Clinician Reviews

A process your body uses to stay warm in cool weather could one day lead to new therapies for obesity.

Scientists have, for the first time, mapped the precise nerve pathways that activate brown fat, or brown adipose tissue (BAT), a specialized fat that generates heat. Low temperatures kick brown fat into gear, helping the body keep its temperature and burning calories in the process.

“It has long been speculated that activating this type of fat may be useful in treating obesity and related metabolic conditions,” said Preethi Srikanthan, MD, an endocrinologist and professor of medicine who oversaw the research at the UCLA School of Medicine. “The challenge has been finding a way of selectively stimulating [it].”

Brown fat is different from the fat typically linked to obesity: the kind that accumulates around the belly, hips, and thighs. That’s white fat. White fat stores energy; brown fat burns it. That’s because brown fat cells have more mitochondria, a part of the cell that generates energy. 

After dissecting the necks of eight human cadavers, Dr. Srikanthan and her team traced the sympathetic nerve branches in the fat pad above the collarbone – where the largest depot of brown fat in adults is stored. They stained the nerves, took samples, and viewed them under a microscope. 

They found that nerves from brown fat traveled to the third and fourth cranial nerves of the brain, bundles of nerve fibers that control blinking and some eye movements.

In a previous case study, damage to these nerves appeared to block a chemical tracer from reaching brown fat. The evidence suggests that changing this nerve supply could alter brown fat activity, potentially leading to new treatments for obesity and metabolic diseases like type 2 diabetes, Dr. Srikanthan said.
 

A possible mechanism for Ozempic?

Brown fat has already been linked to at least one breakthrough in obesity treatment. Some evidence suggests that popular medications like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) may affect brown fat activity. These belong to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. They work by mimicking the hormone GLP-1, which is released in the gut and brain in response to eating glucose (sugary foods or drinks).

“GLP-1 agonists have been shown to increase [brown fat] activity in rodents and humans, but likely indirectly, via activation of specific regions in the brain,” explained Varman Samuel, MD, PhD, an associate professor of medicine at the Yale School of Medicine, New Haven, Conn., and chief of endocrinology for the VA Connecticut Healthcare System. 

The scientific literature is divided on this, but there is enough evidence to support further inquiry, Dr. Srikanthan said. Her team has begun a study to examine that link.
 

Opening the door to future obesity treatments

But their discovery means other new treatments could be on the horizon. 

Previous research had shown that the sympathetic nervous system drives brown fat activity. But now that the UCLA scientists have revealed the exact nerves connecting brown fat to the sympathetic nervous system, we could find ways to stimulate those pathways to activate brown fat – without stimulating the many organs (such as the heart and stomach) also connected to this vast network of nerves, Dr. Srikanthan said. 

Methods for doing that could include medication, electrical stimulation, or heat therapy, according to the study. 

Still, there is reason to temper expectations. “[Brown fat] depots, while highly metabolically active, are quite small,” Dr. Samuel said. “So, the overall contribution to whole-body energy balance in humans will likely be small.”

On the other hand, that prediction doesn’t account for what we don’t know. 

“We’re learning more about how tissues communicate with each other, beyond the release of hormones or metabolites,” Dr. Samuel said. Activating brown fat could trigger “signals that help coordinate whole-body energy metabolism.”

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

A process your body uses to stay warm in cool weather could one day lead to new therapies for obesity.

Scientists have, for the first time, mapped the precise nerve pathways that activate brown fat, or brown adipose tissue (BAT), a specialized fat that generates heat. Low temperatures kick brown fat into gear, helping the body keep its temperature and burning calories in the process.

“It has long been speculated that activating this type of fat may be useful in treating obesity and related metabolic conditions,” said Preethi Srikanthan, MD, an endocrinologist and professor of medicine who oversaw the research at the UCLA School of Medicine. “The challenge has been finding a way of selectively stimulating [it].”

Brown fat is different from the fat typically linked to obesity: the kind that accumulates around the belly, hips, and thighs. That’s white fat. White fat stores energy; brown fat burns it. That’s because brown fat cells have more mitochondria, a part of the cell that generates energy. 

After dissecting the necks of eight human cadavers, Dr. Srikanthan and her team traced the sympathetic nerve branches in the fat pad above the collarbone – where the largest depot of brown fat in adults is stored. They stained the nerves, took samples, and viewed them under a microscope. 

They found that nerves from brown fat traveled to the third and fourth cranial nerves of the brain, bundles of nerve fibers that control blinking and some eye movements.

In a previous case study, damage to these nerves appeared to block a chemical tracer from reaching brown fat. The evidence suggests that changing this nerve supply could alter brown fat activity, potentially leading to new treatments for obesity and metabolic diseases like type 2 diabetes, Dr. Srikanthan said.
 

A possible mechanism for Ozempic?

Brown fat has already been linked to at least one breakthrough in obesity treatment. Some evidence suggests that popular medications like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) may affect brown fat activity. These belong to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. They work by mimicking the hormone GLP-1, which is released in the gut and brain in response to eating glucose (sugary foods or drinks).

“GLP-1 agonists have been shown to increase [brown fat] activity in rodents and humans, but likely indirectly, via activation of specific regions in the brain,” explained Varman Samuel, MD, PhD, an associate professor of medicine at the Yale School of Medicine, New Haven, Conn., and chief of endocrinology for the VA Connecticut Healthcare System. 

The scientific literature is divided on this, but there is enough evidence to support further inquiry, Dr. Srikanthan said. Her team has begun a study to examine that link.
 

Opening the door to future obesity treatments

But their discovery means other new treatments could be on the horizon. 

Previous research had shown that the sympathetic nervous system drives brown fat activity. But now that the UCLA scientists have revealed the exact nerves connecting brown fat to the sympathetic nervous system, we could find ways to stimulate those pathways to activate brown fat – without stimulating the many organs (such as the heart and stomach) also connected to this vast network of nerves, Dr. Srikanthan said. 

Methods for doing that could include medication, electrical stimulation, or heat therapy, according to the study. 

Still, there is reason to temper expectations. “[Brown fat] depots, while highly metabolically active, are quite small,” Dr. Samuel said. “So, the overall contribution to whole-body energy balance in humans will likely be small.”

On the other hand, that prediction doesn’t account for what we don’t know. 

“We’re learning more about how tissues communicate with each other, beyond the release of hormones or metabolites,” Dr. Samuel said. Activating brown fat could trigger “signals that help coordinate whole-body energy metabolism.”

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

A process your body uses to stay warm in cool weather could one day lead to new therapies for obesity.

Scientists have, for the first time, mapped the precise nerve pathways that activate brown fat, or brown adipose tissue (BAT), a specialized fat that generates heat. Low temperatures kick brown fat into gear, helping the body keep its temperature and burning calories in the process.

“It has long been speculated that activating this type of fat may be useful in treating obesity and related metabolic conditions,” said Preethi Srikanthan, MD, an endocrinologist and professor of medicine who oversaw the research at the UCLA School of Medicine. “The challenge has been finding a way of selectively stimulating [it].”

Brown fat is different from the fat typically linked to obesity: the kind that accumulates around the belly, hips, and thighs. That’s white fat. White fat stores energy; brown fat burns it. That’s because brown fat cells have more mitochondria, a part of the cell that generates energy. 

After dissecting the necks of eight human cadavers, Dr. Srikanthan and her team traced the sympathetic nerve branches in the fat pad above the collarbone – where the largest depot of brown fat in adults is stored. They stained the nerves, took samples, and viewed them under a microscope. 

They found that nerves from brown fat traveled to the third and fourth cranial nerves of the brain, bundles of nerve fibers that control blinking and some eye movements.

In a previous case study, damage to these nerves appeared to block a chemical tracer from reaching brown fat. The evidence suggests that changing this nerve supply could alter brown fat activity, potentially leading to new treatments for obesity and metabolic diseases like type 2 diabetes, Dr. Srikanthan said.
 

A possible mechanism for Ozempic?

Brown fat has already been linked to at least one breakthrough in obesity treatment. Some evidence suggests that popular medications like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) may affect brown fat activity. These belong to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. They work by mimicking the hormone GLP-1, which is released in the gut and brain in response to eating glucose (sugary foods or drinks).

“GLP-1 agonists have been shown to increase [brown fat] activity in rodents and humans, but likely indirectly, via activation of specific regions in the brain,” explained Varman Samuel, MD, PhD, an associate professor of medicine at the Yale School of Medicine, New Haven, Conn., and chief of endocrinology for the VA Connecticut Healthcare System. 

The scientific literature is divided on this, but there is enough evidence to support further inquiry, Dr. Srikanthan said. Her team has begun a study to examine that link.
 

Opening the door to future obesity treatments

But their discovery means other new treatments could be on the horizon. 

Previous research had shown that the sympathetic nervous system drives brown fat activity. But now that the UCLA scientists have revealed the exact nerves connecting brown fat to the sympathetic nervous system, we could find ways to stimulate those pathways to activate brown fat – without stimulating the many organs (such as the heart and stomach) also connected to this vast network of nerves, Dr. Srikanthan said. 

Methods for doing that could include medication, electrical stimulation, or heat therapy, according to the study. 

Still, there is reason to temper expectations. “[Brown fat] depots, while highly metabolically active, are quite small,” Dr. Samuel said. “So, the overall contribution to whole-body energy balance in humans will likely be small.”

On the other hand, that prediction doesn’t account for what we don’t know. 

“We’re learning more about how tissues communicate with each other, beyond the release of hormones or metabolites,” Dr. Samuel said. Activating brown fat could trigger “signals that help coordinate whole-body energy metabolism.”

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

VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.

The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.

As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.

“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.

Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.

The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.

Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m². Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.

The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).

The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.

Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.

Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”

Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.

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

VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.

The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.

As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.

“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.

Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.

The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.

Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m². Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.

The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).

The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.

Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.

Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”

Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.

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

VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.

The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.

As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.

“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.

Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.

The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.

Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m². Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.

The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).

The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.

Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.

Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”

Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.

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

The prospect of remission of type 2 diabetes (T2D) has captured the hearts and minds of many patients with T2D and health care professionals, including myself.

I have changed my narrative when supporting my patients with T2D. I used to say that T2D is a progressive condition, but considering seminal recent evidence like the DiRECT trial, I now say that T2D can be a progressive condition. Through significant weight loss, patients can reverse it and achieve remission of T2D. This has given my patients hope that their T2D is no longer an inexorable condition. And hope, of course, is a powerful enabler of change.

However, the million-dollar question is whether remission of T2D can be maintained in the long term in the real-world setting of primary care, which is chiefly where T2D is managed.

