MDedge Endocrinology

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Prophylactic treatment with zoledronic acid (ZA) in individuals at high genetic risk for Paget disease of the bone (PDB) can prevent the development or progression of the condition, according to a new study. The authors argued that the positive results from the trial suggest that individuals with a familial history of PDB should undergo genetic screening.

“If it’s positive, you should be able to have a bone scan and take it from there,” senior author Stuart Ralston, MBChB, MD, professor of rheumatology at the University of Edinburgh (Scotland), said in an interview.

Dr. Ralston

PDB is a chronic skeletal growth disorder that affects an estimated 1-3 million people in the United States and is most prevalent in individuals over 65 years old. Symptoms of the disease may not present until later stages when there is already skeletal damage that cannot be resolved by medications. Earlier intervention in individuals who have not yet shown signs of the condition could potentially halt disease progression, Dr. Ralston said.

Genetics plays a substantial role in PDB, especially pathogenic variants of the gene SQSTM1. An estimated 40%-50% of people with a familial history of PDB have these variants, according to the study, which are associated with earlier PDB onset and more severe disease.

However, it was unclear if early interventions in these higher-risk individuals may result in better health outcomes.

In this new study, published on December 20, 2023, in Annals of the Rheumatic Diseases, researchers recruited participants through family members already diagnosed with PDB who received treatment at outpatient clinics. Over 1400 individuals with PDB underwent genetic testing for pathogenic SQSTM1 variants. If they tested positive, their first-degree relatives — primarily children — were offered the same genetic test. In total, 350 relatives tested positive for these pathogenic SQSTM1 variants, and of these individuals, 222 agreed to participate in the trial.

At the beginning of the study, all participants received a radionuclide bone scan to screen for bone lesions. They also underwent testing for the bone resorption marker type I collagen C-terminal telopeptides (CTX) and the bone formation marker procollagen type I amino-terminal propeptide (P1NP).

Participants were then randomized to receive either a single intravenous infusion of 5 mg of ZA or placebo treatment. Researchers followed up with participants annually for a median of 84 months (7 years), and then baseline assessments were repeated.

A total of 90 individuals in the ZA treatment group and 90 individuals in the placebo group completed the trial.

Participants were, on average, 50 years old at the beginning of the study. In the ZA group, nine individuals had lesions detected in bone scans at baseline, compared with just one at the study’s end. In the placebo group, 12 individuals had detectable lesions at baseline, compared with 11 individuals at the study’s end.

While the proportion of individuals with lesions was similar between the two groups, there were about twice as many lesions overall in the placebo group, compared with the ZA group (29 vs 15), which researchers said was by chance. All but two lesions disappeared in the ZA group, compared with 26 lesions remaining in the placebo group (P < .0001).

“The bone scan reversal of abnormalities was amazing,” said Ralston, where eight of nine patients with lesions in the ZA group “had their bone scan evidence completely wiped out,” he said. “That’s a very powerful result.”

Both CTX and P1NP concentrations fell in the ZA group at 12 months and remained significantly lower than the placebo group throughout the study (P < .0001 for each).

Overall, the researchers reported that eight individuals in the placebo group and no individuals in the ZA group had a poor outcome, defined as new bone lesions or lesions that were unchanged or progressed (odds ratio, 0.08; P = .003). Two individuals in the placebo group developed lesions during the study, compared with none in the ZA group, but this difference was not statistically significant.

Importantly, there were no differences in adverse events between the two groups.

While only a small number of people in the study had legions — around 9% of participants — the effect of ZA is “dramatic,” Linda A. Russell, MD, director of the Osteoporosis and Metabolic Bone Health Center at the Hospital for Special Surgery in New York City, told this news organization.

While clinicians primarily diagnose PDB with X-rays or an alkaline phosphatase blood test, testing for SQSTM1 is a new way to understand if someone is at higher risk for the disease, she said.

“Now, it seems like [the test] is fairly easily available, so probably it’s something we can begin to incorporate into our armamentarium,” Dr. Russell said.

Individuals who test positive for pathogenic variants of SQSTM1 could then get a bone scan, while those who tested negative may not need any additional testing, she added.

Dr. Ralston and coauthors noted that the effect size shown in this study is similar to that of studies examining adjuvant bisphosphonate therapy for postmenopausal women with early breast cancer. That practice, they write, is now a part of the standard of care.

“We believe that a similar approach is now justified in people with a family history of PDB who test positive for SQSTM1 mutations,” they wrote.

However, it is not clear if all individuals with pathogenic SQSTM1 should receive ZA treatment or if treatment should be given to only those with bone lesions.

“Future research to gather the views of people with a family history of PDB will help to inform the most appropriate way forward,” the authors wrote.

The UK Medical Research Council and Arthritis Research UK funded the trial. Zoledronic acid and a placebo were supplied by Novartis. Dr. Ralston reported funding to his institution from Kyowa Kirin, UCB, the Paget’s Association, and the Royal Osteoporosis Society. Some coauthors reported financial relationships with pharmaceutical companies outside the trial. Dr. Russell had no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

There’s no question that glucagon-like peptide 1 (GLP-1) agonists represent a major advance in the treatment of obesity for patients with or without diabetes. In clinical trials, participants lost 15%-20% of their body weight, depending on the drug.

But studies also have shown that once people stop taking these drugs — either by choice, because of shortage, or lack of access — they regain most, if not all, the weight they lost.

Arguably more frustrating is the fact that those who continue on the drug eventually reach a plateau, at which point, the body seemingly stubbornly refuses to lose more weight. Essentially, it stabilizes at its set point, said Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine physician at Massachusetts General Hospital and associate professor at Harvard Medical School in Boston.
 

‘Tug of War’

Every study of weight loss drugs done over the past 40 years or so shows a plateau, Dr. Stanford told this news organization. “If you look at the phentermine/topiramate studies, there’s a plateau. If you look at the bupropion/naltrexone studies, there’s a plateau. Or if we look at bariatric surgery, there’s a plateau. And it’s the same for the newer GLP-1 drugs.”

The reason? “It really depends on where the body gets to,” Dr. Stanford said. “The body knows what it needs to do to maintain itself, and the brain knows where it’s supposed to be. And when you lose weight and reach what you feel is a lower set point, the body resists.”

When the body goes below its set point, the hunger hormone ghrelin, which is housed in the brain, gets reactivated and gradually starts to reemerge, she explained. GLP-1, which is housed in the distal portion of the small intestine and in the colon, also starts to reemerge over time.

“It becomes kind of a tug of war” between the body and whatever weight loss strategy is being implemented, from drugs to surgery to lifestyle changes, Dr. Stanford said. “The patient will start to notice changes in how their body is responding. Usually, they’ll say they don’t feel like the treatment is working the same. But the treatment is working the same as it’s always been working — except their body is now acclimated to it.”

Anne L. Peters, MD, CDE, professor and clinical scholar, Keck School of Medicine of the University of Southern California, and director, agreed that in the simplest terms, a plateau occurs because “the body becomes more and more used to” the weight loss intervention.

However, when you lose weight, you lose both fat mass and lean body mass, and lean body mass is the metabolically active part of your body, explained Dr. Peters. “That’s what burns and basically makes up your basal metabolic rate.”

With weight loss, the metabolism slows down, she said. If patients need 2000 calories a day to survive at a certain weight and then lose 50 pounds, they may then need only a 1000 calories a day. “With any obesity treatment, you reach a point at which your metabolic rate and your daily caloric requirements become equal, and you stop losing weight, even though your daily caloric requirement is less than it was when your weight was higher.”
 

Managing the Plateau

Several strategies can be used to help patients break through a plateau. One is to try multiple weight loss agents with different targets — something often done in the real world, Dr. Stanford said. “You don’t see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They’re on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They’re usually on three, four, five drugs, similar to what we would see with resistant hypertension.”

If a patient plateaus on a GLP-1 drug, Dr. Stanford might add phentermine. When the patient reaches a plateau on phentermine, she would switch again to another agent. “The goal is to use agents that treat different receptors in the brain,” she said. “You would never use two GLP-1 agonists; you would use the GLP-1, and then something that treats norepinephrine, for example.”

At the same time, Dr. Peters noted, “try to get them off the drugs that cause weight gain, like insulin and sulfonylurea agents.”

Tapering the GLP-1 dose can also help, Dr. Peters said. However, she added, “If I’m using a GLP-1 drug for type 2 diabetes, it’s different than if I’m using it just for weight loss. With type 2 diabetes, if you taper too much, the blood sugar and weight will go back up, so you need to reach a balance.”

Dr. Peters has successfully tapered patients from a 2-mg dose down to 1 mg. She has also changed the strategy for some — ie, the patient takes the drug every other week instead of every week. “I even have a patient or two who just take it once a month and that seems to be enough,” she said. “You want to help them be at the dose that maintains their weight and keeps them healthy with the least possible medication.”

Emphasizing lifestyle changes is also important, she said. Although resistance training won’t necessarily help with weight loss, “it’s critical to maintaining lean body mass. If people keep losing and regaining weight, they’re going to lose more and more lean body mass and gain the weight back primarily as fat mass. So, their exercise should include about half aerobic activity and half resistance training.”
 

