing better than those that took them off, and districts that kept masks on the whole time doing best of all.

Prior to the mask mandate lifting, you see very similar COVID rates in districts that would eventually remove the mandate and those that would not, with a bit of noise around the initial Omicron wave which saw just a huge amount of people get infected.

And then, after the mandate was lifted, separation. Districts that held on to masks longer had lower rates of COVID infection.

In all, over the 15-weeks of the study, there were roughly 12,000 extra cases of COVID in the mask-free school districts, which corresponds to about 35% of the total COVID burden during that time. And, yes, kids do well with COVID – on average. But 12,000 extra cases is enough to translate into a significant number of important clinical outcomes – think hospitalizations and post-COVID syndromes. And of course, maybe most importantly, missed school days. Positive kids were not allowed in class no matter what district they were in.

Okay – I promised we’d address confounders. This was not a cluster-randomized trial, where some school districts had their mandates removed based on the vicissitudes of a virtual coin flip, as much as many of us would have been interested to see that. The decision to remove masks was up to the various school boards – and they had a lot of pressure on them from many different directions. But all we need to worry about is whether any of those things that pressure a school board to keep masks on would ALSO lead to fewer COVID cases. That’s how confounders work, and how you can get false results in a study like this.

And yes – districts that kept the masks on longer were different than those who took them right off. But check out how they were different.

The districts that kept masks on longer had more low-income students. More Black and Latino students. More students per classroom. These are all risk factors that increase the risk of COVID infection. In other words, the confounding here goes in the opposite direction of the results. If anything, these factors should make you more certain that masking works.

The authors also adjusted for other factors – the community transmission of COVID-19, vaccination rates, school district sizes, and so on. No major change in the results.

One concern I addressed to Dr. Ellie Murray, the biostatistician on the study – could districts that removed masks simply have been testing more to compensate, leading to increased capturing of cases?

If anything, the schools that kept masks on were testing more than the schools that took them off – again that would tend to imply that the results are even stronger than what was reported.

Is this a perfect study? Of course not – it’s one study, it’s from one state. And the relatively large effects from keeping masks on for one or 2 weeks require us to really embrace the concept of exponential growth of infections, but, if COVID has taught us anything, it is that small changes in initial conditions can have pretty big effects.

My daughter, who goes to a public school here in Connecticut, unmasked, was home with COVID this past week. She’s fine. But you know what? She missed a week of school. I worked from home to be with her – though I didn’t test positive. And that is a real cost to both of us that I think we need to consider when we consider the value of masks. Yes, they’re annoying – but if they keep kids in school, might they be worth it? Perhaps not for now, as cases aren’t surging. But in the future, be it a particularly concerning variant, or a whole new pandemic, we should not discount the simple, cheap, and apparently beneficial act of wearing masks to decrease transmission.

Dr. Perry Wilson is an associate professor of medicine and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He disclosed no relevant conflicts of interest.

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

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

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

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

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

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

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

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

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

Vicious spiral of hyperglycemia and beta-cell damage

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

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

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

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

Blocking metabolic enzyme could maintain insulin secretion

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

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

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

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

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

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

A version of this article first appeared on Medscape UK.

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

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

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

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

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

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

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

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

Vicious spiral of hyperglycemia and beta-cell damage

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

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

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

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

Blocking metabolic enzyme could maintain insulin secretion

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

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

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

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

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

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

A version of this article first appeared on Medscape UK.

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

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

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

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

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

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

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

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

Vicious spiral of hyperglycemia and beta-cell damage

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

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

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

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

Blocking metabolic enzyme could maintain insulin secretion

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

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

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

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

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

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

A version of this article first appeared on Medscape UK.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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

An 18-year-old woman with Crohn’s disease (diagnosed 3 years ago) came to my office for advice regarding management of osteoporosis. Her bone density was low for her age, and she had three low-impact fractures of her long bones in the preceding 4 years.

Loss of weight after the onset of Crohn’s disease, subsequent loss of periods, inflammation associated with her underlying diagnosis, and early treatment with glucocorticoids (known to have deleterious effects on bone) were believed to have caused osteoporosis in this young woman.

A few months previously, she was switched to a medication that doesn’t impair bone health and glucocorticoids were discontinued; her weight began to improve, and her Crohn’s disease was now in remission. Her menses had resumed about 3 months before her visit to my clinic after a prolonged period without periods. She was on calcium and vitamin D supplements, with normal levels of vitamin D.

After reading that exercise was good for bones, she asked me about it. Were there specific types of exercise that would help optimize her chances of improving her bone health?

Many factors determine bone health including (but not limited to) genetics, nutritional status, exercise activity (with mechanical loading of bones), macro- and micronutrient intake, hormonal status, chronic inflammation and other disease states, and medication use.