I therefore relished the opportunity to attend a debate on this topic at the annual meeting of the European Association for the Study of Diabetes in Hamburg, Germany, between Roy Taylor, MD, principal investigator for the DiRECT study and professor of medicine and metabolism at the University of Newcastle, England, and Kamlesh Khunti, MD, PhD, professor of primary care diabetes at the University of Leicester, England.
 

Remarkable weight loss

Dr. Taylor powerfully recapitulated the initial results of the DiRECT study. T2D remission was achieved in 46% of participants who underwent a low-energy formula diet (around 850 calories daily) for 3-5 months. After 2 years’ follow-up, an impressive 36% of participants were still in remission. Dr. Taylor then discussed unpublished 5-year extension follow-up data of the DiRECT study. Average weight loss in the remaining intervention group was 6.1 kg. I echo Taylor’s sentiment that this finding is remarkable in the context of a dietary study.

Overall, 13% of participants were still in remission, and this cohort maintained an average weight loss of 8.9 kg. Dr. Taylor concluded that lasting remission of T2D is indeed feasible in a primary care setting.

Yet he acknowledged that although remission appears feasible in the longer term, it was not necessarily easy, or indeed possible, for everyone. He used a wonderful analogy about climbing Mount Everest: It is feasible, but not everyone can or wants to climb it. And even if you try, you might not reach the top.

This analogy perfectly encapsulates the challenges I have observed when my patients have striven for T2D remission. In my opinion, intensive weight management with a low-energy formula diet is not a panacea for T2D but another tool in our toolbox to offer patients.

He also described some “jaw-dropping” results regarding incidence of cancer: There were no cases of cancer in the intervention group during the 5-year period, but there were eight cases of cancer in the control group. The latter figure is consistent with published data for cancer incidence in patients with T2D and the body mass index (BMI) inclusion criteria for the DiRECT study (a BMI of 27-45 kg/m²). Obesity is an established risk factor for 13 types of cancer, and excess body fat entails an approximately 17% increased risk for cancer-specific mortality. This indeed is a powerful motivator to facilitate meaningful lifestyle change.

In primary care, we also need to be aware that most weight regain usually occurs secondary to a life event (for example, financial, family, or illness). We should reiterate to our patients that weight regain is not a failure; it is just part of life. Once the life event has passed, rapid weight loss can be attempted again. In the “rescue plans” that were integral to the DiRECT study, participants were offered further periods of total diet replacement, depending on quantity of weight gain. In fact, 50% of participants in DiRECT required rescue therapy, and their outcomes, reassuringly, were the same as the other 50%.

Dr. Taylor also quoted data from the ReTUNE study suggesting that weight regain was less of an issue for those with initial BMI of 21-27, and there is “more bang for your buck” in approaching remission of T2D in patients with lower BMI. The fact that people with normal or near-normal BMI can also reverse their T2D was also a game changer for my clinical practice; the concept of an individual or personal fat threshold that results in T2D offers a pragmatic explanation to patients with T2D who are frustrated by the lack of improvements in cardiometabolic parameters despite significant weight loss.

Finally, Dr. Taylor acknowledged the breadth of the definition of T2D remission: A1c < 48 mmol/mol at least 2 months off all antidiabetic medication. This definition includes A1c values within the “prediabetes” range: 42-47 mmol/mol.

He cited 10-year cardiovascular risk data driven by hypertension and dyslipidemia before significant weight loss and compared it with 10-year cardiovascular risk data after significant weight loss. Cardiovascular risk profile was more favorable after weight loss, compared with controls with prediabetes without weight loss, even though some of the intervention group who lost significant weight still had an A1c of 42-47 mmol/mol. Dr. Taylor suggested that we not label these individuals who have lost significant weight as having prediabetes. Instead “postdiabetes” should be preferred, because these patients had more favorable cardiovascular profiles.

This is a very important take-home message for primary care: prediabetes is more than just dysglycemia.
 

New terminology proposed

Dr. Khunti outlined a recent large, systematic review that concluded that the definition of T2D remission encompassed substantial heterogeneity. This heterogeneity complicates the interpretation of previous research on T2D remission and complicates the implementation of remission pathways into routine clinical practice. Furthermore, Dr. Khunti highlighted a recent consensus report on the definition and interpretation of remission in T2D that explicitly stated that the underlying pathophysiology of T2D is rarely normalized completely by interventions, thus reducing the possibility of lasting remission.

Dr. Khunti also challenged the cardiovascular benefits seen after T2D remission. Recent Danish registry data were presented, demonstrating a twofold increased risk for major adverse cardiovascular events over 5 years in individuals who achieved remission of T2D, but not on glucose-lowering drug therapy.

Adherence to strict dietary interventions in the longer term was also addressed. Diet-induced weight loss causes changes in circulating hormones such as ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and leptin, which mediate appetite and drive hunger and an increased preference for energy-dense foods (that is, high-fat or sugary foods), all of which encourage weight regain. Dr. Khunti suggested that other interventions, such as glucagon-like peptide 1 (GLP-1) receptor agonists or bariatric surgery, specifically target some of these hormonal responses.

The challenges in recruitment and retention for lifestyle studies were also discussed; they reflect the challenges of behavioral programs in primary care. The DiRECT study had 20% participation of screened candidates and an attrition rate approaching 30%. The seminal Diabetes Prevention Program study and Finnish Diabetes Prevention Study had similar results. At a population level, individuals do not appear to want to participate in behavioral programs.

Dr. Khunti also warned that the review of annual care processes for diabetes is declining for patients who had achieved remission, possibly because of a false sense of reassurance among health care professionals. It is essential that all those in remission remain under at least annual follow-up, because there is still a risk for future microvascular and macrovascular complications, especially in the event of weight regain.

Dr. Khunti concluded by proposing new terminology for remission: remission of hyperglycemia or euglycemia, aiming for A1c < 48 mmol/mol with or without glucose-lowering therapy. I do agree with this; it reflects the zeitgeist of cardiorenal protective diabetes therapies and is analogous to rheumatoid arthritis, where remission is defined as no disease activity while on therapy. But one size does not fit all.

Sir William Osler’s words provide a fitting conclusion: “If it were not for the great variability among individuals, medicine might as well be a science and not an art.”

Dr. Fernando has disclosed that he has received speakers’ fees from Eli Lilly and Novo Nordisk.

Dr. Fernando is a general practitioner near Edinburgh, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.

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

The prospect of remission of type 2 diabetes (T2D) has captured the hearts and minds of many patients with T2D and health care professionals, including myself.

I have changed my narrative when supporting my patients with T2D. I used to say that T2D is a progressive condition, but considering seminal recent evidence like the DiRECT trial, I now say that T2D can be a progressive condition. Through significant weight loss, patients can reverse it and achieve remission of T2D. This has given my patients hope that their T2D is no longer an inexorable condition. And hope, of course, is a powerful enabler of change.

However, the million-dollar question is whether remission of T2D can be maintained in the long term in the real-world setting of primary care, which is chiefly where T2D is managed.

I therefore relished the opportunity to attend a debate on this topic at the annual meeting of the European Association for the Study of Diabetes in Hamburg, Germany, between Roy Taylor, MD, principal investigator for the DiRECT study and professor of medicine and metabolism at the University of Newcastle, England, and Kamlesh Khunti, MD, PhD, professor of primary care diabetes at the University of Leicester, England.
 

Remarkable weight loss

Dr. Taylor powerfully recapitulated the initial results of the DiRECT study. T2D remission was achieved in 46% of participants who underwent a low-energy formula diet (around 850 calories daily) for 3-5 months. After 2 years’ follow-up, an impressive 36% of participants were still in remission. Dr. Taylor then discussed unpublished 5-year extension follow-up data of the DiRECT study. Average weight loss in the remaining intervention group was 6.1 kg. I echo Taylor’s sentiment that this finding is remarkable in the context of a dietary study.

Overall, 13% of participants were still in remission, and this cohort maintained an average weight loss of 8.9 kg. Dr. Taylor concluded that lasting remission of T2D is indeed feasible in a primary care setting.

Yet he acknowledged that although remission appears feasible in the longer term, it was not necessarily easy, or indeed possible, for everyone. He used a wonderful analogy about climbing Mount Everest: It is feasible, but not everyone can or wants to climb it. And even if you try, you might not reach the top.

This analogy perfectly encapsulates the challenges I have observed when my patients have striven for T2D remission. In my opinion, intensive weight management with a low-energy formula diet is not a panacea for T2D but another tool in our toolbox to offer patients.

He also described some “jaw-dropping” results regarding incidence of cancer: There were no cases of cancer in the intervention group during the 5-year period, but there were eight cases of cancer in the control group. The latter figure is consistent with published data for cancer incidence in patients with T2D and the body mass index (BMI) inclusion criteria for the DiRECT study (a BMI of 27-45 kg/m²). Obesity is an established risk factor for 13 types of cancer, and excess body fat entails an approximately 17% increased risk for cancer-specific mortality. This indeed is a powerful motivator to facilitate meaningful lifestyle change.

In primary care, we also need to be aware that most weight regain usually occurs secondary to a life event (for example, financial, family, or illness). We should reiterate to our patients that weight regain is not a failure; it is just part of life. Once the life event has passed, rapid weight loss can be attempted again. In the “rescue plans” that were integral to the DiRECT study, participants were offered further periods of total diet replacement, depending on quantity of weight gain. In fact, 50% of participants in DiRECT required rescue therapy, and their outcomes, reassuringly, were the same as the other 50%.

Dr. Taylor also quoted data from the ReTUNE study suggesting that weight regain was less of an issue for those with initial BMI of 21-27, and there is “more bang for your buck” in approaching remission of T2D in patients with lower BMI. The fact that people with normal or near-normal BMI can also reverse their T2D was also a game changer for my clinical practice; the concept of an individual or personal fat threshold that results in T2D offers a pragmatic explanation to patients with T2D who are frustrated by the lack of improvements in cardiometabolic parameters despite significant weight loss.

Finally, Dr. Taylor acknowledged the breadth of the definition of T2D remission: A1c < 48 mmol/mol at least 2 months off all antidiabetic medication. This definition includes A1c values within the “prediabetes” range: 42-47 mmol/mol.

He cited 10-year cardiovascular risk data driven by hypertension and dyslipidemia before significant weight loss and compared it with 10-year cardiovascular risk data after significant weight loss. Cardiovascular risk profile was more favorable after weight loss, compared with controls with prediabetes without weight loss, even though some of the intervention group who lost significant weight still had an A1c of 42-47 mmol/mol. Dr. Taylor suggested that we not label these individuals who have lost significant weight as having prediabetes. Instead “postdiabetes” should be preferred, because these patients had more favorable cardiovascular profiles.