Long-term Journey

Setting appropriate expectations is a key part of helping patients accept and deal with a plateau. “This is long-term, lifelong journey,” Dr. Stanford said. “We need to think about obesity as a complex, multifactorial chronic disease, like we think about hypertension or type 2 diabetes or hyperlipidemia.”

Furthermore, and in keeping with that perspective, emerging evidence is demonstrating that GLP-1 drugs also have important nonglycemic benefits that can be achieved and maintained, Dr. Peters said. “Obviously weight loss matters, and weight loss is good for you if you’re overweight or obese. But now we know that GLP-1 drugs have wonderful benefits for the heart as well as renal function.” These are reasons to continue the drugs even in the face of a plateau.

One of Dr. Peters’ patients, a physician with type 2 diabetes, had “fought with her weight her whole life. She’s been on one or another GLP-1 drug for more than 15 years, and while none seem to impact her weight, she’s gone from having relatively poorly controlled to now beautifully controlled diabetes,” Dr. Peters said. “Even if she hasn’t lost, she’s maintained her weight, a benefit since people tend to gain weight as they get older, and she hasn’t gained.”

Another patient was disabled, on oxygen, and had recurrent pulmonary embolisms. “She weighed 420 pounds, and I put her on semaglutide because she was too sick to be considered for bariatric surgery.” When that didn’t work, Dr. Peters switched her to tirzepatide, gradually increasing the dose; the patient lost 80 pounds, her emboli are gone, she can walk down the street, and went back to work.

“Part of why she could do that is that she started exercising,” Dr. Peters noted. “She felt so much better from the drug-related weight loss that she began to do things that help enhance weight loss. She became happier because she was no longer homebound.”

This points to another element that can help patients break through a plateau over time, Dr. Peters said — namely, behavioral health. “The more people lose weight, the more they feel better about themselves, and that may mean that they take better care of themselves. The psychological part of this journey is as important as anything else. Not everyone has the same response to these agents, and there are all sorts of issues behind why people are overweight that physicians can’t ignore.

“So, in addition to managing the drugs and lifestyle, it’s important to make sure that people access the behavioral health help they need, and that once they break through a plateau, they don’t develop an eating disorder or go to the opposite extreme and become too thin, which has happened with some of my patients,” she said. “We need to remember that we’re not just giving patients a miraculous weight loss. We’re helping them to be healthier, mentally as well as physically.”

Dr. Stanford disclosed that she had been a consultant for Calibrate, GoodRx, Pfizer, Eli Lilly, Boehringer Ingelheim, Gelesis, Vida Health, Life Force, Ilant Health, Melli Cell, and Novo Nordisk. Dr. Peters disclosed that she had been a consultant for Vertex, Medscape Medical News, and Lilly; received funding from Abbott and Insulet; and had stock options in Omada Health.

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

The relationship between lipid levels and the development of dementia is an evolving but confusing landscape.

“This is an incredibly complex area, and there really isn’t a clear consensus on this subject because different lipid classes reflect different things,” according to Betsy Mills, PhD, assistant director of aging and Alzheimer’s prevention at the Alzheimer’s Drug Discovery Foundation.

Some studies suggest that excessive lipid levels may increase the risk of developing dementia and Alzheimer’s disease (AD). Others imply that elevated low-density lipoprotein (LDL) cholesterol or even triglycerides may offer some protection against subsequent dementia whereas higher levels of high-density lipoprotein (HDL) cholesterol, hitherto thought to be protective, may have a deleterious effect.

“It depends on what lipids you’re measuring, what you’re using to measure those lipids, what age the person is, and multiple other factors,” Dr. Mills told this news organization.

Teasing out the variables and potential mechanisms for the association between lipids and dementia risk necessitates understanding the role that lipids play in the healthy brain, the negative impact of brain lipid dysregulation, and the interplay between cholesterol in the central nervous system (CNS) and the cholesterol in the rest of the body.

 

Beyond Amyloid

The role of lipids in AD risk has historically been “overlooked,” says Scott Hansen, PhD, associate professor, Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Florida.

“The common narrative is that amyloid is the culprit in AD and certainly that’s the case in familial AD,” he told this news organization. “It’s been assumed that because amyloid deposits are also found in the brains of people with late-onset AD — which is the vast majority of cases — amyloid is the cause, but that’s not clear at all.”

The “limited clinical success” of aducanumab, its “extremely small efficacy” — despite its obvious success in eradicating the amyloid plaques — suggests there’s “much more to the story than amyloid.”

He and a growing community of scientists recognize the role of inflammation and lipids. “The major finding of my lab is that cholesterol actually drives the synthesis of amyloid via inflammation. In other words, amyloid is downstream of cholesterol. Cholesterol drives the inflammation, and the inflammation drives amyloid,” he said.
 

‘Lipid Invasion Model’

Because the brain is an incredibly lipid-rich organ, Dr. Mills said that “any dysregulation in lipid homeostasis will impact the brain because cholesterol is needed for the myelin sheaths, cell membranes, and other functions.”

A healthy brain relies upon healthy lipid regulation, and “since the first description of AD over 100 years ago, the disease has been associated with altered lipids in the brain,” Dr. Hansen noted.

He cited the “ lipid invasion model” as a way of understanding brain lipid dysregulation. This hypothesis posits that AD is driven by external lipids that enter the brain as a result of damage to the blood-brain barrier (BBB).

“Cholesterol in the brain and cholesterol in the periphery — meaning, in the rest of the body, outside the brain — are separate,” Dr. Hansen explained. “The brain produces its own cholesterol and keeps tight control of it.”

Under normal circumstances, cholesterol from the diet doesn’t enter the brain. “Each pool of cholesterol — in the brain and in the periphery — has its own distinct regulatory mechanisms, target cells, and transport mechanisms.”

When the BBB has been compromised, it becomes permeable, allowing LDL cholesterol to enter the brain, said Dr. Hansen. Then the brain’s own lipoproteins transport the invading cholesterol, allowing it to be taken up by neurons. In turn, this causes neuronal amyloid levels to rise, ultimately leading to the creation of amyloid-b plaques. It also plays a role in tau phosphorylation. Both are key features of AD pathology.

Elevated levels of cholesterol and other lipids have been found in amyloid plaques, Dr. Hansen noted. Moreover, studies of brains of patients with AD have pointed to BBB damage.

And the risk factors for AD overlap with the risk factors for damage to the BBB (such as, aging, brain trauma, hypertension, stress, sleep deprivation, smoking, excess alcohol, obesity, diabetes, and APOE4 genotype), according to the lipid invasion model paper cited by Dr. Hansen.
 

‘Chicken and Egg’

“There is a strong link between the brain and the heart, and we know that cardiovascular risk factors have an overlap with dementia risk factors — especially vascular dementia,” said Dr. Mills. 

She explained that an atherogenic lipid profile results in narrowing of the arteries, with less blood reaching the brain. “This can lead to stress in the brain, which drives inflammation and pathology.”

But cholesterol itself plays an important role in inflammation, Dr. Hansen said. In the periphery, it is “part of an integral response to tissue damage and infection.”

In the brain, once cholesterol is synthesized by the astrocytes, it is transported to neurons via the apolipoprotein E (APOE) protein, which plays a role in brain cholesterol homeostasis, Dr. Mills explained. Those with the ε4 allele of APOE (APOE4) tend to have faultier transport and storage of lipids in the brain, relative to the other APOE variants.

It’s known that individuals with APOE4 are particularly vulnerable to late-onset AD, Dr. Hansen observed. By contrast, APOE2 has a more protective effect. “Most people have APOE3, which is ‘in between,’ ” he said.

When there is neuronal uptake of “invading cholesterol,” not only is amyloid produced but also neuroinflammatory cytokines, further driving inflammation. A vicious cycle ensues: Cholesterol induces cytokine release; and cytokine release, in turn, induces cholesterol synthesis — which “suggests an autocatalytic function of cholesterol in the escalation of inflammation,” Dr. Hansen suggested. He noted that permeability of the BBB also allows inflammatory cytokines from elsewhere in the body to invade the brain, further driving inflammation.

Dr. Mills elaborated: “We know that generally, in dementia, there appear to be some changes in cholesterol metabolism in the brain, but it’s a chicken-and-egg question. We know that as the disease progresses, neurons are dying and getting remodeled. Do these changes have to do with the degenerative process, or are the changes in the cholesterol metabolism actually driving the degenerative disease process? It’s probably a combination, but it’s unclear at this point.”
 

Lipids in Plasma vs CSF

Dr. Mills explained that HDL particles in the brain differ from those in the periphery. “In the CNS, you have ‘HDL-like particles,’ which are similar in size and composition [to HDL in the periphery] but aren’t the same particles.” The brain itself generates HDL-like lipoproteins, which are produced by astrocytes and other glial cells and found in cerebrospinal fluid (CSF).

Dyslipidemia in the periphery can be a marker for cardiovascular pathology. In the brain, “it can be an indication that there is active damage going on, depending on which compartment you’re looking at.”

