Diabetes

The recent US Food and Drug Administration (FDA) clearance of two over-the-counter (OTC) continuous glucose monitors (CGMs) — Dexcom’s Stelo and Abbott’s Lingo — has sparked interest in potentially expanding their use to those without diabetes or prediabetes.

There are several valid questions about how the general population might benefit from CGMs. Can they motivate those struggling with overweight to shed pounds? Would they prompt users to follow more healthful eating patterns? Can they act as a canary in the coal mine, alerting users to prediabetes? 

The short answer to these questions is, we don’t know.

“Glucose levels fluctuate in everyone in response to meals, exercise, stress, etc, but there has been no credible research to support CGM use by most people who do not have diabetes,” Jill Crandall, MD, chief of endocrinology at Albert Einstein College of Medicine and Montefiore Health System in New York City, said in an interview.

“The utility of CGM for people without diabetes hasn’t been established and the drive to market CGM as an OTC device seems largely driven by financial considerations,” Crandall said. She advocates instead for a strategy directed at more meaningful objectives.

“For now, efforts should be focused on making CGMs available to patients who will clearly benefit — ie, people with diabetes, especially those who are using insulin and those who are struggling to achieve desired levels of glucose control.” 

Nicole Spartano, PhD, assistant professor of medicine in endocrinology, diabetes, nutrition and weight management at Boston University’s Chobanian & Avedisian School of Medicine in Massachusetts, agreed with this assessment.

“It is definitely too early to make recommendations for patients without diabetes based on their CGM data,” said Spartano, who also serves as the director of the Glucose Monitoring Station at the Framingham Heart Study in Framingham, Massachusetts. “We simply do not have enough follow-up data to tell us which CGM metrics are associated with higher risk for disease.” 

Spartano served as the lead author of a recent study showing time spent in various CGM ranges in a large cohort of individuals without diabetes using the Dexcom G6 Pro model. In the future, she said the data may be used to establish reference ranges for clinicians and individuals.

“We are working on another paper surveying diabetologists and CGM experts about how they interpret CGM reports from individuals without diabetes,” she said in an interview. Although the data are not yet published, Spartano said, “we are finding that clinicians are currently very discordant in how they interpret these reports.”
 

Potential Benefits Right Now

Satish Garg, MD, director of the Adult Clinic at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, Aurora, and editor-in-chief of Diabetes Technology & Therapeutics, is convinced that glucose should be considered another vital sign, like blood pressure, pulse rate, respiration rate, and body temperature. Therefore, he sees the use of a CGM in people without diabetes as a way to build awareness and perhaps prompt behavior modification.

“Someone with an A1c of 4.9 on a normal day may notice that they’ve gained a little bit of weight, and if they use an OTC CGM and start seeing changes, it might help them to modulate their diet themselves, whether they see a dietitian or not,” Garg said.

He gave the example of “a natural behavioral change” occurring when someone using a CGM declines to eat a post-meal dessert after seeing their blood glucose had already risen to 170.

Wearing a CGM also has the potential to alert the user to high blood glucose, leading them to an earlier diagnosis of prediabetes or diabetes, Shichun Bao, MD, PhD, Diabetes Technology Program Leader at the Vanderbilt Eskind Diabetes Clinic of Vanderbilt University in Nashville, Tennessee, said in an interview. She has had cases where a family member of someone with diabetes used the patient’s fingerstick meter, found that their glucose was 280, and self-diagnosed with diabetes.

“It’s the same thing with the CGM,” she said. “If they somehow did not know they have diabetes and they wear a CGM and it shows their sugar is high, that will help them to know to see their provider to get a diagnosis, get treated, and track progression.”

Given the shortage of endocrinologists and long waits for appointments in the United States and elsewhere, it is very likely that primary care physicians will be the ones fielding questions from individuals without diabetes interested in purchasing an OTC CGM. Internist Douglas Paauw, MD, a professor at the University of Washington School of Medicine, Seattle, said in an interview that, for his practice, “the benefits outweigh some of the limitations.”

“I don’t really think somebody who doesn’t have diabetes needs to be using a CGM all the time or long term,” he said. “But I have used it in a few people without diabetes, and I think if someone can afford to use it for 2-4 weeks, especially if they’ve been gaining weight, then they can really recognize what happens to their bodies when they eat certain foods.”

Paauw added that CGMs are a more effective means of teaching his patients than them receiving a lecture from him on healthy eating. “There’s nothing like immediate feedback on what happens to your body to change behavior.”

Similarly, William Golden, medical director at Arkansas Medicaid and professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview that “it is difficult to justify coverage for CGMs on demand — but if people want to invest in their own devices and the technology motivates them to eat better and/or lose weight, then there are benefits to be had.” 
 

Potential Downsides

Although it may seem simple to use an OTC CGM to measure blood glucose on the fly, in the real world it can take patients time to understand these devices, “especially the first day or so, when users are going to get false lows,” Bao said. “Clinicians need to tell them if you don’t feel like your sugar is low and the device says it’s low, whether they do or don’t have diabetes, they should do a fingerstick glucose test to confirm the low before rushing to take in sugar. On the other hand, if they drink a lot of juice, their sugar will go high. So, it can create problems and false results either way.”

Many factors affect glucose, she said. “When you’re sick, glucose can go high, and when you’re very sick, in the ICU, sometimes it can be low. It depends on the situation.” Bao noted that certain vitamins and drugs can also interfere with readings.

Bao doesn’t see value in having people without diabetes monitor their glucose continuously. “If they want to see what foods or exercise do to their body, they will probably benefit from a short trial to gain some insight; otherwise, they’re wasting money,” she said.

Another potential downside is that there’s no head-to-head comparison data with the approved devices, Garg said. “But it’s clear to us that Stelo’s range is very narrow, 70 to 200, whereas the Lingo ranges are pretty much full, from 40 to 400 or 55 to 400. So, we don’t know the accuracy of these sensors.”

Golden observed that for certain patients, CGMs may lead to psychological distress rather than providing a sense of control over their blood glucose levels.

“I have had a nondiabetic patient or two that obsessed about their blood sugars and a device would only magnify their anxiety/neurosis,” he said. “The bottom line is that it’s a tool for a balanced approach to health management, but the daily results must be kept in perspective!”
 

Educate Patients, Primary Care Physicians

To maximize potential benefits for patients without diabetes, clinicians need to be well trained in the use and interpretation of results from the devices, Bao said. They can then better educate their patients, including discussing with them possible pitfalls surrounding their use. 

“For example, a patient may see that their blood glucose, as measured by a fingerstick, is 95, whereas the CGM says 140, and ask, ‘Which one do I trust?’ ”

This is where the patient can be educated about the difference between interstitial glucose, as measured by the CGM, and blood glucose, as measured by the fingerstick. Because it takes about 15 minutes for blood glucose to get to the interstitial tissue, there’s lag time, and the two measurements will differ.

“A discrepancy of 20% is totally acceptable for that reason,” Bao said.

She has also seen several examples where patients were misled by their CGM when its censor became dislodged.

“Sometimes when a sensor has moved, the patient may push it back in because they don’t want to throw it away. But it doesn’t work that way, and they end up with inaccurate readings.” 

At a minimum, Bao added, clinicians and patients should read the package insert but also be aware that it doesn’t list everything that might go wrong or interfere with the device’s accuracy.

Manufacturers of OTC devices should be training primary care and family practice doctors in their use, given the expected “huge” influx of patients wanting to use them, according to Garg.

“If you are expecting endos or diabetes specialists to see these people, that’s never going to happen,” he said. “We have a big shortage of these specialists, so industry has to train these doctors. Patients will bring their doctor’s data, and the clinicians need to learn the basics of how to interpret the glucose values they see. Then they can treat these patients rather than shipping all of them to endos who likely are not available.”

Paauw agreed that CGM training should be directed largely toward primary care professionals, who can help their under-resourced endocrinologist colleagues from seeing an uptick in “the worried well.” 

“The bottom line is that primary care professionals do need to understand the CGM,” he said. “They do need to get comfortable with it. They do need to come up with opinions on how to use it. The public’s going to be using it, and we need to be competent in it and use our subspecialists appropriately.”

Spartano received funding for an investigator-initiated research grant from Novo Nordisk unrelated to the cited CGM studies. Garg , Bao, Paauw, Golden, and Crandall declared no relevant conflicts of interest.

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

The recent US Food and Drug Administration (FDA) clearance of two over-the-counter (OTC) continuous glucose monitors (CGMs) — Dexcom’s Stelo and Abbott’s Lingo — has sparked interest in potentially expanding their use to those without diabetes or prediabetes.