This is a very important take-home message for primary care: prediabetes is more than just dysglycemia.
 

New terminology proposed

Dr. Khunti outlined a recent large, systematic review that concluded that the definition of T2D remission encompassed substantial heterogeneity. This heterogeneity complicates the interpretation of previous research on T2D remission and complicates the implementation of remission pathways into routine clinical practice. Furthermore, Dr. Khunti highlighted a recent consensus report on the definition and interpretation of remission in T2D that explicitly stated that the underlying pathophysiology of T2D is rarely normalized completely by interventions, thus reducing the possibility of lasting remission.

Dr. Khunti also challenged the cardiovascular benefits seen after T2D remission. Recent Danish registry data were presented, demonstrating a twofold increased risk for major adverse cardiovascular events over 5 years in individuals who achieved remission of T2D, but not on glucose-lowering drug therapy.

Adherence to strict dietary interventions in the longer term was also addressed. Diet-induced weight loss causes changes in circulating hormones such as ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and leptin, which mediate appetite and drive hunger and an increased preference for energy-dense foods (that is, high-fat or sugary foods), all of which encourage weight regain. Dr. Khunti suggested that other interventions, such as glucagon-like peptide 1 (GLP-1) receptor agonists or bariatric surgery, specifically target some of these hormonal responses.

The challenges in recruitment and retention for lifestyle studies were also discussed; they reflect the challenges of behavioral programs in primary care. The DiRECT study had 20% participation of screened candidates and an attrition rate approaching 30%. The seminal Diabetes Prevention Program study and Finnish Diabetes Prevention Study had similar results. At a population level, individuals do not appear to want to participate in behavioral programs.

Dr. Khunti also warned that the review of annual care processes for diabetes is declining for patients who had achieved remission, possibly because of a false sense of reassurance among health care professionals. It is essential that all those in remission remain under at least annual follow-up, because there is still a risk for future microvascular and macrovascular complications, especially in the event of weight regain.

Dr. Khunti concluded by proposing new terminology for remission: remission of hyperglycemia or euglycemia, aiming for A1c < 48 mmol/mol with or without glucose-lowering therapy. I do agree with this; it reflects the zeitgeist of cardiorenal protective diabetes therapies and is analogous to rheumatoid arthritis, where remission is defined as no disease activity while on therapy. But one size does not fit all.

Sir William Osler’s words provide a fitting conclusion: “If it were not for the great variability among individuals, medicine might as well be a science and not an art.”

Dr. Fernando has disclosed that he has received speakers’ fees from Eli Lilly and Novo Nordisk.

Dr. Fernando is a general practitioner near Edinburgh, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.

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

The prospect of remission of type 2 diabetes (T2D) has captured the hearts and minds of many patients with T2D and health care professionals, including myself.

I have changed my narrative when supporting my patients with T2D. I used to say that T2D is a progressive condition, but considering seminal recent evidence like the DiRECT trial, I now say that T2D can be a progressive condition. Through significant weight loss, patients can reverse it and achieve remission of T2D. This has given my patients hope that their T2D is no longer an inexorable condition. And hope, of course, is a powerful enabler of change.

However, the million-dollar question is whether remission of T2D can be maintained in the long term in the real-world setting of primary care, which is chiefly where T2D is managed.

I therefore relished the opportunity to attend a debate on this topic at the annual meeting of the European Association for the Study of Diabetes in Hamburg, Germany, between Roy Taylor, MD, principal investigator for the DiRECT study and professor of medicine and metabolism at the University of Newcastle, England, and Kamlesh Khunti, MD, PhD, professor of primary care diabetes at the University of Leicester, England.
 

Remarkable weight loss

Dr. Taylor powerfully recapitulated the initial results of the DiRECT study. T2D remission was achieved in 46% of participants who underwent a low-energy formula diet (around 850 calories daily) for 3-5 months. After 2 years’ follow-up, an impressive 36% of participants were still in remission. Dr. Taylor then discussed unpublished 5-year extension follow-up data of the DiRECT study. Average weight loss in the remaining intervention group was 6.1 kg. I echo Taylor’s sentiment that this finding is remarkable in the context of a dietary study.

Overall, 13% of participants were still in remission, and this cohort maintained an average weight loss of 8.9 kg. Dr. Taylor concluded that lasting remission of T2D is indeed feasible in a primary care setting.

Yet he acknowledged that although remission appears feasible in the longer term, it was not necessarily easy, or indeed possible, for everyone. He used a wonderful analogy about climbing Mount Everest: It is feasible, but not everyone can or wants to climb it. And even if you try, you might not reach the top.

This analogy perfectly encapsulates the challenges I have observed when my patients have striven for T2D remission. In my opinion, intensive weight management with a low-energy formula diet is not a panacea for T2D but another tool in our toolbox to offer patients.

He also described some “jaw-dropping” results regarding incidence of cancer: There were no cases of cancer in the intervention group during the 5-year period, but there were eight cases of cancer in the control group. The latter figure is consistent with published data for cancer incidence in patients with T2D and the body mass index (BMI) inclusion criteria for the DiRECT study (a BMI of 27-45 kg/m²). Obesity is an established risk factor for 13 types of cancer, and excess body fat entails an approximately 17% increased risk for cancer-specific mortality. This indeed is a powerful motivator to facilitate meaningful lifestyle change.

In primary care, we also need to be aware that most weight regain usually occurs secondary to a life event (for example, financial, family, or illness). We should reiterate to our patients that weight regain is not a failure; it is just part of life. Once the life event has passed, rapid weight loss can be attempted again. In the “rescue plans” that were integral to the DiRECT study, participants were offered further periods of total diet replacement, depending on quantity of weight gain. In fact, 50% of participants in DiRECT required rescue therapy, and their outcomes, reassuringly, were the same as the other 50%.

Dr. Taylor also quoted data from the ReTUNE study suggesting that weight regain was less of an issue for those with initial BMI of 21-27, and there is “more bang for your buck” in approaching remission of T2D in patients with lower BMI. The fact that people with normal or near-normal BMI can also reverse their T2D was also a game changer for my clinical practice; the concept of an individual or personal fat threshold that results in T2D offers a pragmatic explanation to patients with T2D who are frustrated by the lack of improvements in cardiometabolic parameters despite significant weight loss.

Finally, Dr. Taylor acknowledged the breadth of the definition of T2D remission: A1c < 48 mmol/mol at least 2 months off all antidiabetic medication. This definition includes A1c values within the “prediabetes” range: 42-47 mmol/mol.

He cited 10-year cardiovascular risk data driven by hypertension and dyslipidemia before significant weight loss and compared it with 10-year cardiovascular risk data after significant weight loss. Cardiovascular risk profile was more favorable after weight loss, compared with controls with prediabetes without weight loss, even though some of the intervention group who lost significant weight still had an A1c of 42-47 mmol/mol. Dr. Taylor suggested that we not label these individuals who have lost significant weight as having prediabetes. Instead “postdiabetes” should be preferred, because these patients had more favorable cardiovascular profiles.

This is a very important take-home message for primary care: prediabetes is more than just dysglycemia.
 

New terminology proposed

Dr. Khunti outlined a recent large, systematic review that concluded that the definition of T2D remission encompassed substantial heterogeneity. This heterogeneity complicates the interpretation of previous research on T2D remission and complicates the implementation of remission pathways into routine clinical practice. Furthermore, Dr. Khunti highlighted a recent consensus report on the definition and interpretation of remission in T2D that explicitly stated that the underlying pathophysiology of T2D is rarely normalized completely by interventions, thus reducing the possibility of lasting remission.

Dr. Khunti also challenged the cardiovascular benefits seen after T2D remission. Recent Danish registry data were presented, demonstrating a twofold increased risk for major adverse cardiovascular events over 5 years in individuals who achieved remission of T2D, but not on glucose-lowering drug therapy.

Adherence to strict dietary interventions in the longer term was also addressed. Diet-induced weight loss causes changes in circulating hormones such as ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and leptin, which mediate appetite and drive hunger and an increased preference for energy-dense foods (that is, high-fat or sugary foods), all of which encourage weight regain. Dr. Khunti suggested that other interventions, such as glucagon-like peptide 1 (GLP-1) receptor agonists or bariatric surgery, specifically target some of these hormonal responses.

The challenges in recruitment and retention for lifestyle studies were also discussed; they reflect the challenges of behavioral programs in primary care. The DiRECT study had 20% participation of screened candidates and an attrition rate approaching 30%. The seminal Diabetes Prevention Program study and Finnish Diabetes Prevention Study had similar results. At a population level, individuals do not appear to want to participate in behavioral programs.

Dr. Khunti also warned that the review of annual care processes for diabetes is declining for patients who had achieved remission, possibly because of a false sense of reassurance among health care professionals. It is essential that all those in remission remain under at least annual follow-up, because there is still a risk for future microvascular and macrovascular complications, especially in the event of weight regain.

Dr. Khunti concluded by proposing new terminology for remission: remission of hyperglycemia or euglycemia, aiming for A1c < 48 mmol/mol with or without glucose-lowering therapy. I do agree with this; it reflects the zeitgeist of cardiorenal protective diabetes therapies and is analogous to rheumatoid arthritis, where remission is defined as no disease activity while on therapy. But one size does not fit all.

Sir William Osler’s words provide a fitting conclusion: “If it were not for the great variability among individuals, medicine might as well be a science and not an art.”

Dr. Fernando has disclosed that he has received speakers’ fees from Eli Lilly and Novo Nordisk.

Dr. Fernando is a general practitioner near Edinburgh, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.

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

Can busy primary care offices continue to care for patients with diabetes? No one would argue that it is involved and takes effort, and health care providers are bankrupt when it comes to sparing additional time for this chronic disease. With roughly 37 million people living with diabetes and 96 million with prediabetes or early type 2 diabetes, and just over 8,000 practicing endocrinologists in the United States, we all need to make time especially in primary care to provide insight and holistic care. With limited time and budget, how do we do this?

First, decide to be involved in caring for patients with diabetes. Diabetes is best managed by interprofessional care teams, so you’re not going it alone. These teams may include physicians; pharmacists; physician assistants; advanced practice nurses; registered nurses; certified diabetes care and education specialists (CDCES); dietitians; and other professionals such as social workers, behavioral health professionals, medical assistants, and community health workers. Know which professionals are available to serve on your team, either within your clinic or as a consultant, and reach out to them to share the care and ease the burden. Remember to refer to these professionals to reinforce the diabetes intervention message to the patient.