She noted that plasma lipid levels and brain CSF lipid levels are “very different.” Research suggests that HDL in the CSF exhibits similar heterogeneity to plasma HDL, but these CSF lipoproteins present at 100-fold lower concentrations, compared to plasma HDL and have unique combinations of protein subpopulations. Lipidomics analysis studies show that these compartments “get very different readings, in terms of the predominant lipid disease state, and they are regulated differently from the way lipids in the periphery are regulated.” 

In the brain, the cholesterol “needs to get shuttled from glial cells to neurons,” so defects in the transport process can disrupt overall brain homeostasis, said Dr. Mills. But since the brain system is separate from the peripheral system, measuring plasma lipids is more likely to point to cardiovascular risks, while changes reflected in CSF lipids are “more indicative of alteration in lipid homeostasis in the brain.”
 

HDL and Triglycerides: A Complicated Story

Dr. Mills noted that HDL in the periphery is “very complicated,” and the idea that HDL, as a measure on its own, is “necessarily ‘good’ isn’t particularly informative.” Rather, HDL is “extremely heterogeneous, very diverse, has different lipid compositions, different classes, and different modifications.” For example, like oxidized LDL, oxidized HDL is also “bad,” preventing the HDL from having protective functions.

Similarly, the apolipoproteins associated with HDL can affect the function of the HDL. “Our understanding of the HDL-like particles in the CNS is limited, but we do understand the APOE4 link,” Dr. Mills said. “It seems that the HDL-like particles containing APOE2 or APOE3 are larger and are more effective at transferring the lipids and cholesterol linked to them relative to APOE4-containing particles.” 

Because HDL is more complex than simply being “good,” measuring HDL doesn’t “give you the full story,” said Dr. Mills. She speculates that this may be why there are studies suggesting that high levels of HDL might not have protective benefits and might even be detrimental. This makes it difficult to look at population studies, where the different subclasses of HDL are not necessarily captured in depth. 

Dr. Mills pointed to another confounding factor, which is that much of the risk for the development of AD appears to be related to the interaction of HDL, LDL, and triglycerides. “When you look at each of these individually, you get a lot of heterogeneity, and it’s unclear what’s driving what,” she said.

An advantage of observational studies is that they give information about which of these markers are associated with trends and disease risks in specific groups vs others. 

“For example, higher levels of triglycerides are associated with cardiovascular risk more in women, relative to men,” she said. And the triglyceride-to-HDL ratio seems “particularly robust” as a measure of cardiovascular health and risk. 

The interpretation of associations with triglycerides can be “tricky” and “confusing” because results differ so much between studies, she said. “There are differences between middle age and older age, which have to do with age-related changes in metabolism and lipid metabolism and not necessarily that the markers are indicating something different,” she said.

Some research has suggested that triglycerides may have a protective effect against dementia, noted Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and director of nutritional psychiatry at MGH Academy.

This may be because the brain “runs mostly on energy from burning triglycerides,” suggested Dr. Naidoo, author of the books Calm Your Mind With Food and This Is Your Brain on Food.

In addition, having higher levels of triglycerides may be linked with having overall healthier behaviors, Dr. Naidoo told this news organization.

Dr. Mills said that in middle-aged individuals, high levels of LDL-C and triglycerides are “often indicative of more atherogenic particles and risk to cardiovascular health, which is a generally negative trajectory. But in older individuals, things become more complicated because there are differences in terms of clearance of some of these particles, tissue clearance and distribution, and nutrient status. So for older individuals, it seems that fluctuations in either direction—either too high or too low—tend to be more informative that some overall dysregulation is going on the system.” 

She emphasized that, in this “emerging area, looking at only one or two studies is confusing. But if you look at the spectrum of studies, you can see a pattern, which is that the regulation gets ‘off,’ as people age.”

 

The Potential Role of Statins

Dr. Mills speculated that there may be “neuroprotective benefits for some of the statins which appear to be related to cardiovascular benefits. But at this point, we don’t have any clear data whether statins actually directly impact brain cholesterol, since it’s a separate pool.”

They could help “by increasing blood flow and reducing narrowing of the arteries, but any direct impact on the brain is still under investigation.”

Dr. Hansen pointed to research suggesting statins taken at midlife appear to be cardioprotective and may be protective of brain health as well, whereas statins initiated in older age do not appear to have these benefits.

He speculated that one reason statins seem less helpful when initiated later in life is that the BBB has already been damaged by systemic inflammation in the periphery, and the neuroinflammatory process resulting in neuronal destruction is already underway. “I think statins aren’t going to fix that problem, so although lowering cholesterol can be helpful in some respects, it might be too late to affect cognition because the nerves have already died and won’t grow back.”
 

Can Dietary Approaches Help?

Dr. Naidoo said that when looking at neurologic and psychiatric disease, “it’s important to think about the ‘long game’ — how can we improve our blood and cardiovascular health earlier in life to help potentiate healthy aging?”

From a nutritional psychiatry standpoint, Dr. Naidoo focuses on nourishing the gut microbiome and decreasing inflammation. “A healthy and balanced microbiome supports cognition, while the composition of gut bacteria is actually drastically different in patients with neurological diseases, such as AD.” 

She recommends a nutrient-dense, anti-inflammatory diet including probiotic-rich foods (such as kimchi, sauerkraut, plain yogurt, and miso). Moreover, “the quality and structure of our fatty acids may be relevant as well: Increasing our intake of polyunsaturated fatty acids and avoiding processed fats like trans fats and hydrogenated oils may benefit our overall brain health.”

Dr. Naidoo recommends extra-virgin olive oil as a source of healthy fat. Its consumption is linked to lower incidence of AD by way of encouraging autophagy, which she calls “our own process of “cellular cleanup.’”

Dr. Naidoo believes that clinicians’ guidance to patients should “focus on healthy nutrition and other lifestyle practices, such as exercise, outdoor time, good sleep, and stress reduction.” 

Dr. Mills notes the importance of omega-3 fatty acids, such as docosahexaenoic acid (DHA) , for brain health. “DHA is a major lipid component of neuronal membranes,” she said. “Because of inefficiencies in metabolism with APOE4, people tend to metabolize more of the lipids on the membranes themselves, so they have higher lipid membrane turnover and a greater need to supplement. Supplementing particularly through diet, with foods such as fatty fish rich in omega-3, can help boost the levels to help keep neuronal membranes intact.”
 

What This Means for the Clinician

“At this point, we see all of these associations between lipids and dementia, but we haven’t worked out exactly what it means on the individual level for an individual patient,” said Dr. Mills. Certainly, the picture is complex, and the understanding is growing and shifting. “The clinical applications remain unclear.”

One potential clinical take-home is that clinicians might consider tracking lipid levels over time. “If you follow a patient and see an increase or decrease [in lipid levels], that can be informative.” Looking at ratios of lipids might be more useful than looking only at a change in a single measure. “If you see trends in a variety of measures that track with one another, it might be more of a sign that something is potentially wrong.” 

Whether the patient should first try a lifestyle intervention or might need medication is a “personalized clinical decision, depending on the individual, their risk factors, and how their levels are going,” said Dr. Mills. 

Dr. Mills, Dr. Hansen, and Dr. Naidoo declared no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

An influential panel is seeking an increase in Medicare’s 2025 payments for clinicians, adding to pressure on Congress to reconsider how the largest US purchaser of health services pays for office visits and related care of the nation’s older citizens and those with disabilities.

The Medicare Payment Advisory Commission (MedPAC) on Thursday voted unanimously in favor of a two-part recommendation on changes to the 2025 physician fee schedule:

• An increase in the base rate equal to half of the projected change in the Medicare Economic Index (MEI). Recent estimates have projected a 2.6% increase in MEI for 2025, which is intended to show how inflation affects the costs of running a medical practice.
• The creation of a safety-net add-on payment under the physician fee schedule to cover care of people with low incomes.

These recommendations echo the calls MedPAC made in a 2023 report to Congress. 

Lawmakers and the Centers for Medicare and Medicaid Services (CMS) rely on MedPAC’s work in deciding how much to pay for services. About 1.3 million clinicians bill Medicare for their work, including about 670,000 physicians.

Thursday’s MedPAC vote comes amid continuing uncertainty about how much the federal government will actually pay clinicians this year through the physician fee schedule.

There are serious efforts underway to undo cuts already demanded by previously passed federal law. In an email, Rep. Larry Buchson, MD, (R-IN) said he remains committed to “eliminating the full 3.37% cut this year while also working toward a permanent solution to halt the downward spiral of physician reimbursement.”

“The Medicare payment cut to physicians will impede patients’ access to care and further accelerate the current path toward consolidation, physician burnout, and closure of medical practices,” Buchson told this news organization. “It’s past time that Congress provides much needed and deserved stability for America’s doctors.”

Congress this month is attempting to complete overdue budget legislation needed to fund federal operations for fiscal 2024, which began October 1, 2023. The pending expiration of a short-term stopgap continuing resolution could provide a vehicle that could also carry legislation that would address the physician fee schedule.

In a Thursday statement, Jesse M. Ehrenfeld, MD, MPH, president of the American Medical Association, commended MedPAC for its recommendations and urged lawmakers to act.