There are several valid questions about how the general population might benefit from CGMs. Can they motivate those struggling with overweight to shed pounds? Would they prompt users to follow more healthful eating patterns? Can they act as a canary in the coal mine, alerting users to prediabetes? 

The short answer to these questions is, we don’t know.

“Glucose levels fluctuate in everyone in response to meals, exercise, stress, etc, but there has been no credible research to support CGM use by most people who do not have diabetes,” Jill Crandall, MD, chief of endocrinology at Albert Einstein College of Medicine and Montefiore Health System in New York City, said in an interview.

“The utility of CGM for people without diabetes hasn’t been established and the drive to market CGM as an OTC device seems largely driven by financial considerations,” Crandall said. She advocates instead for a strategy directed at more meaningful objectives.

“For now, efforts should be focused on making CGMs available to patients who will clearly benefit — ie, people with diabetes, especially those who are using insulin and those who are struggling to achieve desired levels of glucose control.” 

Nicole Spartano, PhD, assistant professor of medicine in endocrinology, diabetes, nutrition and weight management at Boston University’s Chobanian & Avedisian School of Medicine in Massachusetts, agreed with this assessment.

“It is definitely too early to make recommendations for patients without diabetes based on their CGM data,” said Spartano, who also serves as the director of the Glucose Monitoring Station at the Framingham Heart Study in Framingham, Massachusetts. “We simply do not have enough follow-up data to tell us which CGM metrics are associated with higher risk for disease.” 

Spartano served as the lead author of a recent study showing time spent in various CGM ranges in a large cohort of individuals without diabetes using the Dexcom G6 Pro model. In the future, she said the data may be used to establish reference ranges for clinicians and individuals.

“We are working on another paper surveying diabetologists and CGM experts about how they interpret CGM reports from individuals without diabetes,” she said in an interview. Although the data are not yet published, Spartano said, “we are finding that clinicians are currently very discordant in how they interpret these reports.”
 

Potential Benefits Right Now

Satish Garg, MD, director of the Adult Clinic at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, Aurora, and editor-in-chief of Diabetes Technology & Therapeutics, is convinced that glucose should be considered another vital sign, like blood pressure, pulse rate, respiration rate, and body temperature. Therefore, he sees the use of a CGM in people without diabetes as a way to build awareness and perhaps prompt behavior modification.

“Someone with an A1c of 4.9 on a normal day may notice that they’ve gained a little bit of weight, and if they use an OTC CGM and start seeing changes, it might help them to modulate their diet themselves, whether they see a dietitian or not,” Garg said.

He gave the example of “a natural behavioral change” occurring when someone using a CGM declines to eat a post-meal dessert after seeing their blood glucose had already risen to 170.

Wearing a CGM also has the potential to alert the user to high blood glucose, leading them to an earlier diagnosis of prediabetes or diabetes, Shichun Bao, MD, PhD, Diabetes Technology Program Leader at the Vanderbilt Eskind Diabetes Clinic of Vanderbilt University in Nashville, Tennessee, said in an interview. She has had cases where a family member of someone with diabetes used the patient’s fingerstick meter, found that their glucose was 280, and self-diagnosed with diabetes.

“It’s the same thing with the CGM,” she said. “If they somehow did not know they have diabetes and they wear a CGM and it shows their sugar is high, that will help them to know to see their provider to get a diagnosis, get treated, and track progression.”

Given the shortage of endocrinologists and long waits for appointments in the United States and elsewhere, it is very likely that primary care physicians will be the ones fielding questions from individuals without diabetes interested in purchasing an OTC CGM. Internist Douglas Paauw, MD, a professor at the University of Washington School of Medicine, Seattle, said in an interview that, for his practice, “the benefits outweigh some of the limitations.”

“I don’t really think somebody who doesn’t have diabetes needs to be using a CGM all the time or long term,” he said. “But I have used it in a few people without diabetes, and I think if someone can afford to use it for 2-4 weeks, especially if they’ve been gaining weight, then they can really recognize what happens to their bodies when they eat certain foods.”

Paauw added that CGMs are a more effective means of teaching his patients than them receiving a lecture from him on healthy eating. “There’s nothing like immediate feedback on what happens to your body to change behavior.”

Similarly, William Golden, medical director at Arkansas Medicaid and professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview that “it is difficult to justify coverage for CGMs on demand — but if people want to invest in their own devices and the technology motivates them to eat better and/or lose weight, then there are benefits to be had.” 
 

Potential Downsides

Although it may seem simple to use an OTC CGM to measure blood glucose on the fly, in the real world it can take patients time to understand these devices, “especially the first day or so, when users are going to get false lows,” Bao said. “Clinicians need to tell them if you don’t feel like your sugar is low and the device says it’s low, whether they do or don’t have diabetes, they should do a fingerstick glucose test to confirm the low before rushing to take in sugar. On the other hand, if they drink a lot of juice, their sugar will go high. So, it can create problems and false results either way.”

Many factors affect glucose, she said. “When you’re sick, glucose can go high, and when you’re very sick, in the ICU, sometimes it can be low. It depends on the situation.” Bao noted that certain vitamins and drugs can also interfere with readings.

Bao doesn’t see value in having people without diabetes monitor their glucose continuously. “If they want to see what foods or exercise do to their body, they will probably benefit from a short trial to gain some insight; otherwise, they’re wasting money,” she said.

Another potential downside is that there’s no head-to-head comparison data with the approved devices, Garg said. “But it’s clear to us that Stelo’s range is very narrow, 70 to 200, whereas the Lingo ranges are pretty much full, from 40 to 400 or 55 to 400. So, we don’t know the accuracy of these sensors.”

Golden observed that for certain patients, CGMs may lead to psychological distress rather than providing a sense of control over their blood glucose levels.

“I have had a nondiabetic patient or two that obsessed about their blood sugars and a device would only magnify their anxiety/neurosis,” he said. “The bottom line is that it’s a tool for a balanced approach to health management, but the daily results must be kept in perspective!”
 

Educate Patients, Primary Care Physicians

To maximize potential benefits for patients without diabetes, clinicians need to be well trained in the use and interpretation of results from the devices, Bao said. They can then better educate their patients, including discussing with them possible pitfalls surrounding their use. 

“For example, a patient may see that their blood glucose, as measured by a fingerstick, is 95, whereas the CGM says 140, and ask, ‘Which one do I trust?’ ”

This is where the patient can be educated about the difference between interstitial glucose, as measured by the CGM, and blood glucose, as measured by the fingerstick. Because it takes about 15 minutes for blood glucose to get to the interstitial tissue, there’s lag time, and the two measurements will differ.

“A discrepancy of 20% is totally acceptable for that reason,” Bao said.

She has also seen several examples where patients were misled by their CGM when its censor became dislodged.

“Sometimes when a sensor has moved, the patient may push it back in because they don’t want to throw it away. But it doesn’t work that way, and they end up with inaccurate readings.” 

At a minimum, Bao added, clinicians and patients should read the package insert but also be aware that it doesn’t list everything that might go wrong or interfere with the device’s accuracy.

Manufacturers of OTC devices should be training primary care and family practice doctors in their use, given the expected “huge” influx of patients wanting to use them, according to Garg.

“If you are expecting endos or diabetes specialists to see these people, that’s never going to happen,” he said. “We have a big shortage of these specialists, so industry has to train these doctors. Patients will bring their doctor’s data, and the clinicians need to learn the basics of how to interpret the glucose values they see. Then they can treat these patients rather than shipping all of them to endos who likely are not available.”

Paauw agreed that CGM training should be directed largely toward primary care professionals, who can help their under-resourced endocrinologist colleagues from seeing an uptick in “the worried well.” 

“The bottom line is that primary care professionals do need to understand the CGM,” he said. “They do need to get comfortable with it. They do need to come up with opinions on how to use it. The public’s going to be using it, and we need to be competent in it and use our subspecialists appropriately.”

Spartano received funding for an investigator-initiated research grant from Novo Nordisk unrelated to the cited CGM studies. Garg , Bao, Paauw, Golden, and Crandall declared no relevant conflicts of interest.

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

The recent US Food and Drug Administration (FDA) clearance of two over-the-counter (OTC) continuous glucose monitors (CGMs) — Dexcom’s Stelo and Abbott’s Lingo — has sparked interest in potentially expanding their use to those without diabetes or prediabetes.

There are several valid questions about how the general population might benefit from CGMs. Can they motivate those struggling with overweight to shed pounds? Would they prompt users to follow more healthful eating patterns? Can they act as a canary in the coal mine, alerting users to prediabetes? 