Second, incorporate “diabetes only” appointments into your schedule, allowing time to focus on current comprehensive diabetes treatment goals, barriers/inertia for care. Remember to have short-interval follow-up as needed to keep that patient engaged to achieve their targets. Instruct your office staff to create diabetes appointment templates and reminders to patients to bring diabetes-related technologies, medication lists, and diabetes questions to the appointment. When I implemented this change, my patients welcomed the focus on their diabetes health, and they knew we were prioritizing this disease that they have for a lifetime. These appointments did not take away from their other conditions; rather, they often reminded me to stay focused on their diabetes and associated coconditions. 

Taking the time to establish efficient workflows before implementing diabetes care saves countless hours later and immediately maximizes health care provider–patient interactions. Assign specific staff duties and expectations related to diabetes appointments, such as downloading diabetes technology, medication reconciliation, laboratory data, point-of-care hemoglobin A1c, basic foot exam, and patient goals for diabetes care. This allows the prescriber to focus on the glycemic, cardiologic, renal, and metabolic goals and overcome the therapeutic inertia that plagues us all.

Incorporating diabetes-related technology into clinical practice can be a significant time-saver but requires initial onboarding. Set aside a few hours to create a technology clinic flow, and designate at least one team member to be responsible for obtaining patient data before, during, or after encounters. If possible, obtaining data ahead of the visit will enhance efficiency, allowing for meaningful discussion of blood glucose and lifestyle patterns. Diabetes technology reveals the gaps in care and enhances our ability to identify the areas where glycemic intervention is needed. In addition, it reveals the impact of food choices, activity level, stress, and medication adherence to the person living with diabetes. 

Finally, be proactive about therapeutic inertia. This is defined as a prescribers’ failure to intensify or deintensify a patient’s treatment when appropriate to do so. Causes of therapeutic inertia can be placed at the primary care physician level, including time constraints or inexperience in treating diabetes; the patient level, such as concerns about side effects or new treatment regimens; or a systemic level, such as availability of medications or their costs. Be real with yourself: We all have inertia and can identify areas to overcome. Never let inertia be traced back to you.

Not all inertia lives with the health care provider. Patients bring apprehension and concerns, have questions, and just want to share the frustrations associated with living their best life with the disease. Don’t assume that you know what your patients’ treatment barriers are; ask them. If you don’t have an answer, then note it and come up with one by the next follow-up. Remember that this is a chronic disease – a marathon, not a sprint. You don’t have to solve everything at one appointment; rather, keep the momentum going.

Let’s put this into clinical practice. For the next patient with diabetes who comes into your office, discuss with them your intention to prioritize their diabetes by having an appointment set aside to specifically focus on their individual goals and targets for their disease. Have the patient list any barriers and treatment goals they would like to review; flag your schedule to indicate it is a diabetes-only visit; and orient your staff to reconcile diabetes medications and record the patient’s last eye exam, urine albumin-to-creatinine ratio, A1c result, and blood glucose data. During this encounter, identify the patient’s personal targets for control, examine their feet, and review or order necessary laboratory metrics. Explore the patient-reported barriers and make inroads to remove or alleviate these. Advance treatment intervention, and schedule follow-up: every 4-6 weeks if the A1c is > 9%, every 2 months if it’s 7% to < 9%, and every 3-6 months if it’s < 7%. Utilize team diabetes care, such as CDCES referrals, dietitians, online resources, and community members, to help reinforce care and enhance engagement. 

We need to take steps in our clinical practice to make the necessary space to accommodate this pervasive disease affecting nearly one-third of our population. Take a moment to look up and determine what needs to be in place so that you can take care of the people in your practice with diabetes. Laying the groundwork for implementing diabetes-only appointments can be time-consuming, but establishing consistent procedures, developing efficient workflows, and clearly defining roles and responsibilities is well worth the effort. This solid foundation equips the office, health care providers, and staff to care for persons with diabetes and will be invaluable to ensure that time for this care is available in the day-to-day clinical practice.

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

Can busy primary care offices continue to care for patients with diabetes? No one would argue that it is involved and takes effort, and health care providers are bankrupt when it comes to sparing additional time for this chronic disease. With roughly 37 million people living with diabetes and 96 million with prediabetes or early type 2 diabetes, and just over 8,000 practicing endocrinologists in the United States, we all need to make time especially in primary care to provide insight and holistic care. With limited time and budget, how do we do this?

First, decide to be involved in caring for patients with diabetes. Diabetes is best managed by interprofessional care teams, so you’re not going it alone. These teams may include physicians; pharmacists; physician assistants; advanced practice nurses; registered nurses; certified diabetes care and education specialists (CDCES); dietitians; and other professionals such as social workers, behavioral health professionals, medical assistants, and community health workers. Know which professionals are available to serve on your team, either within your clinic or as a consultant, and reach out to them to share the care and ease the burden. Remember to refer to these professionals to reinforce the diabetes intervention message to the patient.

Second, incorporate “diabetes only” appointments into your schedule, allowing time to focus on current comprehensive diabetes treatment goals, barriers/inertia for care. Remember to have short-interval follow-up as needed to keep that patient engaged to achieve their targets. Instruct your office staff to create diabetes appointment templates and reminders to patients to bring diabetes-related technologies, medication lists, and diabetes questions to the appointment. When I implemented this change, my patients welcomed the focus on their diabetes health, and they knew we were prioritizing this disease that they have for a lifetime. These appointments did not take away from their other conditions; rather, they often reminded me to stay focused on their diabetes and associated coconditions. 

Taking the time to establish efficient workflows before implementing diabetes care saves countless hours later and immediately maximizes health care provider–patient interactions. Assign specific staff duties and expectations related to diabetes appointments, such as downloading diabetes technology, medication reconciliation, laboratory data, point-of-care hemoglobin A1c, basic foot exam, and patient goals for diabetes care. This allows the prescriber to focus on the glycemic, cardiologic, renal, and metabolic goals and overcome the therapeutic inertia that plagues us all.

Incorporating diabetes-related technology into clinical practice can be a significant time-saver but requires initial onboarding. Set aside a few hours to create a technology clinic flow, and designate at least one team member to be responsible for obtaining patient data before, during, or after encounters. If possible, obtaining data ahead of the visit will enhance efficiency, allowing for meaningful discussion of blood glucose and lifestyle patterns. Diabetes technology reveals the gaps in care and enhances our ability to identify the areas where glycemic intervention is needed. In addition, it reveals the impact of food choices, activity level, stress, and medication adherence to the person living with diabetes. 

Finally, be proactive about therapeutic inertia. This is defined as a prescribers’ failure to intensify or deintensify a patient’s treatment when appropriate to do so. Causes of therapeutic inertia can be placed at the primary care physician level, including time constraints or inexperience in treating diabetes; the patient level, such as concerns about side effects or new treatment regimens; or a systemic level, such as availability of medications or their costs. Be real with yourself: We all have inertia and can identify areas to overcome. Never let inertia be traced back to you.

Not all inertia lives with the health care provider. Patients bring apprehension and concerns, have questions, and just want to share the frustrations associated with living their best life with the disease. Don’t assume that you know what your patients’ treatment barriers are; ask them. If you don’t have an answer, then note it and come up with one by the next follow-up. Remember that this is a chronic disease – a marathon, not a sprint. You don’t have to solve everything at one appointment; rather, keep the momentum going.

Let’s put this into clinical practice. For the next patient with diabetes who comes into your office, discuss with them your intention to prioritize their diabetes by having an appointment set aside to specifically focus on their individual goals and targets for their disease. Have the patient list any barriers and treatment goals they would like to review; flag your schedule to indicate it is a diabetes-only visit; and orient your staff to reconcile diabetes medications and record the patient’s last eye exam, urine albumin-to-creatinine ratio, A1c result, and blood glucose data. During this encounter, identify the patient’s personal targets for control, examine their feet, and review or order necessary laboratory metrics. Explore the patient-reported barriers and make inroads to remove or alleviate these. Advance treatment intervention, and schedule follow-up: every 4-6 weeks if the A1c is > 9%, every 2 months if it’s 7% to < 9%, and every 3-6 months if it’s < 7%. Utilize team diabetes care, such as CDCES referrals, dietitians, online resources, and community members, to help reinforce care and enhance engagement. 

We need to take steps in our clinical practice to make the necessary space to accommodate this pervasive disease affecting nearly one-third of our population. Take a moment to look up and determine what needs to be in place so that you can take care of the people in your practice with diabetes. Laying the groundwork for implementing diabetes-only appointments can be time-consuming, but establishing consistent procedures, developing efficient workflows, and clearly defining roles and responsibilities is well worth the effort. This solid foundation equips the office, health care providers, and staff to care for persons with diabetes and will be invaluable to ensure that time for this care is available in the day-to-day clinical practice.

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

Can busy primary care offices continue to care for patients with diabetes? No one would argue that it is involved and takes effort, and health care providers are bankrupt when it comes to sparing additional time for this chronic disease. With roughly 37 million people living with diabetes and 96 million with prediabetes or early type 2 diabetes, and just over 8,000 practicing endocrinologists in the United States, we all need to make time especially in primary care to provide insight and holistic care. With limited time and budget, how do we do this?

First, decide to be involved in caring for patients with diabetes. Diabetes is best managed by interprofessional care teams, so you’re not going it alone. These teams may include physicians; pharmacists; physician assistants; advanced practice nurses; registered nurses; certified diabetes care and education specialists (CDCES); dietitians; and other professionals such as social workers, behavioral health professionals, medical assistants, and community health workers. Know which professionals are available to serve on your team, either within your clinic or as a consultant, and reach out to them to share the care and ease the burden. Remember to refer to these professionals to reinforce the diabetes intervention message to the patient.

Second, incorporate “diabetes only” appointments into your schedule, allowing time to focus on current comprehensive diabetes treatment goals, barriers/inertia for care. Remember to have short-interval follow-up as needed to keep that patient engaged to achieve their targets. Instruct your office staff to create diabetes appointment templates and reminders to patients to bring diabetes-related technologies, medication lists, and diabetes questions to the appointment. When I implemented this change, my patients welcomed the focus on their diabetes health, and they knew we were prioritizing this disease that they have for a lifetime. These appointments did not take away from their other conditions; rather, they often reminded me to stay focused on their diabetes and associated coconditions. 

Taking the time to establish efficient workflows before implementing diabetes care saves countless hours later and immediately maximizes health care provider–patient interactions. Assign specific staff duties and expectations related to diabetes appointments, such as downloading diabetes technology, medication reconciliation, laboratory data, point-of-care hemoglobin A1c, basic foot exam, and patient goals for diabetes care. This allows the prescriber to focus on the glycemic, cardiologic, renal, and metabolic goals and overcome the therapeutic inertia that plagues us all.