“Long-term reforms from Congress are overdue to close the unsustainable gap between what Medicare pays physicians and the actual costs of delivering high-quality care,” Dr. Ehrenfeld said. “When adjusted for inflation in practice costs, Medicare physician pay declined 26% from 2001 to 2023.”
 

Continual Struggles

Congress has struggled for years in its attempts to set Medicare payments for office visits and other services covered by the physician fee schedule. A 1990s budget law set the stage for what proved to be untenable reductions in payment through the sustainable growth rate mechanism.

Between 2003 through April 2014, lawmakers passed “doc-fix” legislation 17 times to block the slated cuts, according to the Congressional Research Service. In 2015, Congress passed an intended overhaul of the physician fee schedule through the Medicare Access and CHIP Reauthorization Act (MACRA). As part of this law, Congress eliminated a base automatic inflation adjuster for the physician fee schedule.

In recent years, Congress has acted repeatedly to address MACRA’s mandates for flat base pay. MedPAC and members of both parties in Congress have called for a broad new look at how Medicare pays physicians. 

At Thursday’s meeting, MedPAC member Lawrence Casalino, MD, PhD, MPH, noted that the struggles to keep up with inflation and the “unpredictability of what the payment rates are going to be from year to year really do affect physician morale.”

A version of this article appeared on Medscape.com.

An influential panel is seeking an increase in Medicare’s 2025 payments for clinicians, adding to pressure on Congress to reconsider how the largest US purchaser of health services pays for office visits and related care of the nation’s older citizens and those with disabilities.

The Medicare Payment Advisory Commission (MedPAC) on Thursday voted unanimously in favor of a two-part recommendation on changes to the 2025 physician fee schedule:

• An increase in the base rate equal to half of the projected change in the Medicare Economic Index (MEI). Recent estimates have projected a 2.6% increase in MEI for 2025, which is intended to show how inflation affects the costs of running a medical practice.
• The creation of a safety-net add-on payment under the physician fee schedule to cover care of people with low incomes.

These recommendations echo the calls MedPAC made in a 2023 report to Congress. 

Lawmakers and the Centers for Medicare and Medicaid Services (CMS) rely on MedPAC’s work in deciding how much to pay for services. About 1.3 million clinicians bill Medicare for their work, including about 670,000 physicians.

Thursday’s MedPAC vote comes amid continuing uncertainty about how much the federal government will actually pay clinicians this year through the physician fee schedule.

There are serious efforts underway to undo cuts already demanded by previously passed federal law. In an email, Rep. Larry Buchson, MD, (R-IN) said he remains committed to “eliminating the full 3.37% cut this year while also working toward a permanent solution to halt the downward spiral of physician reimbursement.”

“The Medicare payment cut to physicians will impede patients’ access to care and further accelerate the current path toward consolidation, physician burnout, and closure of medical practices,” Buchson told this news organization. “It’s past time that Congress provides much needed and deserved stability for America’s doctors.”

Congress this month is attempting to complete overdue budget legislation needed to fund federal operations for fiscal 2024, which began October 1, 2023. The pending expiration of a short-term stopgap continuing resolution could provide a vehicle that could also carry legislation that would address the physician fee schedule.

In a Thursday statement, Jesse M. Ehrenfeld, MD, MPH, president of the American Medical Association, commended MedPAC for its recommendations and urged lawmakers to act.

“Long-term reforms from Congress are overdue to close the unsustainable gap between what Medicare pays physicians and the actual costs of delivering high-quality care,” Dr. Ehrenfeld said. “When adjusted for inflation in practice costs, Medicare physician pay declined 26% from 2001 to 2023.”
 

Continual Struggles

Congress has struggled for years in its attempts to set Medicare payments for office visits and other services covered by the physician fee schedule. A 1990s budget law set the stage for what proved to be untenable reductions in payment through the sustainable growth rate mechanism.

Between 2003 through April 2014, lawmakers passed “doc-fix” legislation 17 times to block the slated cuts, according to the Congressional Research Service. In 2015, Congress passed an intended overhaul of the physician fee schedule through the Medicare Access and CHIP Reauthorization Act (MACRA). As part of this law, Congress eliminated a base automatic inflation adjuster for the physician fee schedule.

In recent years, Congress has acted repeatedly to address MACRA’s mandates for flat base pay. MedPAC and members of both parties in Congress have called for a broad new look at how Medicare pays physicians. 

At Thursday’s meeting, MedPAC member Lawrence Casalino, MD, PhD, MPH, noted that the struggles to keep up with inflation and the “unpredictability of what the payment rates are going to be from year to year really do affect physician morale.”

A version of this article appeared on Medscape.com.

An influential panel is seeking an increase in Medicare’s 2025 payments for clinicians, adding to pressure on Congress to reconsider how the largest US purchaser of health services pays for office visits and related care of the nation’s older citizens and those with disabilities.

The Medicare Payment Advisory Commission (MedPAC) on Thursday voted unanimously in favor of a two-part recommendation on changes to the 2025 physician fee schedule:

• An increase in the base rate equal to half of the projected change in the Medicare Economic Index (MEI). Recent estimates have projected a 2.6% increase in MEI for 2025, which is intended to show how inflation affects the costs of running a medical practice.
• The creation of a safety-net add-on payment under the physician fee schedule to cover care of people with low incomes.

These recommendations echo the calls MedPAC made in a 2023 report to Congress. 

Lawmakers and the Centers for Medicare and Medicaid Services (CMS) rely on MedPAC’s work in deciding how much to pay for services. About 1.3 million clinicians bill Medicare for their work, including about 670,000 physicians.

Thursday’s MedPAC vote comes amid continuing uncertainty about how much the federal government will actually pay clinicians this year through the physician fee schedule.

There are serious efforts underway to undo cuts already demanded by previously passed federal law. In an email, Rep. Larry Buchson, MD, (R-IN) said he remains committed to “eliminating the full 3.37% cut this year while also working toward a permanent solution to halt the downward spiral of physician reimbursement.”

“The Medicare payment cut to physicians will impede patients’ access to care and further accelerate the current path toward consolidation, physician burnout, and closure of medical practices,” Buchson told this news organization. “It’s past time that Congress provides much needed and deserved stability for America’s doctors.”

Congress this month is attempting to complete overdue budget legislation needed to fund federal operations for fiscal 2024, which began October 1, 2023. The pending expiration of a short-term stopgap continuing resolution could provide a vehicle that could also carry legislation that would address the physician fee schedule.

In a Thursday statement, Jesse M. Ehrenfeld, MD, MPH, president of the American Medical Association, commended MedPAC for its recommendations and urged lawmakers to act.

“Long-term reforms from Congress are overdue to close the unsustainable gap between what Medicare pays physicians and the actual costs of delivering high-quality care,” Dr. Ehrenfeld said. “When adjusted for inflation in practice costs, Medicare physician pay declined 26% from 2001 to 2023.”
 

Continual Struggles

Congress has struggled for years in its attempts to set Medicare payments for office visits and other services covered by the physician fee schedule. A 1990s budget law set the stage for what proved to be untenable reductions in payment through the sustainable growth rate mechanism.

Between 2003 through April 2014, lawmakers passed “doc-fix” legislation 17 times to block the slated cuts, according to the Congressional Research Service. In 2015, Congress passed an intended overhaul of the physician fee schedule through the Medicare Access and CHIP Reauthorization Act (MACRA). As part of this law, Congress eliminated a base automatic inflation adjuster for the physician fee schedule.

In recent years, Congress has acted repeatedly to address MACRA’s mandates for flat base pay. MedPAC and members of both parties in Congress have called for a broad new look at how Medicare pays physicians. 

At Thursday’s meeting, MedPAC member Lawrence Casalino, MD, PhD, MPH, noted that the struggles to keep up with inflation and the “unpredictability of what the payment rates are going to be from year to year really do affect physician morale.”

A version of this article appeared on Medscape.com.

To lose weight, patients with obesity may be more interested in semaglutide products, but the glucagon-like peptide I agonists, such as Ozempic injections and Rybelsus tablets, are not yet cost-effective, according to a modeling study that compared the drugs with surgery and endoscopy.

Sleeve gastrectomy (SG) for moderate to severe (class II/III) obesity and the less invasive endoscopic sleeve gastroplasty (ESG) for mild (class I) obesity were both cost effective strategies to reduce obesity, the researchers report.

“SG should be offered as the first-line treatment for class II and class III obesity,” write Monica Saumoy, MD, of the Center for Digestive Health, Penn Medicine Princeton Medical Center, Plainsboro, N.J., and coauthors. “ESG is an effective and cost-effective nonsurgical treatment for class I, class II and class III obesity, and more efforts are needed to ensure that patients have access to this procedure.

Penn Medicine

“While semaglutide is highly effective for weight loss, and there is substantial patient interest, it is not currently cost-effective due to its high cost,” they add. “With methods to reduce semaglutide’s annual cost, it may provide an effective and cost-effective method to reduce the morbidity related to obesity.”

The study was published in Gut.
 