Exercise certainly has beneficial effects on bone. Bone-loading activities increase bone formation through the activation of certain cells in bone called osteocytes, which serve as mechanosensors and sense bone loading. Osteocytes make a hormone called sclerostin, which typically inhibits bone formation. When osteocytes sense bone-loading activities, sclerostin secretion reduces, allowing for increased bone formation.

Consistent with this, investigators in Canada have demonstrated greater increases in bone density and strength in schoolchildren who engage in moderate to vigorous physical activity, particularly bone-loading exercise, during the school day, compared with those who don’t (J Bone Miner Res. 2007 Mar;22[3]:434-46; J Bone Miner Res. 2017 Jul;32[7]:1525-36). In females, normal levels of estrogen seem necessary for osteocytes to bring about these effects after bone-loading activities. This is probably one of several reasons why athletes who lose their periods (indicative of low estrogen levels) and develop low bone density with an increased risk for fracture even when they are still at a normal weight (J Clin Endocrinol Metab. 2018 Jun 1;103[6]:2392-402; Med Sci Sports Exerc. 2015 Aug;47[8]:1577-86).

One concern around prescribing bone-loading activity or exercise to persons with osteoporosis is whether it would increase the risk for fracture from the impact on fragile bone. The extent of bone loading safe for fragile bone can be difficult to determine. Furthermore, excessive exercise may worsen bone health by causing weight loss or loss of periods in women. Very careful monitoring may be necessary to ensure that energy balance is maintained. Therefore, the nature and volume of exercise should be discussed with one’s doctor or physical therapist as well as a dietitian (if the patient is seeing one).

In patients with osteoporosis, high-impact activities such as jumping; repetitive impact activities such as running or jogging; and bending and twisting activities such as touching one’s toes, golf, tennis, and bowling aren’t recommended because they increase the risk for fracture. Even yoga poses should be discussed, because some may increase the risk for compression fractures of the vertebrae in the spine.

Strength and resistance training are generally believed to be good for bones. Strength training involves activities that build muscle strength and mass. Resistance training builds muscle strength, mass, and endurance by making muscles work against some form of resistance. Such activities include weight training with free weights or weight machines, use of resistance bands, and use of one’s own body to strengthen major muscle groups (such as through push-ups, squats, lunges, and gluteus maximus extension).

Some amount of weight-bearing aerobic training is also recommended, including walking, low-impact aerobics, the elliptical, and stair-climbing. Non–weight-bearing activities, such as swimming and cycling, typically don’t contribute to improving bone density.

In older individuals with osteoporosis, agility exercises are particularly useful to reduce the fall risk (J Am Geriatr Soc. 2004 May;52[5]:657-65; CMAJ. 2002 Oct 29;167[9]:997-1004). These can be structured to improve hand-eye coordination, foot-eye coordination, static and dynamic balance, and reaction time. Agility exercises with resistance training help improve bone density in older women.

An optimal exercise regimen includes a combination of strength and resistance training; weight-bearing aerobic training; and exercises that build flexibility, stability, and balance. A doctor, physical therapist, or trainer with expertise in the right combination of exercises should be consulted to ensure optimal effects on bone and general health.

In those at risk for overexercising to the point that they start to lose weight or lose their periods, and certainly in all women with disordered eating patterns, a dietitian should be part of the decision team to ensure that energy balance is maintained. In this group, particularly in very-low-weight women with eating disorders, exercise activity is often limited until they reach a healthier weight, and ideally after their menses resume.

For my patient with Crohn’s disease, I recommended that she see a physical therapist and a dietitian for guidance about a graded increase in exercise activity and an exercise regimen that would work best for her. I assess her bone density annually using dual-energy x-ray absorptiometry. Her bone density has gradually improved with the combination of weight gain, resumption of menses, medications for Crohn’s disease that do not affect bone deleteriously, remission of Crohn’s disease, and her exercise regimen.

Dr. Misra is chief of the division of pediatric endocrinology at Mass General Hospital for Children and professor in the department of pediatrics at Harvard Medical School, both in Boston. She reported conflicts of interest with AbbVie, Sanofi, and Ipsen.

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

An 18-year-old woman with Crohn’s disease (diagnosed 3 years ago) came to my office for advice regarding management of osteoporosis. Her bone density was low for her age, and she had three low-impact fractures of her long bones in the preceding 4 years.

Loss of weight after the onset of Crohn’s disease, subsequent loss of periods, inflammation associated with her underlying diagnosis, and early treatment with glucocorticoids (known to have deleterious effects on bone) were believed to have caused osteoporosis in this young woman.

A few months previously, she was switched to a medication that doesn’t impair bone health and glucocorticoids were discontinued; her weight began to improve, and her Crohn’s disease was now in remission. Her menses had resumed about 3 months before her visit to my clinic after a prolonged period without periods. She was on calcium and vitamin D supplements, with normal levels of vitamin D.