Incorporating diabetes-related technology into clinical practice can be a significant time-saver but requires initial onboarding. Set aside a few hours to create a technology clinic flow, and designate at least one team member to be responsible for obtaining patient data before, during, or after encounters. If possible, obtaining data ahead of the visit will enhance efficiency, allowing for meaningful discussion of blood glucose and lifestyle patterns. Diabetes technology reveals the gaps in care and enhances our ability to identify the areas where glycemic intervention is needed. In addition, it reveals the impact of food choices, activity level, stress, and medication adherence to the person living with diabetes. 

Finally, be proactive about therapeutic inertia. This is defined as a prescribers’ failure to intensify or deintensify a patient’s treatment when appropriate to do so. Causes of therapeutic inertia can be placed at the primary care physician level, including time constraints or inexperience in treating diabetes; the patient level, such as concerns about side effects or new treatment regimens; or a systemic level, such as availability of medications or their costs. Be real with yourself: We all have inertia and can identify areas to overcome. Never let inertia be traced back to you.

Not all inertia lives with the health care provider. Patients bring apprehension and concerns, have questions, and just want to share the frustrations associated with living their best life with the disease. Don’t assume that you know what your patients’ treatment barriers are; ask them. If you don’t have an answer, then note it and come up with one by the next follow-up. Remember that this is a chronic disease – a marathon, not a sprint. You don’t have to solve everything at one appointment; rather, keep the momentum going.

Let’s put this into clinical practice. For the next patient with diabetes who comes into your office, discuss with them your intention to prioritize their diabetes by having an appointment set aside to specifically focus on their individual goals and targets for their disease. Have the patient list any barriers and treatment goals they would like to review; flag your schedule to indicate it is a diabetes-only visit; and orient your staff to reconcile diabetes medications and record the patient’s last eye exam, urine albumin-to-creatinine ratio, A1c result, and blood glucose data. During this encounter, identify the patient’s personal targets for control, examine their feet, and review or order necessary laboratory metrics. Explore the patient-reported barriers and make inroads to remove or alleviate these. Advance treatment intervention, and schedule follow-up: every 4-6 weeks if the A1c is > 9%, every 2 months if it’s 7% to < 9%, and every 3-6 months if it’s < 7%. Utilize team diabetes care, such as CDCES referrals, dietitians, online resources, and community members, to help reinforce care and enhance engagement. 

We need to take steps in our clinical practice to make the necessary space to accommodate this pervasive disease affecting nearly one-third of our population. Take a moment to look up and determine what needs to be in place so that you can take care of the people in your practice with diabetes. Laying the groundwork for implementing diabetes-only appointments can be time-consuming, but establishing consistent procedures, developing efficient workflows, and clearly defining roles and responsibilities is well worth the effort. This solid foundation equips the office, health care providers, and staff to care for persons with diabetes and will be invaluable to ensure that time for this care is available in the day-to-day clinical practice.

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

The issue of earlier classification of medical conditions – known as “diagnosis creep” – is leading to many patients becoming eligible for treatments at earlier stages in their disease course, without those treatments having been validated in those particular groups.

This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.

U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.

The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.

The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.

“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.

“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.

This study was published online as a research letter in JAMA Network Open.

Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.

“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”

Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.

“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”

He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.

Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.

“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”

Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.

“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
 

What should clinicians do?

In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.

He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.

And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.

“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.

“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”

Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
 

Are new risk scores needed?

Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.

“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.

“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.

Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.

“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”

He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”

Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.

This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.

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

The issue of earlier classification of medical conditions – known as “diagnosis creep” – is leading to many patients becoming eligible for treatments at earlier stages in their disease course, without those treatments having been validated in those particular groups.

This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.

U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.

The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.

The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.

“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.

“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.

This study was published online as a research letter in JAMA Network Open.

Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.

“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”

Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.

“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”

He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.

Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.

“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”

Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.

“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
 

What should clinicians do?

In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.

He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.

And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.

“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.

“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”

Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
 

Are new risk scores needed?

Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.

“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.

“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.

Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.

“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”

He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”

Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.

This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.

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

The issue of earlier classification of medical conditions – known as “diagnosis creep” – is leading to many patients becoming eligible for treatments at earlier stages in their disease course, without those treatments having been validated in those particular groups.

This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.

U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.

The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.

The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.

“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.

“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.

This study was published online as a research letter in JAMA Network Open.

Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.

“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”

Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.

“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”

He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.

Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.

“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”

Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.

“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
 

What should clinicians do?

In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.

He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.

And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.

“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.

“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”

Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
 

Are new risk scores needed?

Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.

“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.

“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.

Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.

“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”

He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”

Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.

This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.

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

VANCOUVER – A highly controlled retrospective analysis suggests that denosumab (Prolia) leads to greater reduction in fracture risk than does zoledronic acid (Reclast) among treatment-naive postmenopausal women with osteoporosis.

A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.

The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.

NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.

“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.

The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.

The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).

Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).

During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.

The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.

In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.

Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.

The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.

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

VANCOUVER – A highly controlled retrospective analysis suggests that denosumab (Prolia) leads to greater reduction in fracture risk than does zoledronic acid (Reclast) among treatment-naive postmenopausal women with osteoporosis.

A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.

The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.

NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.

“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.

The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.

The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).

Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).

During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.

The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.

In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.

Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.

The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.

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

VANCOUVER – A highly controlled retrospective analysis suggests that denosumab (Prolia) leads to greater reduction in fracture risk than does zoledronic acid (Reclast) among treatment-naive postmenopausal women with osteoporosis.

A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.

The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.

NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.

“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.

The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.

The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).

Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).

During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.

The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.

In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.

Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.

The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.

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

TOPLINE:

Chronic kidney disease is the strongest predictor of sudden cardiac arrest (SCA) in a population of Hispanic and Latinx patients, new data show, suggesting early identification of CKD may provide an opportunity to reduce the risk in these groups. Other predictors included heavy drinking, atrial fibrillation, coronary artery disease, heart failure and diabetes.

METHODOLOGY:

• The study included 295 Hispanic or Latinx patients with out-of-hospital SCA from the PRESTO study in Ventura County, California, and 590 frequency-matched controls from the San Diego site of the population-based HCHS/SOL (Hispanic Community Health Survey/Study of Latinos); in both cohorts, men made up 70% of participants, and the median age was about 63 years.
• Researchers collected data on demographics, medical history, and current health conditions. Of note, 51.2% of SCA cases and 8.8% of control participants had CKD, and 20.0% of cases and 0.7% of the control group were on dialysis.
• Pre-SCA echocardiograms were available for 48% of SCA cases and baseline echocardiograms for more than 99% of control participants.

TAKEAWAY:

• In analyses adjusted for age, sex, and clinical variables, predictors significantly associated with higher odds of SCA included: CKD (odds ratio, 7.3; 95% confidence interval, 3.8-14.3; P < .001), heavy drinking (OR, 4.5), stroke (OR, 3.1), atrial fibrillation (OR, 3.7), coronary artery disease (OR, 2.9), heart failure (OR, 2.5), and diabetes (OR, 1.5).
• Hypertension, hyperlipemia, body mass index, and current smoking status were not significantly associated with SCA.
• In adjusted analyses, heart rate (OR, 1.8 per one standard deviation [1-SD] increase), QTc interval (OR, 2.5 per 1-SD increase) and left ventricular ejection fraction (OR, 4.4 per 1-SD decrease) were significantly associated with SCA, suggesting echocardiogram evaluations could help identify Hispanic or Latinx individuals at increased risk for SCA, wrote the authors.

IN PRACTICE:

“Our study, the first to include feasible numbers of Hispanic or Latino individuals, highlights the importance of renal dysfunction as a risk factor for SCA in the community,” the authors wrote, adding that early identification and management of chronic kidney disease could reduce risk for SCA in this population.

SOURCE:

The study was conducted by Kyndaron Reinier, PhD, MPH, Cedars-Sinai Health System, Los Angeles, and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

Most participants from the HCHS/SOL study were born outside the United States, compared with about half the SCA cases, which could have influenced cardiovascular disease risk, although results did not change considerably when models were adjusted for place of birth. Study participants were predominantly of Mexican heritage, so results may not be generalizable to Hispanic or Latinx individuals from other regions. As medical history was assessed differently in the two studies, there could be some error in estimating the strength of associations. Results from echocardiographic data should be viewed as hypothesis generating because of the potential for residual bias.

DISCLOSURES:

The Ventura PRESTO study was funded, in part, by the National Institutes of Health, and National Heart, Lung, and Blood Institute. The HCHS/SOL was carried out as a collaborative study supported by contracts from the NHLBI.

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

TOPLINE:

Chronic kidney disease is the strongest predictor of sudden cardiac arrest (SCA) in a population of Hispanic and Latinx patients, new data show, suggesting early identification of CKD may provide an opportunity to reduce the risk in these groups. Other predictors included heavy drinking, atrial fibrillation, coronary artery disease, heart failure and diabetes.

METHODOLOGY:

• The study included 295 Hispanic or Latinx patients with out-of-hospital SCA from the PRESTO study in Ventura County, California, and 590 frequency-matched controls from the San Diego site of the population-based HCHS/SOL (Hispanic Community Health Survey/Study of Latinos); in both cohorts, men made up 70% of participants, and the median age was about 63 years.
• Researchers collected data on demographics, medical history, and current health conditions. Of note, 51.2% of SCA cases and 8.8% of control participants had CKD, and 20.0% of cases and 0.7% of the control group were on dialysis.
• Pre-SCA echocardiograms were available for 48% of SCA cases and baseline echocardiograms for more than 99% of control participants.

TAKEAWAY:

• In analyses adjusted for age, sex, and clinical variables, predictors significantly associated with higher odds of SCA included: CKD (odds ratio, 7.3; 95% confidence interval, 3.8-14.3; P < .001), heavy drinking (OR, 4.5), stroke (OR, 3.1), atrial fibrillation (OR, 3.7), coronary artery disease (OR, 2.9), heart failure (OR, 2.5), and diabetes (OR, 1.5).
• Hypertension, hyperlipemia, body mass index, and current smoking status were not significantly associated with SCA.
• In adjusted analyses, heart rate (OR, 1.8 per one standard deviation [1-SD] increase), QTc interval (OR, 2.5 per 1-SD increase) and left ventricular ejection fraction (OR, 4.4 per 1-SD decrease) were significantly associated with SCA, suggesting echocardiogram evaluations could help identify Hispanic or Latinx individuals at increased risk for SCA, wrote the authors.