The short answer to these questions is, we don’t know.

“Glucose levels fluctuate in everyone in response to meals, exercise, stress, etc, but there has been no credible research to support CGM use by most people who do not have diabetes,” Jill Crandall, MD, chief of endocrinology at Albert Einstein College of Medicine and Montefiore Health System in New York City, said in an interview.

“The utility of CGM for people without diabetes hasn’t been established and the drive to market CGM as an OTC device seems largely driven by financial considerations,” Crandall said. She advocates instead for a strategy directed at more meaningful objectives.

“For now, efforts should be focused on making CGMs available to patients who will clearly benefit — ie, people with diabetes, especially those who are using insulin and those who are struggling to achieve desired levels of glucose control.” 

Nicole Spartano, PhD, assistant professor of medicine in endocrinology, diabetes, nutrition and weight management at Boston University’s Chobanian & Avedisian School of Medicine in Massachusetts, agreed with this assessment.

“It is definitely too early to make recommendations for patients without diabetes based on their CGM data,” said Spartano, who also serves as the director of the Glucose Monitoring Station at the Framingham Heart Study in Framingham, Massachusetts. “We simply do not have enough follow-up data to tell us which CGM metrics are associated with higher risk for disease.” 

Spartano served as the lead author of a recent study showing time spent in various CGM ranges in a large cohort of individuals without diabetes using the Dexcom G6 Pro model. In the future, she said the data may be used to establish reference ranges for clinicians and individuals.

“We are working on another paper surveying diabetologists and CGM experts about how they interpret CGM reports from individuals without diabetes,” she said in an interview. Although the data are not yet published, Spartano said, “we are finding that clinicians are currently very discordant in how they interpret these reports.”
 

Potential Benefits Right Now

Satish Garg, MD, director of the Adult Clinic at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, Aurora, and editor-in-chief of Diabetes Technology & Therapeutics, is convinced that glucose should be considered another vital sign, like blood pressure, pulse rate, respiration rate, and body temperature. Therefore, he sees the use of a CGM in people without diabetes as a way to build awareness and perhaps prompt behavior modification.

“Someone with an A1c of 4.9 on a normal day may notice that they’ve gained a little bit of weight, and if they use an OTC CGM and start seeing changes, it might help them to modulate their diet themselves, whether they see a dietitian or not,” Garg said.

He gave the example of “a natural behavioral change” occurring when someone using a CGM declines to eat a post-meal dessert after seeing their blood glucose had already risen to 170.

Wearing a CGM also has the potential to alert the user to high blood glucose, leading them to an earlier diagnosis of prediabetes or diabetes, Shichun Bao, MD, PhD, Diabetes Technology Program Leader at the Vanderbilt Eskind Diabetes Clinic of Vanderbilt University in Nashville, Tennessee, said in an interview. She has had cases where a family member of someone with diabetes used the patient’s fingerstick meter, found that their glucose was 280, and self-diagnosed with diabetes.

“It’s the same thing with the CGM,” she said. “If they somehow did not know they have diabetes and they wear a CGM and it shows their sugar is high, that will help them to know to see their provider to get a diagnosis, get treated, and track progression.”

Given the shortage of endocrinologists and long waits for appointments in the United States and elsewhere, it is very likely that primary care physicians will be the ones fielding questions from individuals without diabetes interested in purchasing an OTC CGM. Internist Douglas Paauw, MD, a professor at the University of Washington School of Medicine, Seattle, said in an interview that, for his practice, “the benefits outweigh some of the limitations.”

“I don’t really think somebody who doesn’t have diabetes needs to be using a CGM all the time or long term,” he said. “But I have used it in a few people without diabetes, and I think if someone can afford to use it for 2-4 weeks, especially if they’ve been gaining weight, then they can really recognize what happens to their bodies when they eat certain foods.”

Paauw added that CGMs are a more effective means of teaching his patients than them receiving a lecture from him on healthy eating. “There’s nothing like immediate feedback on what happens to your body to change behavior.”

Similarly, William Golden, medical director at Arkansas Medicaid and professor of medicine and public health at the University of Arkansas for Medical Sciences, Little Rock, said in an interview that “it is difficult to justify coverage for CGMs on demand — but if people want to invest in their own devices and the technology motivates them to eat better and/or lose weight, then there are benefits to be had.” 
 

Potential Downsides

Although it may seem simple to use an OTC CGM to measure blood glucose on the fly, in the real world it can take patients time to understand these devices, “especially the first day or so, when users are going to get false lows,” Bao said. “Clinicians need to tell them if you don’t feel like your sugar is low and the device says it’s low, whether they do or don’t have diabetes, they should do a fingerstick glucose test to confirm the low before rushing to take in sugar. On the other hand, if they drink a lot of juice, their sugar will go high. So, it can create problems and false results either way.”

Many factors affect glucose, she said. “When you’re sick, glucose can go high, and when you’re very sick, in the ICU, sometimes it can be low. It depends on the situation.” Bao noted that certain vitamins and drugs can also interfere with readings.

Bao doesn’t see value in having people without diabetes monitor their glucose continuously. “If they want to see what foods or exercise do to their body, they will probably benefit from a short trial to gain some insight; otherwise, they’re wasting money,” she said.

Another potential downside is that there’s no head-to-head comparison data with the approved devices, Garg said. “But it’s clear to us that Stelo’s range is very narrow, 70 to 200, whereas the Lingo ranges are pretty much full, from 40 to 400 or 55 to 400. So, we don’t know the accuracy of these sensors.”

Golden observed that for certain patients, CGMs may lead to psychological distress rather than providing a sense of control over their blood glucose levels.

“I have had a nondiabetic patient or two that obsessed about their blood sugars and a device would only magnify their anxiety/neurosis,” he said. “The bottom line is that it’s a tool for a balanced approach to health management, but the daily results must be kept in perspective!”
 

Educate Patients, Primary Care Physicians

To maximize potential benefits for patients without diabetes, clinicians need to be well trained in the use and interpretation of results from the devices, Bao said. They can then better educate their patients, including discussing with them possible pitfalls surrounding their use. 

“For example, a patient may see that their blood glucose, as measured by a fingerstick, is 95, whereas the CGM says 140, and ask, ‘Which one do I trust?’ ”

This is where the patient can be educated about the difference between interstitial glucose, as measured by the CGM, and blood glucose, as measured by the fingerstick. Because it takes about 15 minutes for blood glucose to get to the interstitial tissue, there’s lag time, and the two measurements will differ.

“A discrepancy of 20% is totally acceptable for that reason,” Bao said.

She has also seen several examples where patients were misled by their CGM when its censor became dislodged.

“Sometimes when a sensor has moved, the patient may push it back in because they don’t want to throw it away. But it doesn’t work that way, and they end up with inaccurate readings.” 

At a minimum, Bao added, clinicians and patients should read the package insert but also be aware that it doesn’t list everything that might go wrong or interfere with the device’s accuracy.

Manufacturers of OTC devices should be training primary care and family practice doctors in their use, given the expected “huge” influx of patients wanting to use them, according to Garg.

“If you are expecting endos or diabetes specialists to see these people, that’s never going to happen,” he said. “We have a big shortage of these specialists, so industry has to train these doctors. Patients will bring their doctor’s data, and the clinicians need to learn the basics of how to interpret the glucose values they see. Then they can treat these patients rather than shipping all of them to endos who likely are not available.”

Paauw agreed that CGM training should be directed largely toward primary care professionals, who can help their under-resourced endocrinologist colleagues from seeing an uptick in “the worried well.” 

“The bottom line is that primary care professionals do need to understand the CGM,” he said. “They do need to get comfortable with it. They do need to come up with opinions on how to use it. The public’s going to be using it, and we need to be competent in it and use our subspecialists appropriately.”

Spartano received funding for an investigator-initiated research grant from Novo Nordisk unrelated to the cited CGM studies. Garg , Bao, Paauw, Golden, and Crandall declared no relevant conflicts of interest.

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

The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?

“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”

AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
 

‘Mediocre Markers’

AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.

Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.

“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”

Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”

What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.

“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
 

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.

NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.

There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.

“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”

If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.

“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”

Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.

However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.

“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
 

A New Biomarker for AIN?

Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.

“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.

“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”

“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”

Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”

Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.

“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”

In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”

Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.

Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”

Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.

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

The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?

“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”

AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
 

‘Mediocre Markers’

AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.

Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.

“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”

Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”

What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.

“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
 

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.

NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.

There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.

“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”

If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.

“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”

Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.

However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.