Cost Concerns

One in two Americans will likely be obese by 2030, according to current models, and nearly one in four adults will be severely obese.

Several weight-loss therapies exist to treat obesity. Evidence shows bariatric surgery is effective in reducing weight, metabolic comorbidities, and mortality in people with obesity compared with lifestyle intervention alone, but surgery has risks, adverse events, and poor national uptake. Patients are likely more interested in less invasive options, the authors write.

Recent trials have reported effective weight loss from less invasive options. A five-year follow-up of the randomized controlled MERIT trial found that ESG was associated with a 13.6% total body weight loss for people with mild to moderate obesity.

On the pharmaceutical front, other randomized controlled trials have shown that semaglutide is linked with as much as 17% total body weight loss at two years. Also, recent guidance from the American Gastroenterological Association (AGA) states that long-term treatment with a semaglutide is the preferred strategy for weight loss.

“However, concerns about the cost and the cost-effectiveness of these [less invasive] interventions have limited their usage in the USA,” the study authors write.

The aim of the study was to perform a cost-effectiveness analysis comparing SG, ESG, semaglutide, and lifestyle interventions (LI) for patients with obesity in class I (defined as BMI 30-34.9 kg/m²), class II (35-29.9 kg/m²), and class III (>40kg/m²) obesity.

Researchers used a state-transition, semi-Markov microsimulation model to analyze the effectiveness of ESG, SG, semaglutide, and LI in a simulated 40-year-old with three different base-case scenarios of class I, II, or III obesity. They then performed a detailed threshold and sensitivity analysis to change the cost of treatment modalities and the semaglutide adherence rate. Outcome measures included a willingness-to-pay threshold of US $100,000/quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICERs).
 

Cost-Effectiveness of Treatments

When the treatment modalities were compared with each other, findings showed that for class I obesity, ESG was cost effective (US $4,105/QALY). For class II and III obesity, SG was cost-effective as well (US $5,883/QALY) and (US $7,821/QALY), respectively.

In all classes of obesity, SG and ESG were cost-effective compared with LI. Semaglutide was not cost-effective compared with LI for class I, II, and III obesity (ICER US $508,414/QALY, $420,483/QALY, and $350,637/QALY, respectively).

“For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US $1,879 (class III), US $1,204 (class II), or US $297 (class I) annually,” the authors note.

The authors addressed recent guidelines to consider bariatric surgery in all obese patients. They recommend SG remain the standard of care for patients with severe obesity.

But national projections show that SG would address only 0.5% of life-years lost due to obesity.

“Barring a dramatic increase in patient adherence, bariatric surgery will not likely successfully mitigate the harm from the obesity epidemic,” they write.

“ESG may fill this gap and provide an additional option for patients with obesity as it demonstrated sustained weight loss at 2-5 years.” While insurance coverage is limited, they write, “our model demonstrates that payer coverage for ESG would provide an alternative tool to combat the obesity epidemic as part of a multidisciplinary approach.”

Semaglutide shows sustained weight loss in trials for up to two years but has a substantial annual cost, the authors note.

At lower prices, semaglutide can make a “major impact on the obesity pandemic as it can be prescribed in multiple healthcare settings and due to increased patient interested in non-invasive obesity treatment,” they write.

One limitation to the study is a lack of long-term data available for ESG and semaglutide. Authors were also not able to use a lifetime horizon because of a lack of long-term weight loss.

One study author reports financial relationships with BSC, Cook Medical, Surgical Intuitive, and Olympus America. Another author reports relationships with ACI, AGA-Varia, BSC, Dark Canyon Labs, Endiatx, Medtronic, Olympus, Virgo Systems; equity: AGA-Varia, Dark Canyon Labs, Endiatx, EndoSound, and Virgo Systems. The rest of the authors have no conflicts to disclose.

To lose weight, patients with obesity may be more interested in semaglutide products, but the glucagon-like peptide I agonists, such as Ozempic injections and Rybelsus tablets, are not yet cost-effective, according to a modeling study that compared the drugs with surgery and endoscopy.

Sleeve gastrectomy (SG) for moderate to severe (class II/III) obesity and the less invasive endoscopic sleeve gastroplasty (ESG) for mild (class I) obesity were both cost effective strategies to reduce obesity, the researchers report.

“SG should be offered as the first-line treatment for class II and class III obesity,” write Monica Saumoy, MD, of the Center for Digestive Health, Penn Medicine Princeton Medical Center, Plainsboro, N.J., and coauthors. “ESG is an effective and cost-effective nonsurgical treatment for class I, class II and class III obesity, and more efforts are needed to ensure that patients have access to this procedure.

Penn Medicine

“While semaglutide is highly effective for weight loss, and there is substantial patient interest, it is not currently cost-effective due to its high cost,” they add. “With methods to reduce semaglutide’s annual cost, it may provide an effective and cost-effective method to reduce the morbidity related to obesity.”

The study was published in Gut.
 

Cost Concerns

One in two Americans will likely be obese by 2030, according to current models, and nearly one in four adults will be severely obese.

Several weight-loss therapies exist to treat obesity. Evidence shows bariatric surgery is effective in reducing weight, metabolic comorbidities, and mortality in people with obesity compared with lifestyle intervention alone, but surgery has risks, adverse events, and poor national uptake. Patients are likely more interested in less invasive options, the authors write.

Recent trials have reported effective weight loss from less invasive options. A five-year follow-up of the randomized controlled MERIT trial found that ESG was associated with a 13.6% total body weight loss for people with mild to moderate obesity.

On the pharmaceutical front, other randomized controlled trials have shown that semaglutide is linked with as much as 17% total body weight loss at two years. Also, recent guidance from the American Gastroenterological Association (AGA) states that long-term treatment with a semaglutide is the preferred strategy for weight loss.

“However, concerns about the cost and the cost-effectiveness of these [less invasive] interventions have limited their usage in the USA,” the study authors write.

The aim of the study was to perform a cost-effectiveness analysis comparing SG, ESG, semaglutide, and lifestyle interventions (LI) for patients with obesity in class I (defined as BMI 30-34.9 kg/m²), class II (35-29.9 kg/m²), and class III (>40kg/m²) obesity.

Researchers used a state-transition, semi-Markov microsimulation model to analyze the effectiveness of ESG, SG, semaglutide, and LI in a simulated 40-year-old with three different base-case scenarios of class I, II, or III obesity. They then performed a detailed threshold and sensitivity analysis to change the cost of treatment modalities and the semaglutide adherence rate. Outcome measures included a willingness-to-pay threshold of US $100,000/quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICERs).
 

Cost-Effectiveness of Treatments

When the treatment modalities were compared with each other, findings showed that for class I obesity, ESG was cost effective (US $4,105/QALY). For class II and III obesity, SG was cost-effective as well (US $5,883/QALY) and (US $7,821/QALY), respectively.

In all classes of obesity, SG and ESG were cost-effective compared with LI. Semaglutide was not cost-effective compared with LI for class I, II, and III obesity (ICER US $508,414/QALY, $420,483/QALY, and $350,637/QALY, respectively).

“For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US $1,879 (class III), US $1,204 (class II), or US $297 (class I) annually,” the authors note.

The authors addressed recent guidelines to consider bariatric surgery in all obese patients. They recommend SG remain the standard of care for patients with severe obesity.

But national projections show that SG would address only 0.5% of life-years lost due to obesity.

“Barring a dramatic increase in patient adherence, bariatric surgery will not likely successfully mitigate the harm from the obesity epidemic,” they write.

“ESG may fill this gap and provide an additional option for patients with obesity as it demonstrated sustained weight loss at 2-5 years.” While insurance coverage is limited, they write, “our model demonstrates that payer coverage for ESG would provide an alternative tool to combat the obesity epidemic as part of a multidisciplinary approach.”

Semaglutide shows sustained weight loss in trials for up to two years but has a substantial annual cost, the authors note.

At lower prices, semaglutide can make a “major impact on the obesity pandemic as it can be prescribed in multiple healthcare settings and due to increased patient interested in non-invasive obesity treatment,” they write.

One limitation to the study is a lack of long-term data available for ESG and semaglutide. Authors were also not able to use a lifetime horizon because of a lack of long-term weight loss.

One study author reports financial relationships with BSC, Cook Medical, Surgical Intuitive, and Olympus America. Another author reports relationships with ACI, AGA-Varia, BSC, Dark Canyon Labs, Endiatx, Medtronic, Olympus, Virgo Systems; equity: AGA-Varia, Dark Canyon Labs, Endiatx, EndoSound, and Virgo Systems. The rest of the authors have no conflicts to disclose.

To lose weight, patients with obesity may be more interested in semaglutide products, but the glucagon-like peptide I agonists, such as Ozempic injections and Rybelsus tablets, are not yet cost-effective, according to a modeling study that compared the drugs with surgery and endoscopy.

Sleeve gastrectomy (SG) for moderate to severe (class II/III) obesity and the less invasive endoscopic sleeve gastroplasty (ESG) for mild (class I) obesity were both cost effective strategies to reduce obesity, the researchers report.