IN PRACTICE:

“Our study, the first to include feasible numbers of Hispanic or Latino individuals, highlights the importance of renal dysfunction as a risk factor for SCA in the community,” the authors wrote, adding that early identification and management of chronic kidney disease could reduce risk for SCA in this population.

SOURCE:

The study was conducted by Kyndaron Reinier, PhD, MPH, Cedars-Sinai Health System, Los Angeles, and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

Most participants from the HCHS/SOL study were born outside the United States, compared with about half the SCA cases, which could have influenced cardiovascular disease risk, although results did not change considerably when models were adjusted for place of birth. Study participants were predominantly of Mexican heritage, so results may not be generalizable to Hispanic or Latinx individuals from other regions. As medical history was assessed differently in the two studies, there could be some error in estimating the strength of associations. Results from echocardiographic data should be viewed as hypothesis generating because of the potential for residual bias.

DISCLOSURES:

The Ventura PRESTO study was funded, in part, by the National Institutes of Health, and National Heart, Lung, and Blood Institute. The HCHS/SOL was carried out as a collaborative study supported by contracts from the NHLBI.

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

TOPLINE:

Chronic kidney disease is the strongest predictor of sudden cardiac arrest (SCA) in a population of Hispanic and Latinx patients, new data show, suggesting early identification of CKD may provide an opportunity to reduce the risk in these groups. Other predictors included heavy drinking, atrial fibrillation, coronary artery disease, heart failure and diabetes.

METHODOLOGY:

• The study included 295 Hispanic or Latinx patients with out-of-hospital SCA from the PRESTO study in Ventura County, California, and 590 frequency-matched controls from the San Diego site of the population-based HCHS/SOL (Hispanic Community Health Survey/Study of Latinos); in both cohorts, men made up 70% of participants, and the median age was about 63 years.
• Researchers collected data on demographics, medical history, and current health conditions. Of note, 51.2% of SCA cases and 8.8% of control participants had CKD, and 20.0% of cases and 0.7% of the control group were on dialysis.
• Pre-SCA echocardiograms were available for 48% of SCA cases and baseline echocardiograms for more than 99% of control participants.

TAKEAWAY:

• In analyses adjusted for age, sex, and clinical variables, predictors significantly associated with higher odds of SCA included: CKD (odds ratio, 7.3; 95% confidence interval, 3.8-14.3; P < .001), heavy drinking (OR, 4.5), stroke (OR, 3.1), atrial fibrillation (OR, 3.7), coronary artery disease (OR, 2.9), heart failure (OR, 2.5), and diabetes (OR, 1.5).
• Hypertension, hyperlipemia, body mass index, and current smoking status were not significantly associated with SCA.
• In adjusted analyses, heart rate (OR, 1.8 per one standard deviation [1-SD] increase), QTc interval (OR, 2.5 per 1-SD increase) and left ventricular ejection fraction (OR, 4.4 per 1-SD decrease) were significantly associated with SCA, suggesting echocardiogram evaluations could help identify Hispanic or Latinx individuals at increased risk for SCA, wrote the authors.

IN PRACTICE:

“Our study, the first to include feasible numbers of Hispanic or Latino individuals, highlights the importance of renal dysfunction as a risk factor for SCA in the community,” the authors wrote, adding that early identification and management of chronic kidney disease could reduce risk for SCA in this population.

SOURCE:

The study was conducted by Kyndaron Reinier, PhD, MPH, Cedars-Sinai Health System, Los Angeles, and colleagues. It was published online in the Journal of the American Heart Association.

LIMITATIONS:

Most participants from the HCHS/SOL study were born outside the United States, compared with about half the SCA cases, which could have influenced cardiovascular disease risk, although results did not change considerably when models were adjusted for place of birth. Study participants were predominantly of Mexican heritage, so results may not be generalizable to Hispanic or Latinx individuals from other regions. As medical history was assessed differently in the two studies, there could be some error in estimating the strength of associations. Results from echocardiographic data should be viewed as hypothesis generating because of the potential for residual bias.

DISCLOSURES:

The Ventura PRESTO study was funded, in part, by the National Institutes of Health, and National Heart, Lung, and Blood Institute. The HCHS/SOL was carried out as a collaborative study supported by contracts from the NHLBI.

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

TOPLINE:

Nearly one in five adolescents are living with prediabetes, a condition where blood glucose levels are elevated, but are not high enough for a type 2 diabetes (T2D) diagnosis. According to a new study, higher levels of nonfasting glucose and hemoglobin A1c, and worsening obesity are important predictors of progression to T2D. In addition, metformin and weight stabilization may prove to be important interventions for preventing T2D in kids.

METHODOLOGY:

• Researchers did a retrospective chart review of patient data from Vanderbilt University Medical Center Pediatric Prediabetes Clinic, Nashville, Tenn., from May 2015 to August 2022.
• The study included 552 children with prediabetes, defined as abnormal blood glucose (fasting plasma glucose [FPG] ≥ 100 mg/dL, random glucose ≥ 150 mg/dL), or hemoglobin A1c equal to or greater than 5.9%.
• Based on follow-up visits, patients were classified as having progressed to T2D, or nonprogression.
• Researchers analyzed the patients’ initial visit A1c, fasting C-peptide, 2-hour glucose, fasting glucose, and body mass index (BMI), among other baseline characteristics.

TAKEAWAY:

• Thirty-six children (6.5%) progressed to T2D during the duration of the study period.
• The average time to T2D diagnosis was much longer in patients taking metformin (43 months), compared with those not taking the prescribed medication (28 months).
• Worsening obesity was strongly associated with T2D progression – patients who progressed to T2D had a higher BMI at baseline and had continued weight gain.
• A higher baseline A1c, fasting C-peptide, and 2-hour glucose were also associated with progression to T2D.
• In the multivariable analysis, both A1c and 2-hour glucose were strong independent predictors of progression.
• Fasting plasma glucose was not associated with progression to T2D.

IN PRACTICE:

“Weight stabilization and metformin therapy could be important interventions for diabetes prevention in children,” study author Ashley H. Shoemaker, MD, MSci, a pediatric endocrinologist at Vanderbilt University Medical Center in Nashville, Tenn., said in a press release.

In addition, A1c plus a nonfasting glucose may be a feasible way to identify high-risk pediatric patients in a clinical setting.
 

SOURCE:

This study was performed by Natasha Belsky, Jaclyn Tamaroff, and Ashley H. Shoemaker of the Vanderbilt University Medical Center and the Vanderbilt University School of Medicine in Nashville, Tenn. It was published October 12, 2023, in the Journal of the Endocrine Society

LIMITATIONS:

Additional patients who developed T2D may have been lost to follow-up, since the authors did not contact patients to confirm their disease status. The authors were also unable to establish racial differences in the progression to T2D because of missing data.

DISCLOSURES:

Funding for this study was provided by the National Center for Advancing Translational Sciences. One author has research contracts with Novo Nordisk and Boehringer Ingelheim.

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

TOPLINE:

Nearly one in five adolescents are living with prediabetes, a condition where blood glucose levels are elevated, but are not high enough for a type 2 diabetes (T2D) diagnosis. According to a new study, higher levels of nonfasting glucose and hemoglobin A1c, and worsening obesity are important predictors of progression to T2D. In addition, metformin and weight stabilization may prove to be important interventions for preventing T2D in kids.

METHODOLOGY:

• Researchers did a retrospective chart review of patient data from Vanderbilt University Medical Center Pediatric Prediabetes Clinic, Nashville, Tenn., from May 2015 to August 2022.
• The study included 552 children with prediabetes, defined as abnormal blood glucose (fasting plasma glucose [FPG] ≥ 100 mg/dL, random glucose ≥ 150 mg/dL), or hemoglobin A1c equal to or greater than 5.9%.
• Based on follow-up visits, patients were classified as having progressed to T2D, or nonprogression.
• Researchers analyzed the patients’ initial visit A1c, fasting C-peptide, 2-hour glucose, fasting glucose, and body mass index (BMI), among other baseline characteristics.

TAKEAWAY:

• Thirty-six children (6.5%) progressed to T2D during the duration of the study period.
• The average time to T2D diagnosis was much longer in patients taking metformin (43 months), compared with those not taking the prescribed medication (28 months).
• Worsening obesity was strongly associated with T2D progression – patients who progressed to T2D had a higher BMI at baseline and had continued weight gain.
• A higher baseline A1c, fasting C-peptide, and 2-hour glucose were also associated with progression to T2D.
• In the multivariable analysis, both A1c and 2-hour glucose were strong independent predictors of progression.
• Fasting plasma glucose was not associated with progression to T2D.

IN PRACTICE:

“Weight stabilization and metformin therapy could be important interventions for diabetes prevention in children,” study author Ashley H. Shoemaker, MD, MSci, a pediatric endocrinologist at Vanderbilt University Medical Center in Nashville, Tenn., said in a press release.

In addition, A1c plus a nonfasting glucose may be a feasible way to identify high-risk pediatric patients in a clinical setting.
 

SOURCE:

This study was performed by Natasha Belsky, Jaclyn Tamaroff, and Ashley H. Shoemaker of the Vanderbilt University Medical Center and the Vanderbilt University School of Medicine in Nashville, Tenn. It was published October 12, 2023, in the Journal of the Endocrine Society

LIMITATIONS:

Additional patients who developed T2D may have been lost to follow-up, since the authors did not contact patients to confirm their disease status. The authors were also unable to establish racial differences in the progression to T2D because of missing data.

DISCLOSURES:

Funding for this study was provided by the National Center for Advancing Translational Sciences. One author has research contracts with Novo Nordisk and Boehringer Ingelheim.

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

TOPLINE:

Nearly one in five adolescents are living with prediabetes, a condition where blood glucose levels are elevated, but are not high enough for a type 2 diabetes (T2D) diagnosis. According to a new study, higher levels of nonfasting glucose and hemoglobin A1c, and worsening obesity are important predictors of progression to T2D. In addition, metformin and weight stabilization may prove to be important interventions for preventing T2D in kids.

METHODOLOGY:

• Researchers did a retrospective chart review of patient data from Vanderbilt University Medical Center Pediatric Prediabetes Clinic, Nashville, Tenn., from May 2015 to August 2022.
• The study included 552 children with prediabetes, defined as abnormal blood glucose (fasting plasma glucose [FPG] ≥ 100 mg/dL, random glucose ≥ 150 mg/dL), or hemoglobin A1c equal to or greater than 5.9%.
• Based on follow-up visits, patients were classified as having progressed to T2D, or nonprogression.
• Researchers analyzed the patients’ initial visit A1c, fasting C-peptide, 2-hour glucose, fasting glucose, and body mass index (BMI), among other baseline characteristics.