“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
 

A New Biomarker for AIN?

Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.

“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.

“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”

“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”

Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”

Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.

“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”

In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”

Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.

Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”

Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.

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

The search for a better biomarker than creatine for acute kidney injury (AKI) has been “long and elusive.” However, could researchers be on the right path now?

“The thinking is moving away from trying to find one biomarker that can be used for different types of kidney injury to a recognition that AKI is not just a single disease that a patient has or doesn’t have,” Rob D. Nerenz, PhD, an associate professor in the Department of Pathology and Laboratory Medicine at the Medical College of Wisconsin, Milwaukee, told this news organization. “It’s lots of different diseases that all affect the kidney in different ways.”

AKI is actually a “loose collection” of hepatorenal, cardiorenal, nephrotoxic, and sepsis-associated syndromes, as well as acute interstitial nephritis (AIN), he said. “So the question is not: ‘Is AKI present — yes or no?’ It’s: ‘What kind of AKI is present, and how do I treat it?’ ”
 

‘Mediocre Markers’

AKI affects about 10%-30% of hospitalized patients, according to Nerenz. It’s associated with an increased risk for adverse outcomes, including post-AKI chronic kidney disease and a mortality rate of approximately 24%.

Currently, AKI is defined by a rapid increase in serum creatinine, a decrease in urine output, or both.

“Those are mediocre markers,” Nerenz said, as serum creatinine is not very sensitive to acute change, and the increase is often detected after the therapeutic window of intervention has passed. In addition, “it only tells us that the kidneys are unhappy; it doesn’t say anything about the cause.”

Urine output is limited as a marker because many conditions affect it. “If you’re dehydrated, urine output is going to decrease,” he said. “And in some forms of AKI, urine output actually goes up.”

What’s needed, he said, is a more sensitive biomarker that’s detectable within a shorter timeframe of 2-6 hours following injury.

“Right now, we’re looking at 48 hours before a change becomes apparent, and that’s just too long. Plus, it should be kidney specific. One of the major limitations of the biomarkers that have been evaluated to this point is that, yes, they’re released by the kidney, but they’re also released by other tissue types within the body, and that hinders their effectiveness as a marker.”
 

Neutrophil Gelatinase-Associated Lipocalin (NGAL)

Although research on better biomarkers is ongoing, “there’s also a recognition that some of the protein markers that have been around for a while, if used appropriately, can provide value,” Nerenz said. These include, among others, NGAL.

NGAL works well in pediatric patients without other comorbidities, but it has been less useful in adult patients because it is also released by other cell types. However, recent research suggests it shows promise in patients with both cirrhosis and AKI.

There are three main causes of AKI in cirrhosis, Nerenz explained. The first is prerenal and can be primarily addressed through rehydration.

“When these patients come in, clinicians won’t do anything right away other than provide fluids. If creatinine improves over the 48-hour period of fluid replenishment, then the patient is sent home because there really isn’t extensive damage to the kidneys.”

If improvement isn’t seen after those 48 hours, then it could be one of two things: Hepatorenal syndrome or acute tubular necrosis. Patients with hepatorenal syndrome are candidates for terlipressin, which the Food and Drug Administration (FDA) approved for this indication in 2022 after it displayed notable efficacy in a double-blind study.

“You don’t want to give terlipressin to just anybody because if the issue is not a diminished blood supply to the kidney, it’s not going to help, and comes with some serious side effects, such as respiratory failure,” Nerenz explained. “Having a biomarker that can distinguish between hepatorenal syndrome and acute tubular necrosis really helps clinicians confidently identify which patients are good candidates for this drug. Right now, we’re flying blind to a certain extent, basically using clinical intuition.”

Currently, the determination of NGAL is FDA cleared only for pediatric use. One way hospitals have dealt with that is by making the test in their own labs, using appropriate reagents, validation, and so forth. These tests are then safe for use in adults but haven’t gone through the FDA approval process.

However, the FDA’s recent announcement stating that the agency should oversee lab-developed tests has made this situation unclear, Nerenz said.

“At this point, we don’t know if there’s still an opportunity to take the NGAL test (or any other cleared biomarker) and validate it for use in a different patient population. Many hospital labs simply don’t have the resources to take these tests through the whole FDA approval process.”
 

A New Biomarker for AIN?

Meanwhile, research is also moving forward on a better biomarker for AIN, which is also under the AKI umbrella.

“It’s important to diagnose AIN because it has a very specific treatment,” Dennis G. Moledina, MD, PhD, Yale School of Medicine in New Haven, Connecticut, told this news organization.

“AIN is caused by a bunch of different medications, such as proton pump inhibitors, cancer drugs, nonsteroidal anti-inflammatory drugs, and antibiotics, so when someone has this condition, you have to stop potentially life-saving medications and give unnecessary and potentially toxic immunosuppressive drugs, like prednisone,” he said. “If you get the diagnosis wrong, you’re stopping vital drugs and giving immunosuppression for no reason. And if you miss the diagnosis, AIN can lead to permanent chronic kidney disease.”

“Right now, the only way to diagnose AIN is to do a kidney biopsy, which is risky because it can often lead to significant bleeding,” he said. “Some people can’t undergo a biopsy because they’re on medications that increase the risk of bleeding, and they can’t be stopped.”

Furthermore, he noted, “the longer a patient takes a drug that’s causing AIN without getting a diagnosis, the less the chances of recovery because the longer you let this kidney inflammation go on, the more fibrosis and permanent damage develops. So it is important to diagnose it as early as possible, and that’s again why we have a real need for a noninvasive biomarker that can be tested rapidly.”

Moledina and colleagues have been working on identifying a suitable biomarker for close to 10 years, the latest example of which is their 2023 study validating urinary CXCL9 as just such a marker.

“We’re most excited about CXCL9 because it’s already used to diagnose some other diseases in plasma,” Moledina said. “We think that we can convince labs to test it in urine.”

In an accompanying editorial, Mark Canney, PhD, and colleagues at the University of Ottawa and The Ottawa Hospital in Ontario, Canada, wrote that the CXCL9 study findings “are exciting because they provide a road map of where diagnostics can get to for this common, yet poorly identified and treated, cause of kidney damage. The need for a different approach can be readily identified from the fact that clinicians’ gestalt for diagnosing AIN was almost tantamount to tossing a coin (AUC, 0.57). CXCL9 alone outperformed not only the clinician’s prebiopsy suspicion but also an existing diagnostic model and other candidate biomarkers both in the discovery and external validation cohorts.”

Like NGAL, CXCL9 will have to go through the FDA approval process before it can be used for AIN. Therefore, it may be a few years before it can become routinely available, Moledina said.

Nevertheless, Nerenz added, “I think the next steps for AKI are probably continuing on this path of context-dependent, selective biomarker use. I anticipate that we’ll see ongoing development in this space, just expanding to a wider variety of clinical scenarios.”

Nerenz declared receiving research funding from Abbott Labs for evaluation of an AKI biomarker. Moledina is a co-inventor on a pending patent, “Methods and Systems for Diagnosis of Acute Interstitial Nephritis”; a cofounder of the diagnostics company Predict AIN; and a consultant for Biohaven.

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

“Cortisol” has become a household word, popularized by social media and tagged in videos that garnered nearly 800 million views in 2023. This is linked to the also-trending term “moon face,” which TikTok influencers and others have suggested is caused by high cortisol levels and, conversely, can be reduced through stress reduction.

Although it’s true that cortisol is a hormone associated with stress, elevated stress levels are unlikely, by themselves, to cause the rounded facial features associated with “moon face.”

“When we hear the term ‘moon face,’ we’re typically referring to Cushing syndrome [CS] or treatment with prolonged high-dose glucocorticoids,” said Anat Ben-Shlomo, MD, co-director of the Multidisciplinary Adrenal Program, Pituitary Center, Division of Endocrinology, Diabetes and Metabolism at Cedars-Sinai Medical Center, Los Angeles. Medscape Medical News previously discussed moon face in an article detailing how to diagnose CS.

Ben-Shlomo noted that the labels “moon face” and “moon facies” should be avoided for their potentially derogatory, unprofessional-sounding connotations, and that the preferred terms are “rounded face” or “round plethoric face.”

There are several disorders that can be associated with facial roundness, not all of which relate to elevated cortisol.

“It’s important for clinicians to be able distinguish between presentations due to other pathophysiologies, identify the unique constellation of Cushing-associated signs and symptoms, engage in a differential diagnosis, and treat whatever the condition is appropriately,” Katherine Sherif, MD, professor and vice chair of academic affairs, Department of Medicine, Thomas Jefferson University, Philadelphia, said in an interview.
 