After reading that exercise was good for bones, she asked me about it. Were there specific types of exercise that would help optimize her chances of improving her bone health?

Many factors determine bone health including (but not limited to) genetics, nutritional status, exercise activity (with mechanical loading of bones), macro- and micronutrient intake, hormonal status, chronic inflammation and other disease states, and medication use.

Exercise certainly has beneficial effects on bone. Bone-loading activities increase bone formation through the activation of certain cells in bone called osteocytes, which serve as mechanosensors and sense bone loading. Osteocytes make a hormone called sclerostin, which typically inhibits bone formation. When osteocytes sense bone-loading activities, sclerostin secretion reduces, allowing for increased bone formation.

Consistent with this, investigators in Canada have demonstrated greater increases in bone density and strength in schoolchildren who engage in moderate to vigorous physical activity, particularly bone-loading exercise, during the school day, compared with those who don’t (J Bone Miner Res. 2007 Mar;22[3]:434-46; J Bone Miner Res. 2017 Jul;32[7]:1525-36). In females, normal levels of estrogen seem necessary for osteocytes to bring about these effects after bone-loading activities. This is probably one of several reasons why athletes who lose their periods (indicative of low estrogen levels) and develop low bone density with an increased risk for fracture even when they are still at a normal weight (J Clin Endocrinol Metab. 2018 Jun 1;103[6]:2392-402; Med Sci Sports Exerc. 2015 Aug;47[8]:1577-86).

One concern around prescribing bone-loading activity or exercise to persons with osteoporosis is whether it would increase the risk for fracture from the impact on fragile bone. The extent of bone loading safe for fragile bone can be difficult to determine. Furthermore, excessive exercise may worsen bone health by causing weight loss or loss of periods in women. Very careful monitoring may be necessary to ensure that energy balance is maintained. Therefore, the nature and volume of exercise should be discussed with one’s doctor or physical therapist as well as a dietitian (if the patient is seeing one).

In patients with osteoporosis, high-impact activities such as jumping; repetitive impact activities such as running or jogging; and bending and twisting activities such as touching one’s toes, golf, tennis, and bowling aren’t recommended because they increase the risk for fracture. Even yoga poses should be discussed, because some may increase the risk for compression fractures of the vertebrae in the spine.

Strength and resistance training are generally believed to be good for bones. Strength training involves activities that build muscle strength and mass. Resistance training builds muscle strength, mass, and endurance by making muscles work against some form of resistance. Such activities include weight training with free weights or weight machines, use of resistance bands, and use of one’s own body to strengthen major muscle groups (such as through push-ups, squats, lunges, and gluteus maximus extension).

Some amount of weight-bearing aerobic training is also recommended, including walking, low-impact aerobics, the elliptical, and stair-climbing. Non–weight-bearing activities, such as swimming and cycling, typically don’t contribute to improving bone density.

In older individuals with osteoporosis, agility exercises are particularly useful to reduce the fall risk (J Am Geriatr Soc. 2004 May;52[5]:657-65; CMAJ. 2002 Oct 29;167[9]:997-1004). These can be structured to improve hand-eye coordination, foot-eye coordination, static and dynamic balance, and reaction time. Agility exercises with resistance training help improve bone density in older women.

An optimal exercise regimen includes a combination of strength and resistance training; weight-bearing aerobic training; and exercises that build flexibility, stability, and balance. A doctor, physical therapist, or trainer with expertise in the right combination of exercises should be consulted to ensure optimal effects on bone and general health.

In those at risk for overexercising to the point that they start to lose weight or lose their periods, and certainly in all women with disordered eating patterns, a dietitian should be part of the decision team to ensure that energy balance is maintained. In this group, particularly in very-low-weight women with eating disorders, exercise activity is often limited until they reach a healthier weight, and ideally after their menses resume.

For my patient with Crohn’s disease, I recommended that she see a physical therapist and a dietitian for guidance about a graded increase in exercise activity and an exercise regimen that would work best for her. I assess her bone density annually using dual-energy x-ray absorptiometry. Her bone density has gradually improved with the combination of weight gain, resumption of menses, medications for Crohn’s disease that do not affect bone deleteriously, remission of Crohn’s disease, and her exercise regimen.

Dr. Misra is chief of the division of pediatric endocrinology at Mass General Hospital for Children and professor in the department of pediatrics at Harvard Medical School, both in Boston. She reported conflicts of interest with AbbVie, Sanofi, and Ipsen.

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

An 18-year-old woman with Crohn’s disease (diagnosed 3 years ago) came to my office for advice regarding management of osteoporosis. Her bone density was low for her age, and she had three low-impact fractures of her long bones in the preceding 4 years.

Loss of weight after the onset of Crohn’s disease, subsequent loss of periods, inflammation associated with her underlying diagnosis, and early treatment with glucocorticoids (known to have deleterious effects on bone) were believed to have caused osteoporosis in this young woman.