TAKEAWAY:

• Thirty-six children (6.5%) progressed to T2D during the duration of the study period.
• The average time to T2D diagnosis was much longer in patients taking metformin (43 months), compared with those not taking the prescribed medication (28 months).
• Worsening obesity was strongly associated with T2D progression – patients who progressed to T2D had a higher BMI at baseline and had continued weight gain.
• A higher baseline A1c, fasting C-peptide, and 2-hour glucose were also associated with progression to T2D.
• In the multivariable analysis, both A1c and 2-hour glucose were strong independent predictors of progression.
• Fasting plasma glucose was not associated with progression to T2D.

IN PRACTICE:

“Weight stabilization and metformin therapy could be important interventions for diabetes prevention in children,” study author Ashley H. Shoemaker, MD, MSci, a pediatric endocrinologist at Vanderbilt University Medical Center in Nashville, Tenn., said in a press release.

In addition, A1c plus a nonfasting glucose may be a feasible way to identify high-risk pediatric patients in a clinical setting.
 

SOURCE:

This study was performed by Natasha Belsky, Jaclyn Tamaroff, and Ashley H. Shoemaker of the Vanderbilt University Medical Center and the Vanderbilt University School of Medicine in Nashville, Tenn. It was published October 12, 2023, in the Journal of the Endocrine Society

LIMITATIONS:

Additional patients who developed T2D may have been lost to follow-up, since the authors did not contact patients to confirm their disease status. The authors were also unable to establish racial differences in the progression to T2D because of missing data.

DISCLOSURES:

Funding for this study was provided by the National Center for Advancing Translational Sciences. One author has research contracts with Novo Nordisk and Boehringer Ingelheim.

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

HAMBURG, GERMANY – The investigational incretin receptor agonist pemvidutide produced significant weight loss and other cardiometabolic benefits in a phase 2 randomized trial, adding a different type of “twincretin” to a growing mix of incretin-based weight-loss drugs in development that also offer additional benefits.

Pemvidutide (Altimmune Inc) is a long-acting “balanced” dual agonist of both glucagon-like peptide 1 (GLP-1) and glucagon that is in development for the treatment of obesity and nonalcoholic steatohepatitis (NASH) but not type 2 diabetes, as its effect on glucose is neutral. Phase 1 data for pemvidutide’s liver effect were presented in 2022.

In contrast, the dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide (Mounjaro, Lilly) has been approved for the treatment of type 2 diabetes. It awaits an indication for obesity.

“When you look [at] the results for any given agent, think about obesity as a series of problems. Some overlap, and some don’t. While about 20%-25% of people with obesity also have type 2 diabetes, not everybody does. So the compounds that don’t lower glucose ... those will be great for others who have [fatty liver disease] or hyperlipidemia. ... It’s not going to be one compound for everybody,” said Louis J. Aronne, MD, director of the center for weight management and metabolic clinical research, Weill Cornell Medicine, New York.

Results of a new 24-week interim analysis of data from the phase 2 pemvidutide trial, called MOMENTUM, were presented at the annual meeting of the European Association for the Study of Diabetes by Dr. Aronne.

Included in that session were encore presentations of data for another GLP-1-glucagon dual agonist, survodutide, as well as data for Eli Lilly’s GLP-1-GIP-glucagon “triagonist,” retatrutide. Retatrutide is in development to induce weight loss, while survodutide (Boehringer Ingelheim and Zealand Pharma), like pemvidutide, is in development to induce weight loss and treat fatty liver disease.

Added Dr. Aronne, “As good as [the triple agonist] retatrutide looks, I doubt that every single person with obesity in the world will be treated with it. ... Think about this as a field, the way you treat diabetes and every other chronic illness.”

Asked to comment, session moderator Rajna Golubic, PhD, of the Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, told this news organization, “We need to think in terms of treating beyond weight loss. ... We need to look at the person holistically and at other aspects of cardiometabolic health and treat in a personalized way and choose treatments according to the comorbidities people have.”

Regarding the dual GLP-1-glucagon agonists, including pemvidutide, Dr. Golubic pointed out that the glucagon agonism does the opposite of glucose-lowering agents but that the compound is “balanced for greater affinity for the GLP-1 receptor vs. glucagon, so that the beneficial effects outweigh the effect for glucose but it still harnesses the benefits of glucagon on liver with a decrease in liver fat, with positive effects on heart, positive effects on kidneys, and other beneficial metabolic effects.”
 

Pemvidutide lowers weight, LDL cholesterol, triglycerides, and blood pressure

Dr. Aronne began his presentation by noting that dyslipidemia, fatty liver disease, and hypertension are the most significant comorbidities of obesity, occurring in 66%-70%, 58%-75%, and 45%-55% of patients, respectively, while type 2 diabetes is less common, at 19%-23%.

Pemvidutide’s GLP-1 receptor agonism reduces appetite, inflammation, and gastric emptying, while glucagon agonism increases lipolysis, mobilizes fat, and increases energy expenditure, Dr. Aronne explained.

The 48-week phase 2 MOMENTUM trial randomly assigned 320 participants with overweight or obesity and at least one obesity-related comorbidity but not diabetes to receive weekly doses of 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or placebo. The two lower pemvidutide doses were initiated immediately without titration, while the 2.4-mg dose was titrated rapidly over 4 weeks.

In a prespecified interim analysis of 160 participants, the percent body weight loss at 24 weeks was 10.7%, 9.4%, and 7.3% with the 2.4-mg, 1.8-mg, and 1.2-mg doses, respectively (P < .001). All weight loss values were significant; weight loss with placebo was a nonsignificant 1%.

The proportions of patients who lost at least 5% of their body weight were 84.6%, 66.7%, and 66.7%, respectively, vs. 25% with placebo. Half of the patients who received the 2.4-mg and 1.8-mg doses lost at least 10% of their body weight. Reductions in waist circumference followed suit; the patients who received the 2.4-mg dose lost an average of 10.2 cm, or “in the U.S., about 4 inches or 4 belt loops. That’s pretty good, you need a new belt,” Dr. Aronne commented.

Significant reductions in total cholesterol and triglyceride levels were also seen at week 24 by 16.5% and 25.0%, respectively, with the 2.4-mg dose. Low-density lipoprotein cholesterol levels also dropped, although not significantly; high-density lipoprotein levels dropped significantly.

Systolic blood pressure dropped by 5.5 mm Hg, and diastolic blood pressure dropped by 1.8 mm Hg in the 2.4-mg group and by lesser degrees among the patients who received lower doses. There were no significant changes in heart rate, Dr. Aronne noted.

Glucose homeostasis was preserved in all groups throughout the 24 weeks.

As with all drugs in the incretin class, gastrointestinal adverse events were common. Severe vomiting occurred in one person in the 1.8-mg group and in four with 2.4 mg. Efforts will be made to reduce that in subsequent trials, Dr. Aronne said.

“We have learned over time that going more gradually in titrating up these agents is a better strategy, allowing dose reduction may be a better strategy, and allowing antiemetics temporarily as we increase the dose is a lesson that many have learned doing these trials and of course in our clinical practices,” he commented.

Dr. Golubic told this news organization that the recent emergence of potent incretin-based weight loss drugs is “a huge paradigm shift. The prevalence of obesity will be 35% or higher by 2035. Bariatric surgery isn’t feasible for everyone, and it’s very expensive, so we need drugs to provide benefits in terms of lowering weight, glucose, and other cardiometabolic risk factors.”

The full 48-week data for MOMENTUM will be announced in the fourth quarter of 2023.

Dr. Aronne has received consulting fees from and serves on advisory boards for Allurion, Altimmune, Atria, Gelesis, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Optum, Eli Lilly, Senda Biosciences, and Versanis; has received research funding from Allurion, AstraZeneca, Gelesis, Janssen Pharmaceuticals, Novo Nordisk, and Eli Lilly; has equity interests in Allurion, ERX Pharmaceuticals, Gelesis, Intellihealth, Jamieson Wellness, and Myos Corp; and serves on a board of directors for ERX Pharmaceuticals, Intellihealth, and Jamieson Wellness. Dr. Golubic has received research support from AstraZeneca.

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

HAMBURG, GERMANY – The investigational incretin receptor agonist pemvidutide produced significant weight loss and other cardiometabolic benefits in a phase 2 randomized trial, adding a different type of “twincretin” to a growing mix of incretin-based weight-loss drugs in development that also offer additional benefits.

Pemvidutide (Altimmune Inc) is a long-acting “balanced” dual agonist of both glucagon-like peptide 1 (GLP-1) and glucagon that is in development for the treatment of obesity and nonalcoholic steatohepatitis (NASH) but not type 2 diabetes, as its effect on glucose is neutral. Phase 1 data for pemvidutide’s liver effect were presented in 2022.

In contrast, the dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide (Mounjaro, Lilly) has been approved for the treatment of type 2 diabetes. It awaits an indication for obesity.

“When you look [at] the results for any given agent, think about obesity as a series of problems. Some overlap, and some don’t. While about 20%-25% of people with obesity also have type 2 diabetes, not everybody does. So the compounds that don’t lower glucose ... those will be great for others who have [fatty liver disease] or hyperlipidemia. ... It’s not going to be one compound for everybody,” said Louis J. Aronne, MD, director of the center for weight management and metabolic clinical research, Weill Cornell Medicine, New York.

Results of a new 24-week interim analysis of data from the phase 2 pemvidutide trial, called MOMENTUM, were presented at the annual meeting of the European Association for the Study of Diabetes by Dr. Aronne.

Included in that session were encore presentations of data for another GLP-1-glucagon dual agonist, survodutide, as well as data for Eli Lilly’s GLP-1-GIP-glucagon “triagonist,” retatrutide. Retatrutide is in development to induce weight loss, while survodutide (Boehringer Ingelheim and Zealand Pharma), like pemvidutide, is in development to induce weight loss and treat fatty liver disease.

Added Dr. Aronne, “As good as [the triple agonist] retatrutide looks, I doubt that every single person with obesity in the world will be treated with it. ... Think about this as a field, the way you treat diabetes and every other chronic illness.”

Asked to comment, session moderator Rajna Golubic, PhD, of the Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, told this news organization, “We need to think in terms of treating beyond weight loss. ... We need to look at the person holistically and at other aspects of cardiometabolic health and treat in a personalized way and choose treatments according to the comorbidities people have.”