The Unique Presentation of CS

CS results from “prolonged elevation” in plasma cortisol levels caused by either exogenous steroid use or excess endogenous steroid production.

“The shape of the face isn’t the only feature associated with CS,” Ben-Shlomo said. “There’s central obesity, particularly in the neck, supraclavicular area, chest, and abdomen. You sometimes see a posterior cervical thoracic fat pad, colloquially — but unprofessionally — called a ‘cervical hump.’ Simultaneously, the arms and legs are getting thinner.” The development of a round, plethoric face is common in long-standing significant CS, and a reddening of the skin can appear.

Additional symptoms include hirsutism and acne. “These can also be seen in other conditions, such as PCOS [polycystic ovary syndrome] but, combined with the other facial features, are more suggestive of CS,” Ben-Shlomo said.

Deep, wide purple striae appear in the trunk, breast, upper arms, and thighs, but not in the face, Ben-Shlomo advised. These appear as the fragile, thinning under-skin breaks when the patient gains weight.

Additional metabolic issues that can occur comorbidly include insulin resistance and diabetes, hypertension, osteoporosis, dyslipidemia, ecchymoses, increased susceptibility to infections, mood changes, cognitive dysfunction, low libido, infertility, weakness of muscles in the shoulders and thighs, episodes of bleeding and/or clotting, and an increased risk for heart attacks and strokes, Ben-Shlomo said.

“Not everyone presents with full-blown disease, but if you see any of these symptoms, be suspicious of CS and conduct a biochemical evaluation.” Three screening tests to use as a starting point are recommended by the Pituitary Society’s updated Consensus on Diagnosis and Management of Cushing’s Disease. The tests should be repeated to account for intra-patient variability. If two or all three tests are positive, clinicians should be suspicious of CS and move to additional testing to identify the underlying cause, Ben-Shlomo said.
 

‘Subclinical’ CS

Ben-Shlomo highlighted a condition called minimal autonomous cortisol secretion (formerly “subclinical CS”). “This condition is found when a person has an adrenal nodule that produces cortisol in excess, however not to levels observed in CS. An abnormal finding on the overnight 1-mg low-dose dexamethasone suppression test (LDDST) will identify this disorder, showing mildly unsuppressed morning cortisol level, while all other tests will be within normal range.”

She described minimal autonomous cortisol secretion as a form of “smoldering CS,” which has become more commonly diagnosed. “The condition needs to be treated because the patient can develop insulin resistance, metabolic syndrome, and osteoporosis over time.”

Once a cause has been determined, the optimal course of action is to take a multidisciplinary approach because CS affects multiple systems.
 

‘Pseudo-Cushing Syndrome’

A variety of abnormalities of the hypothalamus-pituitary adrenal (HPA) axis can be associated with hypercortisolemia and a rounder facial appearance but aren’t actually CS, Ben-Shlomo said.

Often called “pseudo-Cushing syndrome,” these conditions have recently been renamed “non-neoplastic hypercortisolism” or “physiologic non-neoplastic endogenous hypercortisolism.” They share some clinical and biochemical features of CS, but the hypercortisolemia is usually secondary to other factors. They increase the secretion of hypothalamic corticotropin-releasing hormone, which stimulates adrenocorticotropic hormone (ACTH) and adrenal cortisol secretion.
 

Identifying PCOS

PCOS is often associated with central obesity, Sherif noted, but not all women with PCOS have overweight or a central distribution of fat.

“Ask about menstrual periods and whether they come monthly,” Sherif advised. “If women using hormonal contraception say they have a regular cycle, ask if their cycle was regular prior to starting contraception. So many women with PCOS are undiagnosed because they started contraception in their teens to ‘regulate their periods’ and never realized they had PCOS.”

Additional symptoms of PCOS and its impact are found in the figure below.

Medscape

• Irregular menstrual cycles
• Clinical hyperandrogenism or biochemical hyperandrogenism
• Polycystic ovarian morphology on transvaginal ultrasonography or high anti-mullerian hormone (applicable only if patient is ≥ 8 years from menarche)

If PCOS is suspected, further tests can be conducted to confirm or rule out the diagnosis.
 

Alcohol Abuse: Alcohol abuse stimulates hypothalamic corticotropin-releasing hormone, leading to increased ACTH levels. It’s associated with a higher fasting cortisol level, particularly at 8:30 AM or so, and attributable to impaired cortisol clearance due to alcohol-related hepatic dysfunction. The LDDST will show abnormal cortisol suppression.

Sherif advised asking patients about alcohol use, recommending treatment for alcohol use disorder, and repeating clinical and biochemical workup after patients have discontinued alcohol consumption for ≥ 1 month.
 

Eating Disorders Mimicking CS: Eating disorders, particularly anorexia nervosa, are associated with endocrine abnormalities, amenorrhea, impaired body temperature regulation, and hypercortisolism, likely due to chronic fasting-related stress. Dysregulation of the HPA axis may linger, even after weight recovery.

It’s unlikely that patients with anorexia will display the “rounded face” associated with hypercortisolism, but some research suggests that anorexia can result in a disproportionate accumulation of central adiposity after recovery from the illness.
 

Neuropsychiatric Disorders: Major depressive disorder (MDD) is associated with HPA axis hyperactivity, with 20%-30% of patients with MDD showing hypercortisolemia. The post-awakening cortisol surge is more pronounced in those with MDD, and about half of patients with MDD also have high evening cortisol levels, suggesting disrupted diurnal cortisol rhythms.

Some patients with MDD have greater resistance to the feedback action of glucocorticoids on HPA axis activity, with weaker sensitivity often restored by effective pharmacotherapy of the depressive condition. Neuropsychiatric disorders are also associated with reduced activity of cortisol-deactivating enzymes. Posttraumatic stress disorder and anxiety are similarly associated with hypercortisolemia.

Addressing neuropsychiatric conditions with appropriate pharmacotherapy and psychotherapy can restore cortisol levels to normal proportions.
 

Diabetes, Obesity, and Metabolic Syndrome: Diabetes, obesity, and metabolic syndrome can occur comorbidly with CS, and many patients with these conditions may display both a rounder face, some central adiposity, and hypercortisolemia. For example, obesity is often related to a hyperresponsive HPA axis, with elevated cortisol secretion but normal-to-low circulatory concentrations.

Obesity is associated with increased cortisol reactivity after acute physical and/or psychosocial stressors but preserved pituitary sensitivity to feedback inhibition by the LDDST. When these conditions are appropriately managed with pharmacotherapy and lifestyle changes, cortisol levels should normalize, according to the experts.
 

Hypothyroidism: Hypothyroidism— Hashimoto disease as well as the subclinical variety — can be associated with weight gain, which may take the form of central obesity. Some research suggests a bidirectional relationship between hypothyroidism and obesity.

“Years ago, we didn’t conduct thyroid tests very often but now they’re easy to do, so we usually catch people with hypothyroidism at the beginning of the condition,” Sherif said. “If the patient’s thyroid hasn’t been checked in a year or so, thyroid hormone testing should be conducted.”

Thyroid disease can easily be managed with the administration of thyroid hormones.
 

Obstructive Sleep Apnea (OSA): OSA has an impact on HPA axis activation, especially when accompanied by obesity and hypertension. A meta-analysis of 22 studies, encompassing over 600 participants, found that continuous positive airway pressure treatment in patients with OSA reduced cortisol levels as well as blood pressure.

Treatment With Exogenous Corticosteroids: Oral corticosteroid treatment is a cornerstone of therapy in transplant, rheumatic, and autoimmune diseases. The impact of chronic exposure to exogenous glucocorticoids is similar to that with endogenous glucocorticoids.

Sherif said corticosteroid treatment can cause facial roundness in as little as 2 weeks and is characteristic in people taking these agents for longer periods. Although the effects are most pronounced with oral agents, systemic effects can be associated with inhaled corticosteroids as well.

Finding alternative anti-inflammatory treatments is advisable, if possible. The co-administration of metformin might lead to improvements in both the metabolic profile and the clinical outcomes of patients receiving glucocorticoids for inflammatory conditions.
 

Educating Patients: “There’s much we still don’t know about hypercortisolemia and CS, including the reasons for its impact on metabolic derangement and for the accumulation of fat in particular adipose patterns,” Ben-Shlomo said. “But experienced endocrinologists do know relatively well how to diagnose the condition, distinguish it from other conditions presenting with central obesity or a rounder face, and treat it.”