“SG should be offered as the first-line treatment for class II and class III obesity,” write Monica Saumoy, MD, of the Center for Digestive Health, Penn Medicine Princeton Medical Center, Plainsboro, N.J., and coauthors. “ESG is an effective and cost-effective nonsurgical treatment for class I, class II and class III obesity, and more efforts are needed to ensure that patients have access to this procedure.

Penn Medicine

“While semaglutide is highly effective for weight loss, and there is substantial patient interest, it is not currently cost-effective due to its high cost,” they add. “With methods to reduce semaglutide’s annual cost, it may provide an effective and cost-effective method to reduce the morbidity related to obesity.”

The study was published in Gut.
 

Cost Concerns

One in two Americans will likely be obese by 2030, according to current models, and nearly one in four adults will be severely obese.

Several weight-loss therapies exist to treat obesity. Evidence shows bariatric surgery is effective in reducing weight, metabolic comorbidities, and mortality in people with obesity compared with lifestyle intervention alone, but surgery has risks, adverse events, and poor national uptake. Patients are likely more interested in less invasive options, the authors write.

Recent trials have reported effective weight loss from less invasive options. A five-year follow-up of the randomized controlled MERIT trial found that ESG was associated with a 13.6% total body weight loss for people with mild to moderate obesity.

On the pharmaceutical front, other randomized controlled trials have shown that semaglutide is linked with as much as 17% total body weight loss at two years. Also, recent guidance from the American Gastroenterological Association (AGA) states that long-term treatment with a semaglutide is the preferred strategy for weight loss.

“However, concerns about the cost and the cost-effectiveness of these [less invasive] interventions have limited their usage in the USA,” the study authors write.

The aim of the study was to perform a cost-effectiveness analysis comparing SG, ESG, semaglutide, and lifestyle interventions (LI) for patients with obesity in class I (defined as BMI 30-34.9 kg/m²), class II (35-29.9 kg/m²), and class III (>40kg/m²) obesity.

Researchers used a state-transition, semi-Markov microsimulation model to analyze the effectiveness of ESG, SG, semaglutide, and LI in a simulated 40-year-old with three different base-case scenarios of class I, II, or III obesity. They then performed a detailed threshold and sensitivity analysis to change the cost of treatment modalities and the semaglutide adherence rate. Outcome measures included a willingness-to-pay threshold of US $100,000/quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICERs).
 

Cost-Effectiveness of Treatments

When the treatment modalities were compared with each other, findings showed that for class I obesity, ESG was cost effective (US $4,105/QALY). For class II and III obesity, SG was cost-effective as well (US $5,883/QALY) and (US $7,821/QALY), respectively.

In all classes of obesity, SG and ESG were cost-effective compared with LI. Semaglutide was not cost-effective compared with LI for class I, II, and III obesity (ICER US $508,414/QALY, $420,483/QALY, and $350,637/QALY, respectively).

“For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US $1,879 (class III), US $1,204 (class II), or US $297 (class I) annually,” the authors note.

The authors addressed recent guidelines to consider bariatric surgery in all obese patients. They recommend SG remain the standard of care for patients with severe obesity.

But national projections show that SG would address only 0.5% of life-years lost due to obesity.

“Barring a dramatic increase in patient adherence, bariatric surgery will not likely successfully mitigate the harm from the obesity epidemic,” they write.

“ESG may fill this gap and provide an additional option for patients with obesity as it demonstrated sustained weight loss at 2-5 years.” While insurance coverage is limited, they write, “our model demonstrates that payer coverage for ESG would provide an alternative tool to combat the obesity epidemic as part of a multidisciplinary approach.”

Semaglutide shows sustained weight loss in trials for up to two years but has a substantial annual cost, the authors note.

At lower prices, semaglutide can make a “major impact on the obesity pandemic as it can be prescribed in multiple healthcare settings and due to increased patient interested in non-invasive obesity treatment,” they write.

One limitation to the study is a lack of long-term data available for ESG and semaglutide. Authors were also not able to use a lifetime horizon because of a lack of long-term weight loss.

One study author reports financial relationships with BSC, Cook Medical, Surgical Intuitive, and Olympus America. Another author reports relationships with ACI, AGA-Varia, BSC, Dark Canyon Labs, Endiatx, Medtronic, Olympus, Virgo Systems; equity: AGA-Varia, Dark Canyon Labs, Endiatx, EndoSound, and Virgo Systems. The rest of the authors have no conflicts to disclose.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

Infection with COVID-19 conferred a nearly twofold risk of developing alopecia areata (AA), results from a large analysis of Korean patients demonstrated.

“There is a growing number of reports on new onset, exacerbation, and recurrence of AA after COVID-19,” corresponding author Jin Park, MD, PhD, of the department of dermatology at Jeonbuk National University Medical School, South Korea, and colleagues wrote in a research letter published online January 10, 2024, in JAMA Dermatology. “However, evidence supporting an association between COVID-19 and AA is limited.”

To investigate the association between COVID-19 and AA, the researchers used data from the Korea Disease Control and Prevention Agency–COVID-19–National Health Insurance Service cohort to conduct a propensity score–matched, nationwide, population-based cohort study from October 8, 2020, to September 30, 2021. They used Cox proportional hazards regression to calculate the incidence, prevalence, and adjusted hazard ratios (AHRs) for AA.

The cohort consisted of 259,369 patients with COVID-19 and 259,369 uninfected controls. The researchers observed an increased risk of telogen effluvium in patients with COVID-19 compared with the uninfected controls (AHR, 6.40; 95% CI, 4.92-8.33), while the incidence of epidermal cysts, benign skin tumors, and other negative control outcomes did not differ between groups.

Meanwhile, the incidence of AA in patients with COVID-19 was significantly higher compared with the uninfected controls (43.19 per 10,000 person-years [PY]), regardless of clinical subtype. This translated into an AHR of 1.82 (95% CI, 1.60-2.07). In other findings, the incidence of patchy AA and alopecia totalis and alopecia universalis (AT/AU) was 35.94 and 7.24 per 10,000 PY in patients with COVID-19 compared with 19.43 and 4.18 per 10,000 PY in uninfected controls, respectively.

“These findings support the possible role of COVID-19 in AA occurrence and exacerbation, although other environmental factors, such as psychological stress, may have also contributed to AA development during the pandemic,” the authors concluded. “Plausible mechanisms of AA following COVID-19 include antigenic molecular mimicry between SARS-CoV-2 and hair follicle autoantigens, cytokine shifting, and bystander activation.”

They acknowledged certain limitations of the analysis, including the potential for detection or misclassification bias and the fact that it did not evaluate causality between the two conditions.

Shari Lipner, MD, PhD, associate professor of dermatology at Weill Cornell Medicine, New York, who was asked to comment on the study, said that strengths of the study include the large sample size, and the use of positive and negative outcome controls, and that the incidence and prevalence of AA in Korea was stable during the prepandemic period. “A weakness of the study is that all alopecia areata cases may not have necessarily been confirmed,” Dr. Lipner told this news organization.

“Based on this study, dermatologists may consider AA in the differential diagnosis for a patient presenting with hair loss with recent COVID-19 diagnosis,” she added, noting that the potential for prevention of AA flares is also a reason to recommend COVID-19 vaccination for patients with a history of AA.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to comment on the study, said that while the analysis suggests a definite epidemiologic association between COVID-19 and AA, “any causal relationship needs further study.” She added that she has no specific advice for patients who develop AA following a COVID-19 infection. “Any conversation about AA can be difficult because there is no way to prognosticate if someone will just have one small, localized area of hair loss,” or several small areas, versus loss of all hair on the head or even the body as well, Dr. Ko explained.

The study was supported with grants from the National Research Foundation of the Korean Government and the Ministry of Health and Welfare, Republic of Korea. The authors, as well as Dr. Lipner and Dr. Ko, reported having no relevant disclosures.

Infection with COVID-19 conferred a nearly twofold risk of developing alopecia areata (AA), results from a large analysis of Korean patients demonstrated.

“There is a growing number of reports on new onset, exacerbation, and recurrence of AA after COVID-19,” corresponding author Jin Park, MD, PhD, of the department of dermatology at Jeonbuk National University Medical School, South Korea, and colleagues wrote in a research letter published online January 10, 2024, in JAMA Dermatology. “However, evidence supporting an association between COVID-19 and AA is limited.”

To investigate the association between COVID-19 and AA, the researchers used data from the Korea Disease Control and Prevention Agency–COVID-19–National Health Insurance Service cohort to conduct a propensity score–matched, nationwide, population-based cohort study from October 8, 2020, to September 30, 2021. They used Cox proportional hazards regression to calculate the incidence, prevalence, and adjusted hazard ratios (AHRs) for AA.

The cohort consisted of 259,369 patients with COVID-19 and 259,369 uninfected controls. The researchers observed an increased risk of telogen effluvium in patients with COVID-19 compared with the uninfected controls (AHR, 6.40; 95% CI, 4.92-8.33), while the incidence of epidermal cysts, benign skin tumors, and other negative control outcomes did not differ between groups.