A few months previously, she was switched to a medication that doesn’t impair bone health and glucocorticoids were discontinued; her weight began to improve, and her Crohn’s disease was now in remission. Her menses had resumed about 3 months before her visit to my clinic after a prolonged period without periods. She was on calcium and vitamin D supplements, with normal levels of vitamin D.

After reading that exercise was good for bones, she asked me about it. Were there specific types of exercise that would help optimize her chances of improving her bone health?

Many factors determine bone health including (but not limited to) genetics, nutritional status, exercise activity (with mechanical loading of bones), macro- and micronutrient intake, hormonal status, chronic inflammation and other disease states, and medication use.

Exercise certainly has beneficial effects on bone. Bone-loading activities increase bone formation through the activation of certain cells in bone called osteocytes, which serve as mechanosensors and sense bone loading. Osteocytes make a hormone called sclerostin, which typically inhibits bone formation. When osteocytes sense bone-loading activities, sclerostin secretion reduces, allowing for increased bone formation.

Consistent with this, investigators in Canada have demonstrated greater increases in bone density and strength in schoolchildren who engage in moderate to vigorous physical activity, particularly bone-loading exercise, during the school day, compared with those who don’t (J Bone Miner Res. 2007 Mar;22[3]:434-46; J Bone Miner Res. 2017 Jul;32[7]:1525-36). In females, normal levels of estrogen seem necessary for osteocytes to bring about these effects after bone-loading activities. This is probably one of several reasons why athletes who lose their periods (indicative of low estrogen levels) and develop low bone density with an increased risk for fracture even when they are still at a normal weight (J Clin Endocrinol Metab. 2018 Jun 1;103[6]:2392-402; Med Sci Sports Exerc. 2015 Aug;47[8]:1577-86).

One concern around prescribing bone-loading activity or exercise to persons with osteoporosis is whether it would increase the risk for fracture from the impact on fragile bone. The extent of bone loading safe for fragile bone can be difficult to determine. Furthermore, excessive exercise may worsen bone health by causing weight loss or loss of periods in women. Very careful monitoring may be necessary to ensure that energy balance is maintained. Therefore, the nature and volume of exercise should be discussed with one’s doctor or physical therapist as well as a dietitian (if the patient is seeing one).

In patients with osteoporosis, high-impact activities such as jumping; repetitive impact activities such as running or jogging; and bending and twisting activities such as touching one’s toes, golf, tennis, and bowling aren’t recommended because they increase the risk for fracture. Even yoga poses should be discussed, because some may increase the risk for compression fractures of the vertebrae in the spine.

Strength and resistance training are generally believed to be good for bones. Strength training involves activities that build muscle strength and mass. Resistance training builds muscle strength, mass, and endurance by making muscles work against some form of resistance. Such activities include weight training with free weights or weight machines, use of resistance bands, and use of one’s own body to strengthen major muscle groups (such as through push-ups, squats, lunges, and gluteus maximus extension).

Some amount of weight-bearing aerobic training is also recommended, including walking, low-impact aerobics, the elliptical, and stair-climbing. Non–weight-bearing activities, such as swimming and cycling, typically don’t contribute to improving bone density.

In older individuals with osteoporosis, agility exercises are particularly useful to reduce the fall risk (J Am Geriatr Soc. 2004 May;52[5]:657-65; CMAJ. 2002 Oct 29;167[9]:997-1004). These can be structured to improve hand-eye coordination, foot-eye coordination, static and dynamic balance, and reaction time. Agility exercises with resistance training help improve bone density in older women.

An optimal exercise regimen includes a combination of strength and resistance training; weight-bearing aerobic training; and exercises that build flexibility, stability, and balance. A doctor, physical therapist, or trainer with expertise in the right combination of exercises should be consulted to ensure optimal effects on bone and general health.

In those at risk for overexercising to the point that they start to lose weight or lose their periods, and certainly in all women with disordered eating patterns, a dietitian should be part of the decision team to ensure that energy balance is maintained. In this group, particularly in very-low-weight women with eating disorders, exercise activity is often limited until they reach a healthier weight, and ideally after their menses resume.

For my patient with Crohn’s disease, I recommended that she see a physical therapist and a dietitian for guidance about a graded increase in exercise activity and an exercise regimen that would work best for her. I assess her bone density annually using dual-energy x-ray absorptiometry. Her bone density has gradually improved with the combination of weight gain, resumption of menses, medications for Crohn’s disease that do not affect bone deleteriously, remission of Crohn’s disease, and her exercise regimen.

Dr. Misra is chief of the division of pediatric endocrinology at Mass General Hospital for Children and professor in the department of pediatrics at Harvard Medical School, both in Boston. She reported conflicts of interest with AbbVie, Sanofi, and Ipsen.

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