Given the casual use of the terms “moon face” and “extra cortisol” on social media, it’s important for physicians to educate patients about what elevated cortisol does and doesn’t do, and design treatment strategies accordingly.

Neither Ben-Shlomo nor Sherif reported having any disclosures.

A version of this article appeared on Medscape.com.

“Cortisol” has become a household word, popularized by social media and tagged in videos that garnered nearly 800 million views in 2023. This is linked to the also-trending term “moon face,” which TikTok influencers and others have suggested is caused by high cortisol levels and, conversely, can be reduced through stress reduction.

Although it’s true that cortisol is a hormone associated with stress, elevated stress levels are unlikely, by themselves, to cause the rounded facial features associated with “moon face.”

“When we hear the term ‘moon face,’ we’re typically referring to Cushing syndrome [CS] or treatment with prolonged high-dose glucocorticoids,” said Anat Ben-Shlomo, MD, co-director of the Multidisciplinary Adrenal Program, Pituitary Center, Division of Endocrinology, Diabetes and Metabolism at Cedars-Sinai Medical Center, Los Angeles. Medscape Medical News previously discussed moon face in an article detailing how to diagnose CS.

Ben-Shlomo noted that the labels “moon face” and “moon facies” should be avoided for their potentially derogatory, unprofessional-sounding connotations, and that the preferred terms are “rounded face” or “round plethoric face.”

There are several disorders that can be associated with facial roundness, not all of which relate to elevated cortisol.

“It’s important for clinicians to be able distinguish between presentations due to other pathophysiologies, identify the unique constellation of Cushing-associated signs and symptoms, engage in a differential diagnosis, and treat whatever the condition is appropriately,” Katherine Sherif, MD, professor and vice chair of academic affairs, Department of Medicine, Thomas Jefferson University, Philadelphia, said in an interview.
 

The Unique Presentation of CS

CS results from “prolonged elevation” in plasma cortisol levels caused by either exogenous steroid use or excess endogenous steroid production.

“The shape of the face isn’t the only feature associated with CS,” Ben-Shlomo said. “There’s central obesity, particularly in the neck, supraclavicular area, chest, and abdomen. You sometimes see a posterior cervical thoracic fat pad, colloquially — but unprofessionally — called a ‘cervical hump.’ Simultaneously, the arms and legs are getting thinner.” The development of a round, plethoric face is common in long-standing significant CS, and a reddening of the skin can appear.

Additional symptoms include hirsutism and acne. “These can also be seen in other conditions, such as PCOS [polycystic ovary syndrome] but, combined with the other facial features, are more suggestive of CS,” Ben-Shlomo said.

Deep, wide purple striae appear in the trunk, breast, upper arms, and thighs, but not in the face, Ben-Shlomo advised. These appear as the fragile, thinning under-skin breaks when the patient gains weight.

Additional metabolic issues that can occur comorbidly include insulin resistance and diabetes, hypertension, osteoporosis, dyslipidemia, ecchymoses, increased susceptibility to infections, mood changes, cognitive dysfunction, low libido, infertility, weakness of muscles in the shoulders and thighs, episodes of bleeding and/or clotting, and an increased risk for heart attacks and strokes, Ben-Shlomo said.

“Not everyone presents with full-blown disease, but if you see any of these symptoms, be suspicious of CS and conduct a biochemical evaluation.” Three screening tests to use as a starting point are recommended by the Pituitary Society’s updated Consensus on Diagnosis and Management of Cushing’s Disease. The tests should be repeated to account for intra-patient variability. If two or all three tests are positive, clinicians should be suspicious of CS and move to additional testing to identify the underlying cause, Ben-Shlomo said.
 

‘Subclinical’ CS

Ben-Shlomo highlighted a condition called minimal autonomous cortisol secretion (formerly “subclinical CS”). “This condition is found when a person has an adrenal nodule that produces cortisol in excess, however not to levels observed in CS. An abnormal finding on the overnight 1-mg low-dose dexamethasone suppression test (LDDST) will identify this disorder, showing mildly unsuppressed morning cortisol level, while all other tests will be within normal range.”

She described minimal autonomous cortisol secretion as a form of “smoldering CS,” which has become more commonly diagnosed. “The condition needs to be treated because the patient can develop insulin resistance, metabolic syndrome, and osteoporosis over time.”

Once a cause has been determined, the optimal course of action is to take a multidisciplinary approach because CS affects multiple systems.
 

‘Pseudo-Cushing Syndrome’

A variety of abnormalities of the hypothalamus-pituitary adrenal (HPA) axis can be associated with hypercortisolemia and a rounder facial appearance but aren’t actually CS, Ben-Shlomo said.

Often called “pseudo-Cushing syndrome,” these conditions have recently been renamed “non-neoplastic hypercortisolism” or “physiologic non-neoplastic endogenous hypercortisolism.” They share some clinical and biochemical features of CS, but the hypercortisolemia is usually secondary to other factors. They increase the secretion of hypothalamic corticotropin-releasing hormone, which stimulates adrenocorticotropic hormone (ACTH) and adrenal cortisol secretion.
 

Identifying PCOS

PCOS is often associated with central obesity, Sherif noted, but not all women with PCOS have overweight or a central distribution of fat.

“Ask about menstrual periods and whether they come monthly,” Sherif advised. “If women using hormonal contraception say they have a regular cycle, ask if their cycle was regular prior to starting contraception. So many women with PCOS are undiagnosed because they started contraception in their teens to ‘regulate their periods’ and never realized they had PCOS.”

Additional symptoms of PCOS and its impact are found in the figure below.

Medscape

• Irregular menstrual cycles
• Clinical hyperandrogenism or biochemical hyperandrogenism
• Polycystic ovarian morphology on transvaginal ultrasonography or high anti-mullerian hormone (applicable only if patient is ≥ 8 years from menarche)

If PCOS is suspected, further tests can be conducted to confirm or rule out the diagnosis.
 

Alcohol Abuse: Alcohol abuse stimulates hypothalamic corticotropin-releasing hormone, leading to increased ACTH levels. It’s associated with a higher fasting cortisol level, particularly at 8:30 AM or so, and attributable to impaired cortisol clearance due to alcohol-related hepatic dysfunction. The LDDST will show abnormal cortisol suppression.

Sherif advised asking patients about alcohol use, recommending treatment for alcohol use disorder, and repeating clinical and biochemical workup after patients have discontinued alcohol consumption for ≥ 1 month.
 

Eating Disorders Mimicking CS: Eating disorders, particularly anorexia nervosa, are associated with endocrine abnormalities, amenorrhea, impaired body temperature regulation, and hypercortisolism, likely due to chronic fasting-related stress. Dysregulation of the HPA axis may linger, even after weight recovery.

It’s unlikely that patients with anorexia will display the “rounded face” associated with hypercortisolism, but some research suggests that anorexia can result in a disproportionate accumulation of central adiposity after recovery from the illness.
 

Neuropsychiatric Disorders: Major depressive disorder (MDD) is associated with HPA axis hyperactivity, with 20%-30% of patients with MDD showing hypercortisolemia. The post-awakening cortisol surge is more pronounced in those with MDD, and about half of patients with MDD also have high evening cortisol levels, suggesting disrupted diurnal cortisol rhythms.

Some patients with MDD have greater resistance to the feedback action of glucocorticoids on HPA axis activity, with weaker sensitivity often restored by effective pharmacotherapy of the depressive condition. Neuropsychiatric disorders are also associated with reduced activity of cortisol-deactivating enzymes. Posttraumatic stress disorder and anxiety are similarly associated with hypercortisolemia.

Addressing neuropsychiatric conditions with appropriate pharmacotherapy and psychotherapy can restore cortisol levels to normal proportions.
 

Diabetes, Obesity, and Metabolic Syndrome: Diabetes, obesity, and metabolic syndrome can occur comorbidly with CS, and many patients with these conditions may display both a rounder face, some central adiposity, and hypercortisolemia. For example, obesity is often related to a hyperresponsive HPA axis, with elevated cortisol secretion but normal-to-low circulatory concentrations.

Obesity is associated with increased cortisol reactivity after acute physical and/or psychosocial stressors but preserved pituitary sensitivity to feedback inhibition by the LDDST. When these conditions are appropriately managed with pharmacotherapy and lifestyle changes, cortisol levels should normalize, according to the experts.
 

Hypothyroidism: Hypothyroidism— Hashimoto disease as well as the subclinical variety — can be associated with weight gain, which may take the form of central obesity. Some research suggests a bidirectional relationship between hypothyroidism and obesity.