Meanwhile, the incidence of AA in patients with COVID-19 was significantly higher compared with the uninfected controls (43.19 per 10,000 person-years [PY]), regardless of clinical subtype. This translated into an AHR of 1.82 (95% CI, 1.60-2.07). In other findings, the incidence of patchy AA and alopecia totalis and alopecia universalis (AT/AU) was 35.94 and 7.24 per 10,000 PY in patients with COVID-19 compared with 19.43 and 4.18 per 10,000 PY in uninfected controls, respectively.

“These findings support the possible role of COVID-19 in AA occurrence and exacerbation, although other environmental factors, such as psychological stress, may have also contributed to AA development during the pandemic,” the authors concluded. “Plausible mechanisms of AA following COVID-19 include antigenic molecular mimicry between SARS-CoV-2 and hair follicle autoantigens, cytokine shifting, and bystander activation.”

They acknowledged certain limitations of the analysis, including the potential for detection or misclassification bias and the fact that it did not evaluate causality between the two conditions.

Shari Lipner, MD, PhD, associate professor of dermatology at Weill Cornell Medicine, New York, who was asked to comment on the study, said that strengths of the study include the large sample size, and the use of positive and negative outcome controls, and that the incidence and prevalence of AA in Korea was stable during the prepandemic period. “A weakness of the study is that all alopecia areata cases may not have necessarily been confirmed,” Dr. Lipner told this news organization.

“Based on this study, dermatologists may consider AA in the differential diagnosis for a patient presenting with hair loss with recent COVID-19 diagnosis,” she added, noting that the potential for prevention of AA flares is also a reason to recommend COVID-19 vaccination for patients with a history of AA.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to comment on the study, said that while the analysis suggests a definite epidemiologic association between COVID-19 and AA, “any causal relationship needs further study.” She added that she has no specific advice for patients who develop AA following a COVID-19 infection. “Any conversation about AA can be difficult because there is no way to prognosticate if someone will just have one small, localized area of hair loss,” or several small areas, versus loss of all hair on the head or even the body as well, Dr. Ko explained.

The study was supported with grants from the National Research Foundation of the Korean Government and the Ministry of Health and Welfare, Republic of Korea. The authors, as well as Dr. Lipner and Dr. Ko, reported having no relevant disclosures.

Infection with COVID-19 conferred a nearly twofold risk of developing alopecia areata (AA), results from a large analysis of Korean patients demonstrated.

“There is a growing number of reports on new onset, exacerbation, and recurrence of AA after COVID-19,” corresponding author Jin Park, MD, PhD, of the department of dermatology at Jeonbuk National University Medical School, South Korea, and colleagues wrote in a research letter published online January 10, 2024, in JAMA Dermatology. “However, evidence supporting an association between COVID-19 and AA is limited.”

To investigate the association between COVID-19 and AA, the researchers used data from the Korea Disease Control and Prevention Agency–COVID-19–National Health Insurance Service cohort to conduct a propensity score–matched, nationwide, population-based cohort study from October 8, 2020, to September 30, 2021. They used Cox proportional hazards regression to calculate the incidence, prevalence, and adjusted hazard ratios (AHRs) for AA.

The cohort consisted of 259,369 patients with COVID-19 and 259,369 uninfected controls. The researchers observed an increased risk of telogen effluvium in patients with COVID-19 compared with the uninfected controls (AHR, 6.40; 95% CI, 4.92-8.33), while the incidence of epidermal cysts, benign skin tumors, and other negative control outcomes did not differ between groups.

Meanwhile, the incidence of AA in patients with COVID-19 was significantly higher compared with the uninfected controls (43.19 per 10,000 person-years [PY]), regardless of clinical subtype. This translated into an AHR of 1.82 (95% CI, 1.60-2.07). In other findings, the incidence of patchy AA and alopecia totalis and alopecia universalis (AT/AU) was 35.94 and 7.24 per 10,000 PY in patients with COVID-19 compared with 19.43 and 4.18 per 10,000 PY in uninfected controls, respectively.

“These findings support the possible role of COVID-19 in AA occurrence and exacerbation, although other environmental factors, such as psychological stress, may have also contributed to AA development during the pandemic,” the authors concluded. “Plausible mechanisms of AA following COVID-19 include antigenic molecular mimicry between SARS-CoV-2 and hair follicle autoantigens, cytokine shifting, and bystander activation.”

They acknowledged certain limitations of the analysis, including the potential for detection or misclassification bias and the fact that it did not evaluate causality between the two conditions.

Shari Lipner, MD, PhD, associate professor of dermatology at Weill Cornell Medicine, New York, who was asked to comment on the study, said that strengths of the study include the large sample size, and the use of positive and negative outcome controls, and that the incidence and prevalence of AA in Korea was stable during the prepandemic period. “A weakness of the study is that all alopecia areata cases may not have necessarily been confirmed,” Dr. Lipner told this news organization.

“Based on this study, dermatologists may consider AA in the differential diagnosis for a patient presenting with hair loss with recent COVID-19 diagnosis,” she added, noting that the potential for prevention of AA flares is also a reason to recommend COVID-19 vaccination for patients with a history of AA.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to comment on the study, said that while the analysis suggests a definite epidemiologic association between COVID-19 and AA, “any causal relationship needs further study.” She added that she has no specific advice for patients who develop AA following a COVID-19 infection. “Any conversation about AA can be difficult because there is no way to prognosticate if someone will just have one small, localized area of hair loss,” or several small areas, versus loss of all hair on the head or even the body as well, Dr. Ko explained.

The study was supported with grants from the National Research Foundation of the Korean Government and the Ministry of Health and Welfare, Republic of Korea. The authors, as well as Dr. Lipner and Dr. Ko, reported having no relevant disclosures.

Exposure to endocrine-disrupting chemicals (EDCs) via daily use of plastics is a major contributor to the overall disease burden in the United States and the associated costs to society amount to more than 1% of the gross domestic product, revealed a large-scale analysis.

The research, published in the Journal of the Endocrine Society, indicated that taken together, the disease burden attributable to EDCs used in the manufacture of plastics added up to almost $250 billion in 2018 alone.

“The diseases due to plastics run the entire life course from preterm birth to obesity, heart disease, and cancers,” commented lead author Leonardo Trasande, MD, MPP, Jim G. Hendrick, MD Professor of Pediatrics, Department of Pediatrics, NYU Langone Medical Center, New York, in a release.

“Our study drives home the need to address chemicals used in plastic materials” through global treaties and other policy initiatives, he said, so as to “reduce these costs” in line with reductions in exposure to the chemicals.

Co-author Michael Belliveau, Executive Director at Defend Our Health in Portland, ME, agreed, saying: “We can reduce these health costs and the prevalence of chronic endocrine diseases such as diabetes and obesity if governments and companies enact policies that minimize exposure to EDCs to protect public health and the environment.”

Plastics may contain any one of a number of EDCs, such as polybrominated diphenylethers in flame retardant additives, phthalates in food packaging, bisphenols in can linings, and perfluoroalkyl and polyfluoroalkyl substances (PFAS) in nonstick cooking utensils.

These chemicals have been shown to leach and disturb the body’s hormone systems, increasing the risk for cancer, diabetes, reproductive disorders, neurological impairments in developing fetuses and children, and even death.

In March 2022, the United Nations Environment Assembly committed to a global plastics treaty to “end plastic pollution and forge an international legally binding agreement by 2024” that “addresses the full life cycle of plastic, including its production, design and disposal.”

Minimizing EDC Exposure

But what can doctors tell their patients today to help them reduce their exposure to EDCs?

“There are safe and simple steps that people can take to limit their exposure to the chemicals of greatest concern,” Dr. Trasande told this news organization.

This can be partly achieved by reducing plastic use down to its essentials. “To use an example, when you are flying, fill up a stainless steel container after clearing security. At home, use glass or stainless steel” rather than plastic bottles or containers.

In particular, “avoiding microwaving plastic is important,” Dr. Trasande said, “even if a container says it’s microwave-safe.”

He warned that “many chemicals used in plastic are not covalently bound, and heat facilitates leaching into food. Microscopic contaminants can also get into food when you microwave plastic.”

Dr. Trasande also suggests limiting canned food consumption and avoiding cleaning plastic food containers in machine dishwashers.

Calculating the Disease Burden

To accurately assess the “the tradeoffs involved in the ongoing reliance on plastic production as a source of economic productivity,” the current researchers calculated the attributable disease burden and cost related to EDCs used in plastic materials in the United States in 2018.

Building on previously published analyses, they used industry reports, publications by national and international governing bodies, and peer-reviewed publications to determine the usage of each type of EDC and its attributable disease and disability burden.

This plastic-related fraction (PRF) of disease burden was then used to calculate an updated cost estimate for each EDC, based on the assumption that the disease burden is directly proportional to its exposure.

They found that for bisphenol A, 97.5% of its use, and therefore its estimated PRF of disease burden, was related to the manufacture of plastics, while this figure was 98%-100% for phthalates. For PDBE, 98% of its use was in plastics vs 93% for PFAS.