Regarding the dual GLP-1-glucagon agonists, including pemvidutide, Dr. Golubic pointed out that the glucagon agonism does the opposite of glucose-lowering agents but that the compound is “balanced for greater affinity for the GLP-1 receptor vs. glucagon, so that the beneficial effects outweigh the effect for glucose but it still harnesses the benefits of glucagon on liver with a decrease in liver fat, with positive effects on heart, positive effects on kidneys, and other beneficial metabolic effects.”
 

Pemvidutide lowers weight, LDL cholesterol, triglycerides, and blood pressure

Dr. Aronne began his presentation by noting that dyslipidemia, fatty liver disease, and hypertension are the most significant comorbidities of obesity, occurring in 66%-70%, 58%-75%, and 45%-55% of patients, respectively, while type 2 diabetes is less common, at 19%-23%.

Pemvidutide’s GLP-1 receptor agonism reduces appetite, inflammation, and gastric emptying, while glucagon agonism increases lipolysis, mobilizes fat, and increases energy expenditure, Dr. Aronne explained.

The 48-week phase 2 MOMENTUM trial randomly assigned 320 participants with overweight or obesity and at least one obesity-related comorbidity but not diabetes to receive weekly doses of 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or placebo. The two lower pemvidutide doses were initiated immediately without titration, while the 2.4-mg dose was titrated rapidly over 4 weeks.

In a prespecified interim analysis of 160 participants, the percent body weight loss at 24 weeks was 10.7%, 9.4%, and 7.3% with the 2.4-mg, 1.8-mg, and 1.2-mg doses, respectively (P < .001). All weight loss values were significant; weight loss with placebo was a nonsignificant 1%.

The proportions of patients who lost at least 5% of their body weight were 84.6%, 66.7%, and 66.7%, respectively, vs. 25% with placebo. Half of the patients who received the 2.4-mg and 1.8-mg doses lost at least 10% of their body weight. Reductions in waist circumference followed suit; the patients who received the 2.4-mg dose lost an average of 10.2 cm, or “in the U.S., about 4 inches or 4 belt loops. That’s pretty good, you need a new belt,” Dr. Aronne commented.

Significant reductions in total cholesterol and triglyceride levels were also seen at week 24 by 16.5% and 25.0%, respectively, with the 2.4-mg dose. Low-density lipoprotein cholesterol levels also dropped, although not significantly; high-density lipoprotein levels dropped significantly.

Systolic blood pressure dropped by 5.5 mm Hg, and diastolic blood pressure dropped by 1.8 mm Hg in the 2.4-mg group and by lesser degrees among the patients who received lower doses. There were no significant changes in heart rate, Dr. Aronne noted.

Glucose homeostasis was preserved in all groups throughout the 24 weeks.

As with all drugs in the incretin class, gastrointestinal adverse events were common. Severe vomiting occurred in one person in the 1.8-mg group and in four with 2.4 mg. Efforts will be made to reduce that in subsequent trials, Dr. Aronne said.

“We have learned over time that going more gradually in titrating up these agents is a better strategy, allowing dose reduction may be a better strategy, and allowing antiemetics temporarily as we increase the dose is a lesson that many have learned doing these trials and of course in our clinical practices,” he commented.

Dr. Golubic told this news organization that the recent emergence of potent incretin-based weight loss drugs is “a huge paradigm shift. The prevalence of obesity will be 35% or higher by 2035. Bariatric surgery isn’t feasible for everyone, and it’s very expensive, so we need drugs to provide benefits in terms of lowering weight, glucose, and other cardiometabolic risk factors.”

The full 48-week data for MOMENTUM will be announced in the fourth quarter of 2023.

Dr. Aronne has received consulting fees from and serves on advisory boards for Allurion, Altimmune, Atria, Gelesis, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Optum, Eli Lilly, Senda Biosciences, and Versanis; has received research funding from Allurion, AstraZeneca, Gelesis, Janssen Pharmaceuticals, Novo Nordisk, and Eli Lilly; has equity interests in Allurion, ERX Pharmaceuticals, Gelesis, Intellihealth, Jamieson Wellness, and Myos Corp; and serves on a board of directors for ERX Pharmaceuticals, Intellihealth, and Jamieson Wellness. Dr. Golubic has received research support from AstraZeneca.

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

HAMBURG, GERMANY – The investigational incretin receptor agonist pemvidutide produced significant weight loss and other cardiometabolic benefits in a phase 2 randomized trial, adding a different type of “twincretin” to a growing mix of incretin-based weight-loss drugs in development that also offer additional benefits.

Pemvidutide (Altimmune Inc) is a long-acting “balanced” dual agonist of both glucagon-like peptide 1 (GLP-1) and glucagon that is in development for the treatment of obesity and nonalcoholic steatohepatitis (NASH) but not type 2 diabetes, as its effect on glucose is neutral. Phase 1 data for pemvidutide’s liver effect were presented in 2022.

In contrast, the dual GLP-1-glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide (Mounjaro, Lilly) has been approved for the treatment of type 2 diabetes. It awaits an indication for obesity.

“When you look [at] the results for any given agent, think about obesity as a series of problems. Some overlap, and some don’t. While about 20%-25% of people with obesity also have type 2 diabetes, not everybody does. So the compounds that don’t lower glucose ... those will be great for others who have [fatty liver disease] or hyperlipidemia. ... It’s not going to be one compound for everybody,” said Louis J. Aronne, MD, director of the center for weight management and metabolic clinical research, Weill Cornell Medicine, New York.

Results of a new 24-week interim analysis of data from the phase 2 pemvidutide trial, called MOMENTUM, were presented at the annual meeting of the European Association for the Study of Diabetes by Dr. Aronne.

Included in that session were encore presentations of data for another GLP-1-glucagon dual agonist, survodutide, as well as data for Eli Lilly’s GLP-1-GIP-glucagon “triagonist,” retatrutide. Retatrutide is in development to induce weight loss, while survodutide (Boehringer Ingelheim and Zealand Pharma), like pemvidutide, is in development to induce weight loss and treat fatty liver disease.

Added Dr. Aronne, “As good as [the triple agonist] retatrutide looks, I doubt that every single person with obesity in the world will be treated with it. ... Think about this as a field, the way you treat diabetes and every other chronic illness.”

Asked to comment, session moderator Rajna Golubic, PhD, of the Oxford (England) Centre for Diabetes, Endocrinology and Metabolism, told this news organization, “We need to think in terms of treating beyond weight loss. ... We need to look at the person holistically and at other aspects of cardiometabolic health and treat in a personalized way and choose treatments according to the comorbidities people have.”

Regarding the dual GLP-1-glucagon agonists, including pemvidutide, Dr. Golubic pointed out that the glucagon agonism does the opposite of glucose-lowering agents but that the compound is “balanced for greater affinity for the GLP-1 receptor vs. glucagon, so that the beneficial effects outweigh the effect for glucose but it still harnesses the benefits of glucagon on liver with a decrease in liver fat, with positive effects on heart, positive effects on kidneys, and other beneficial metabolic effects.”
 

Pemvidutide lowers weight, LDL cholesterol, triglycerides, and blood pressure

Dr. Aronne began his presentation by noting that dyslipidemia, fatty liver disease, and hypertension are the most significant comorbidities of obesity, occurring in 66%-70%, 58%-75%, and 45%-55% of patients, respectively, while type 2 diabetes is less common, at 19%-23%.

Pemvidutide’s GLP-1 receptor agonism reduces appetite, inflammation, and gastric emptying, while glucagon agonism increases lipolysis, mobilizes fat, and increases energy expenditure, Dr. Aronne explained.

The 48-week phase 2 MOMENTUM trial randomly assigned 320 participants with overweight or obesity and at least one obesity-related comorbidity but not diabetes to receive weekly doses of 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or placebo. The two lower pemvidutide doses were initiated immediately without titration, while the 2.4-mg dose was titrated rapidly over 4 weeks.

In a prespecified interim analysis of 160 participants, the percent body weight loss at 24 weeks was 10.7%, 9.4%, and 7.3% with the 2.4-mg, 1.8-mg, and 1.2-mg doses, respectively (P < .001). All weight loss values were significant; weight loss with placebo was a nonsignificant 1%.

The proportions of patients who lost at least 5% of their body weight were 84.6%, 66.7%, and 66.7%, respectively, vs. 25% with placebo. Half of the patients who received the 2.4-mg and 1.8-mg doses lost at least 10% of their body weight. Reductions in waist circumference followed suit; the patients who received the 2.4-mg dose lost an average of 10.2 cm, or “in the U.S., about 4 inches or 4 belt loops. That’s pretty good, you need a new belt,” Dr. Aronne commented.

Significant reductions in total cholesterol and triglyceride levels were also seen at week 24 by 16.5% and 25.0%, respectively, with the 2.4-mg dose. Low-density lipoprotein cholesterol levels also dropped, although not significantly; high-density lipoprotein levels dropped significantly.

Systolic blood pressure dropped by 5.5 mm Hg, and diastolic blood pressure dropped by 1.8 mm Hg in the 2.4-mg group and by lesser degrees among the patients who received lower doses. There were no significant changes in heart rate, Dr. Aronne noted.

Glucose homeostasis was preserved in all groups throughout the 24 weeks.

As with all drugs in the incretin class, gastrointestinal adverse events were common. Severe vomiting occurred in one person in the 1.8-mg group and in four with 2.4 mg. Efforts will be made to reduce that in subsequent trials, Dr. Aronne said.

“We have learned over time that going more gradually in titrating up these agents is a better strategy, allowing dose reduction may be a better strategy, and allowing antiemetics temporarily as we increase the dose is a lesson that many have learned doing these trials and of course in our clinical practices,” he commented.

Dr. Golubic told this news organization that the recent emergence of potent incretin-based weight loss drugs is “a huge paradigm shift. The prevalence of obesity will be 35% or higher by 2035. Bariatric surgery isn’t feasible for everyone, and it’s very expensive, so we need drugs to provide benefits in terms of lowering weight, glucose, and other cardiometabolic risk factors.”

The full 48-week data for MOMENTUM will be announced in the fourth quarter of 2023.

Dr. Aronne has received consulting fees from and serves on advisory boards for Allurion, Altimmune, Atria, Gelesis, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Optum, Eli Lilly, Senda Biosciences, and Versanis; has received research funding from Allurion, AstraZeneca, Gelesis, Janssen Pharmaceuticals, Novo Nordisk, and Eli Lilly; has equity interests in Allurion, ERX Pharmaceuticals, Gelesis, Intellihealth, Jamieson Wellness, and Myos Corp; and serves on a board of directors for ERX Pharmaceuticals, Intellihealth, and Jamieson Wellness. Dr. Golubic has received research support from AstraZeneca.

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

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.