“Years ago, we didn’t conduct thyroid tests very often but now they’re easy to do, so we usually catch people with hypothyroidism at the beginning of the condition,” Sherif said. “If the patient’s thyroid hasn’t been checked in a year or so, thyroid hormone testing should be conducted.”

Thyroid disease can easily be managed with the administration of thyroid hormones.
 

Obstructive Sleep Apnea (OSA): OSA has an impact on HPA axis activation, especially when accompanied by obesity and hypertension. A meta-analysis of 22 studies, encompassing over 600 participants, found that continuous positive airway pressure treatment in patients with OSA reduced cortisol levels as well as blood pressure.

Treatment With Exogenous Corticosteroids: Oral corticosteroid treatment is a cornerstone of therapy in transplant, rheumatic, and autoimmune diseases. The impact of chronic exposure to exogenous glucocorticoids is similar to that with endogenous glucocorticoids.

Sherif said corticosteroid treatment can cause facial roundness in as little as 2 weeks and is characteristic in people taking these agents for longer periods. Although the effects are most pronounced with oral agents, systemic effects can be associated with inhaled corticosteroids as well.

Finding alternative anti-inflammatory treatments is advisable, if possible. The co-administration of metformin might lead to improvements in both the metabolic profile and the clinical outcomes of patients receiving glucocorticoids for inflammatory conditions.
 

Educating Patients: “There’s much we still don’t know about hypercortisolemia and CS, including the reasons for its impact on metabolic derangement and for the accumulation of fat in particular adipose patterns,” Ben-Shlomo said. “But experienced endocrinologists do know relatively well how to diagnose the condition, distinguish it from other conditions presenting with central obesity or a rounder face, and treat it.”

Given the casual use of the terms “moon face” and “extra cortisol” on social media, it’s important for physicians to educate patients about what elevated cortisol does and doesn’t do, and design treatment strategies accordingly.

Neither Ben-Shlomo nor Sherif reported having any disclosures.

A version of this article appeared on Medscape.com.

“Cortisol” has become a household word, popularized by social media and tagged in videos that garnered nearly 800 million views in 2023. This is linked to the also-trending term “moon face,” which TikTok influencers and others have suggested is caused by high cortisol levels and, conversely, can be reduced through stress reduction.

Although it’s true that cortisol is a hormone associated with stress, elevated stress levels are unlikely, by themselves, to cause the rounded facial features associated with “moon face.”

“When we hear the term ‘moon face,’ we’re typically referring to Cushing syndrome [CS] or treatment with prolonged high-dose glucocorticoids,” said Anat Ben-Shlomo, MD, co-director of the Multidisciplinary Adrenal Program, Pituitary Center, Division of Endocrinology, Diabetes and Metabolism at Cedars-Sinai Medical Center, Los Angeles. Medscape Medical News previously discussed moon face in an article detailing how to diagnose CS.

Ben-Shlomo noted that the labels “moon face” and “moon facies” should be avoided for their potentially derogatory, unprofessional-sounding connotations, and that the preferred terms are “rounded face” or “round plethoric face.”

There are several disorders that can be associated with facial roundness, not all of which relate to elevated cortisol.

“It’s important for clinicians to be able distinguish between presentations due to other pathophysiologies, identify the unique constellation of Cushing-associated signs and symptoms, engage in a differential diagnosis, and treat whatever the condition is appropriately,” Katherine Sherif, MD, professor and vice chair of academic affairs, Department of Medicine, Thomas Jefferson University, Philadelphia, said in an interview.
 

The Unique Presentation of CS

CS results from “prolonged elevation” in plasma cortisol levels caused by either exogenous steroid use or excess endogenous steroid production.

“The shape of the face isn’t the only feature associated with CS,” Ben-Shlomo said. “There’s central obesity, particularly in the neck, supraclavicular area, chest, and abdomen. You sometimes see a posterior cervical thoracic fat pad, colloquially — but unprofessionally — called a ‘cervical hump.’ Simultaneously, the arms and legs are getting thinner.” The development of a round, plethoric face is common in long-standing significant CS, and a reddening of the skin can appear.

Additional symptoms include hirsutism and acne. “These can also be seen in other conditions, such as PCOS [polycystic ovary syndrome] but, combined with the other facial features, are more suggestive of CS,” Ben-Shlomo said.

Deep, wide purple striae appear in the trunk, breast, upper arms, and thighs, but not in the face, Ben-Shlomo advised. These appear as the fragile, thinning under-skin breaks when the patient gains weight.

Additional metabolic issues that can occur comorbidly include insulin resistance and diabetes, hypertension, osteoporosis, dyslipidemia, ecchymoses, increased susceptibility to infections, mood changes, cognitive dysfunction, low libido, infertility, weakness of muscles in the shoulders and thighs, episodes of bleeding and/or clotting, and an increased risk for heart attacks and strokes, Ben-Shlomo said.

“Not everyone presents with full-blown disease, but if you see any of these symptoms, be suspicious of CS and conduct a biochemical evaluation.” Three screening tests to use as a starting point are recommended by the Pituitary Society’s updated Consensus on Diagnosis and Management of Cushing’s Disease. The tests should be repeated to account for intra-patient variability. If two or all three tests are positive, clinicians should be suspicious of CS and move to additional testing to identify the underlying cause, Ben-Shlomo said.
 

‘Subclinical’ CS

Ben-Shlomo highlighted a condition called minimal autonomous cortisol secretion (formerly “subclinical CS”). “This condition is found when a person has an adrenal nodule that produces cortisol in excess, however not to levels observed in CS. An abnormal finding on the overnight 1-mg low-dose dexamethasone suppression test (LDDST) will identify this disorder, showing mildly unsuppressed morning cortisol level, while all other tests will be within normal range.”

She described minimal autonomous cortisol secretion as a form of “smoldering CS,” which has become more commonly diagnosed. “The condition needs to be treated because the patient can develop insulin resistance, metabolic syndrome, and osteoporosis over time.”

Once a cause has been determined, the optimal course of action is to take a multidisciplinary approach because CS affects multiple systems.
 

‘Pseudo-Cushing Syndrome’

A variety of abnormalities of the hypothalamus-pituitary adrenal (HPA) axis can be associated with hypercortisolemia and a rounder facial appearance but aren’t actually CS, Ben-Shlomo said.

Often called “pseudo-Cushing syndrome,” these conditions have recently been renamed “non-neoplastic hypercortisolism” or “physiologic non-neoplastic endogenous hypercortisolism.” They share some clinical and biochemical features of CS, but the hypercortisolemia is usually secondary to other factors. They increase the secretion of hypothalamic corticotropin-releasing hormone, which stimulates adrenocorticotropic hormone (ACTH) and adrenal cortisol secretion.
 

Identifying PCOS

PCOS is often associated with central obesity, Sherif noted, but not all women with PCOS have overweight or a central distribution of fat.

“Ask about menstrual periods and whether they come monthly,” Sherif advised. “If women using hormonal contraception say they have a regular cycle, ask if their cycle was regular prior to starting contraception. So many women with PCOS are undiagnosed because they started contraception in their teens to ‘regulate their periods’ and never realized they had PCOS.”

Additional symptoms of PCOS and its impact are found in the figure below.

Medscape

• Irregular menstrual cycles
• Clinical hyperandrogenism or biochemical hyperandrogenism
• Polycystic ovarian morphology on transvaginal ultrasonography or high anti-mullerian hormone (applicable only if patient is ≥ 8 years from menarche)

If PCOS is suspected, further tests can be conducted to confirm or rule out the diagnosis.
 

Alcohol Abuse: Alcohol abuse stimulates hypothalamic corticotropin-releasing hormone, leading to increased ACTH levels. It’s associated with a higher fasting cortisol level, particularly at 8:30 AM or so, and attributable to impaired cortisol clearance due to alcohol-related hepatic dysfunction. The LDDST will show abnormal cortisol suppression.

Sherif advised asking patients about alcohol use, recommending treatment for alcohol use disorder, and repeating clinical and biochemical workup after patients have discontinued alcohol consumption for ≥ 1 month.
 

Eating Disorders Mimicking CS: Eating disorders, particularly anorexia nervosa, are associated with endocrine abnormalities, amenorrhea, impaired body temperature regulation, and hypercortisolism, likely due to chronic fasting-related stress. Dysregulation of the HPA axis may linger, even after weight recovery.

It’s unlikely that patients with anorexia will display the “rounded face” associated with hypercortisolism, but some research suggests that anorexia can result in a disproportionate accumulation of central adiposity after recovery from the illness.
 