The researchers then estimated that the total plastic-attributable disease burden in the United States in 2018 cost the nation $249 billion, or 1.22% of the gross domestic product. Of this, $159 billion was linked to PDBE exposure, which is associated with diseases such as cancer.

Moreover, $1.02 billion plastic-attributable disease burden was associated with bisphenol A exposure, which can have potentially harmful health effects on the immune system; followed by $66.7 billion due to phthalates, which are linked to preterm birth, reduced sperm count, and childhood obesity; and $22.4 billion due to PFAS, which are associated with kidney failure and gestational diabetes.

The study was supported by the National Institutes of Health and the Passport Foundation.

Dr. Trasande declared relationships with Audible, Houghton Mifflin, Paidos, and Kobunsha, none of which relate to the present manuscript.

No other financial relationships were declared.

A version of this article appeared on Medscape.com.

Exposure to endocrine-disrupting chemicals (EDCs) via daily use of plastics is a major contributor to the overall disease burden in the United States and the associated costs to society amount to more than 1% of the gross domestic product, revealed a large-scale analysis.

The research, published in the Journal of the Endocrine Society, indicated that taken together, the disease burden attributable to EDCs used in the manufacture of plastics added up to almost $250 billion in 2018 alone.

“The diseases due to plastics run the entire life course from preterm birth to obesity, heart disease, and cancers,” commented lead author Leonardo Trasande, MD, MPP, Jim G. Hendrick, MD Professor of Pediatrics, Department of Pediatrics, NYU Langone Medical Center, New York, in a release.

“Our study drives home the need to address chemicals used in plastic materials” through global treaties and other policy initiatives, he said, so as to “reduce these costs” in line with reductions in exposure to the chemicals.

Co-author Michael Belliveau, Executive Director at Defend Our Health in Portland, ME, agreed, saying: “We can reduce these health costs and the prevalence of chronic endocrine diseases such as diabetes and obesity if governments and companies enact policies that minimize exposure to EDCs to protect public health and the environment.”

Plastics may contain any one of a number of EDCs, such as polybrominated diphenylethers in flame retardant additives, phthalates in food packaging, bisphenols in can linings, and perfluoroalkyl and polyfluoroalkyl substances (PFAS) in nonstick cooking utensils.

These chemicals have been shown to leach and disturb the body’s hormone systems, increasing the risk for cancer, diabetes, reproductive disorders, neurological impairments in developing fetuses and children, and even death.

In March 2022, the United Nations Environment Assembly committed to a global plastics treaty to “end plastic pollution and forge an international legally binding agreement by 2024” that “addresses the full life cycle of plastic, including its production, design and disposal.”

Minimizing EDC Exposure

But what can doctors tell their patients today to help them reduce their exposure to EDCs?

“There are safe and simple steps that people can take to limit their exposure to the chemicals of greatest concern,” Dr. Trasande told this news organization.

This can be partly achieved by reducing plastic use down to its essentials. “To use an example, when you are flying, fill up a stainless steel container after clearing security. At home, use glass or stainless steel” rather than plastic bottles or containers.

In particular, “avoiding microwaving plastic is important,” Dr. Trasande said, “even if a container says it’s microwave-safe.”

He warned that “many chemicals used in plastic are not covalently bound, and heat facilitates leaching into food. Microscopic contaminants can also get into food when you microwave plastic.”

Dr. Trasande also suggests limiting canned food consumption and avoiding cleaning plastic food containers in machine dishwashers.

Calculating the Disease Burden

To accurately assess the “the tradeoffs involved in the ongoing reliance on plastic production as a source of economic productivity,” the current researchers calculated the attributable disease burden and cost related to EDCs used in plastic materials in the United States in 2018.

Building on previously published analyses, they used industry reports, publications by national and international governing bodies, and peer-reviewed publications to determine the usage of each type of EDC and its attributable disease and disability burden.

This plastic-related fraction (PRF) of disease burden was then used to calculate an updated cost estimate for each EDC, based on the assumption that the disease burden is directly proportional to its exposure.

They found that for bisphenol A, 97.5% of its use, and therefore its estimated PRF of disease burden, was related to the manufacture of plastics, while this figure was 98%-100% for phthalates. For PDBE, 98% of its use was in plastics vs 93% for PFAS.

The researchers then estimated that the total plastic-attributable disease burden in the United States in 2018 cost the nation $249 billion, or 1.22% of the gross domestic product. Of this, $159 billion was linked to PDBE exposure, which is associated with diseases such as cancer.

Moreover, $1.02 billion plastic-attributable disease burden was associated with bisphenol A exposure, which can have potentially harmful health effects on the immune system; followed by $66.7 billion due to phthalates, which are linked to preterm birth, reduced sperm count, and childhood obesity; and $22.4 billion due to PFAS, which are associated with kidney failure and gestational diabetes.

The study was supported by the National Institutes of Health and the Passport Foundation.

Dr. Trasande declared relationships with Audible, Houghton Mifflin, Paidos, and Kobunsha, none of which relate to the present manuscript.

No other financial relationships were declared.

A version of this article appeared on Medscape.com.

Exposure to endocrine-disrupting chemicals (EDCs) via daily use of plastics is a major contributor to the overall disease burden in the United States and the associated costs to society amount to more than 1% of the gross domestic product, revealed a large-scale analysis.

The research, published in the Journal of the Endocrine Society, indicated that taken together, the disease burden attributable to EDCs used in the manufacture of plastics added up to almost $250 billion in 2018 alone.

“The diseases due to plastics run the entire life course from preterm birth to obesity, heart disease, and cancers,” commented lead author Leonardo Trasande, MD, MPP, Jim G. Hendrick, MD Professor of Pediatrics, Department of Pediatrics, NYU Langone Medical Center, New York, in a release.

“Our study drives home the need to address chemicals used in plastic materials” through global treaties and other policy initiatives, he said, so as to “reduce these costs” in line with reductions in exposure to the chemicals.

Co-author Michael Belliveau, Executive Director at Defend Our Health in Portland, ME, agreed, saying: “We can reduce these health costs and the prevalence of chronic endocrine diseases such as diabetes and obesity if governments and companies enact policies that minimize exposure to EDCs to protect public health and the environment.”

Plastics may contain any one of a number of EDCs, such as polybrominated diphenylethers in flame retardant additives, phthalates in food packaging, bisphenols in can linings, and perfluoroalkyl and polyfluoroalkyl substances (PFAS) in nonstick cooking utensils.

These chemicals have been shown to leach and disturb the body’s hormone systems, increasing the risk for cancer, diabetes, reproductive disorders, neurological impairments in developing fetuses and children, and even death.

In March 2022, the United Nations Environment Assembly committed to a global plastics treaty to “end plastic pollution and forge an international legally binding agreement by 2024” that “addresses the full life cycle of plastic, including its production, design and disposal.”

Minimizing EDC Exposure

But what can doctors tell their patients today to help them reduce their exposure to EDCs?

“There are safe and simple steps that people can take to limit their exposure to the chemicals of greatest concern,” Dr. Trasande told this news organization.

This can be partly achieved by reducing plastic use down to its essentials. “To use an example, when you are flying, fill up a stainless steel container after clearing security. At home, use glass or stainless steel” rather than plastic bottles or containers.

In particular, “avoiding microwaving plastic is important,” Dr. Trasande said, “even if a container says it’s microwave-safe.”

He warned that “many chemicals used in plastic are not covalently bound, and heat facilitates leaching into food. Microscopic contaminants can also get into food when you microwave plastic.”

Dr. Trasande also suggests limiting canned food consumption and avoiding cleaning plastic food containers in machine dishwashers.

Calculating the Disease Burden

To accurately assess the “the tradeoffs involved in the ongoing reliance on plastic production as a source of economic productivity,” the current researchers calculated the attributable disease burden and cost related to EDCs used in plastic materials in the United States in 2018.

Building on previously published analyses, they used industry reports, publications by national and international governing bodies, and peer-reviewed publications to determine the usage of each type of EDC and its attributable disease and disability burden.

This plastic-related fraction (PRF) of disease burden was then used to calculate an updated cost estimate for each EDC, based on the assumption that the disease burden is directly proportional to its exposure.

They found that for bisphenol A, 97.5% of its use, and therefore its estimated PRF of disease burden, was related to the manufacture of plastics, while this figure was 98%-100% for phthalates. For PDBE, 98% of its use was in plastics vs 93% for PFAS.

The researchers then estimated that the total plastic-attributable disease burden in the United States in 2018 cost the nation $249 billion, or 1.22% of the gross domestic product. Of this, $159 billion was linked to PDBE exposure, which is associated with diseases such as cancer.

Moreover, $1.02 billion plastic-attributable disease burden was associated with bisphenol A exposure, which can have potentially harmful health effects on the immune system; followed by $66.7 billion due to phthalates, which are linked to preterm birth, reduced sperm count, and childhood obesity; and $22.4 billion due to PFAS, which are associated with kidney failure and gestational diabetes.

The study was supported by the National Institutes of Health and the Passport Foundation.

Dr. Trasande declared relationships with Audible, Houghton Mifflin, Paidos, and Kobunsha, none of which relate to the present manuscript.

No other financial relationships were declared.

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.