Neuropsychiatric Disorders: Major depressive disorder (MDD) is associated with HPA axis hyperactivity, with 20%-30% of patients with MDD showing hypercortisolemia. The post-awakening cortisol surge is more pronounced in those with MDD, and about half of patients with MDD also have high evening cortisol levels, suggesting disrupted diurnal cortisol rhythms.

Some patients with MDD have greater resistance to the feedback action of glucocorticoids on HPA axis activity, with weaker sensitivity often restored by effective pharmacotherapy of the depressive condition. Neuropsychiatric disorders are also associated with reduced activity of cortisol-deactivating enzymes. Posttraumatic stress disorder and anxiety are similarly associated with hypercortisolemia.

Addressing neuropsychiatric conditions with appropriate pharmacotherapy and psychotherapy can restore cortisol levels to normal proportions.
 

Diabetes, Obesity, and Metabolic Syndrome: Diabetes, obesity, and metabolic syndrome can occur comorbidly with CS, and many patients with these conditions may display both a rounder face, some central adiposity, and hypercortisolemia. For example, obesity is often related to a hyperresponsive HPA axis, with elevated cortisol secretion but normal-to-low circulatory concentrations.

Obesity is associated with increased cortisol reactivity after acute physical and/or psychosocial stressors but preserved pituitary sensitivity to feedback inhibition by the LDDST. When these conditions are appropriately managed with pharmacotherapy and lifestyle changes, cortisol levels should normalize, according to the experts.
 

Hypothyroidism: Hypothyroidism— Hashimoto disease as well as the subclinical variety — can be associated with weight gain, which may take the form of central obesity. Some research suggests a bidirectional relationship between hypothyroidism and obesity.

“Years ago, we didn’t conduct thyroid tests very often but now they’re easy to do, so we usually catch people with hypothyroidism at the beginning of the condition,” Sherif said. “If the patient’s thyroid hasn’t been checked in a year or so, thyroid hormone testing should be conducted.”

Thyroid disease can easily be managed with the administration of thyroid hormones.
 

Obstructive Sleep Apnea (OSA): OSA has an impact on HPA axis activation, especially when accompanied by obesity and hypertension. A meta-analysis of 22 studies, encompassing over 600 participants, found that continuous positive airway pressure treatment in patients with OSA reduced cortisol levels as well as blood pressure.

Treatment With Exogenous Corticosteroids: Oral corticosteroid treatment is a cornerstone of therapy in transplant, rheumatic, and autoimmune diseases. The impact of chronic exposure to exogenous glucocorticoids is similar to that with endogenous glucocorticoids.

Sherif said corticosteroid treatment can cause facial roundness in as little as 2 weeks and is characteristic in people taking these agents for longer periods. Although the effects are most pronounced with oral agents, systemic effects can be associated with inhaled corticosteroids as well.

Finding alternative anti-inflammatory treatments is advisable, if possible. The co-administration of metformin might lead to improvements in both the metabolic profile and the clinical outcomes of patients receiving glucocorticoids for inflammatory conditions.
 

Educating Patients: “There’s much we still don’t know about hypercortisolemia and CS, including the reasons for its impact on metabolic derangement and for the accumulation of fat in particular adipose patterns,” Ben-Shlomo said. “But experienced endocrinologists do know relatively well how to diagnose the condition, distinguish it from other conditions presenting with central obesity or a rounder face, and treat it.”

Given the casual use of the terms “moon face” and “extra cortisol” on social media, it’s important for physicians to educate patients about what elevated cortisol does and doesn’t do, and design treatment strategies accordingly.

Neither Ben-Shlomo nor Sherif reported having any disclosures.

A version of this article appeared on Medscape.com.

More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.^1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.³ About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m², persisting for ≥ 3 months.⁴

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.

According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.³ SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.⁵ The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A_1c (HbA_1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.

Methods

The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.

Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m², and had an initial HbA_1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA_1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m²) compared with stage 3a (eGFR 45-59 mL/min/1.73 m²) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA_1c < 7%, 30 had HbA_1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m², 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m², 1 had no baseline eGFR, and 1 was the spouse of a veteran.

Statistical Analysis

All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.

Results

Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.

The primary endpoint was the differences in HbA_1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA_1c levels were statistically significant (Table 2). HbA_1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).

Secondary Endpoint

There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).

Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).

Discussion

This study showed a statistically significant change in HbA_1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m², patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.

The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA_1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.^6,7,8

Limitations

This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.

Patients with eGFR < 30 mL/min/1.73 m² make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.⁹ Furthermore, many veterans had an initial HbA_1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.

Conclusions

While the reduction in HbA_1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA_1c levels in patients with CKD.

More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.^1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.³ About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m², persisting for ≥ 3 months.⁴

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.

According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.³ SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.⁵ The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A_1c (HbA_1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.

Methods

The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.

Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m², and had an initial HbA_1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA_1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m²) compared with stage 3a (eGFR 45-59 mL/min/1.73 m²) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA_1c < 7%, 30 had HbA_1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m², 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m², 1 had no baseline eGFR, and 1 was the spouse of a veteran.

Statistical Analysis

All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.

Results

Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.

The primary endpoint was the differences in HbA_1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA_1c levels were statistically significant (Table 2). HbA_1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).

Secondary Endpoint

There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).

Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).

Discussion

This study showed a statistically significant change in HbA_1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m², patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.

The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA_1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.^6,7,8

Limitations

This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.

Patients with eGFR < 30 mL/min/1.73 m² make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.⁹ Furthermore, many veterans had an initial HbA_1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.

Conclusions

While the reduction in HbA_1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA_1c levels in patients with CKD.

More than 37 million Americans have diabetes mellitus (DM), and approximately 90% have type 2 DM (T2DM), including about 25% of veterans.^1,2 The current guidelines suggest that therapy depends on a patient's comorbidities, management needs, and patient-centered treatment factors.³ About 1 in 3 adults with DM have chronic kidney disease (CKD), defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m², persisting for ≥ 3 months.⁴

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. They exert their effects by preventing the reabsorption of filtered glucose from the tubular lumen. There are 4 SGLT-2 inhibitors approved by the US Food and Drug Administration: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Empagliflozin is currently the preferred SGLT-2 inhibitor on the US Department of Veterans Affairs (VA) formulary.

According to the American Diabetes Association guidelines, empagliflozin is considered when an individual has or is at risk for atherosclerotic cardiovascular disease, heart failure, and CKD.³ SGLT-2 inhibitors are a favorable option due to their low risk for hypoglycemia while also promoting weight loss. The EMPEROR-Reduced trial demonstrated that, in addition to benefits for patients with heart failure, empagliflozin also slowed the progressive decline in kidney function in those with and without DM.⁵ The purpose of this study was to evaluate the effectiveness of empagliflozin on hemoglobin A_1c (HbA_1c) levels in patients with CKD at the Hershel “Woody” Williams VA Medical Center (HWWVAMC) in Huntington, West Virginia, along with other laboratory test markers.

Methods

The Marshall University Institutional Review Board #1 (Medical) and the HWWVAMC institutional review board and research and development committee each reviewed and approved this study. A retrospective chart review was conducted on patients diagnosed with T2DM and stage 3 CKD who were prescribed empagliflozin for DM management between January 1, 2015, and October 1, 2022, yielding 1771 patients. Data were obtained through the VHA Corporate Data Warehouse (CDW) and stored on the VA Informatics and Computing Infrastructure (VINCI) research server.

Patients were included if they were aged 18 to 89 years, prescribed empagliflozin by a VA clinician for the treatment of T2DM, had an eGFR between 30 and 59 mL/min/1.73 m², and had an initial HbA_1c between 7% and 10%. Using further random sampling, patients were either excluded or divided into, those with stage 3a CKD and those with stage 3b CKD. The primary endpoint of this study was the change in HbA_1c levels in patients with stage 3b CKD (eGFR 30-44 mL/min/1.73 m²) compared with stage 3a (eGFR 45-59 mL/min/1.73 m²) after 12 months. The secondary endpoints included effects on renal function, weight, blood pressure, incidence of adverse drug events, and cardiovascular events. Of the excluded, 38 had HbA_1c < 7%, 30 had HbA_1c ≥ 10%, 21 did not have data at 1-year mark, 15 had the medication discontinued due to decline in renal function, 14 discontinued their medication without documented reason, 10 discontinued their medication due to adverse drug reactions (ADRs), 12 had eGFR > 60 mL/ min/1.73 m², 9 died within 1 year of initiation, 4 had eGFR < 30 mL/min/1.73 m², 1 had no baseline eGFR, and 1 was the spouse of a veteran.

Statistical Analysis

All statistical analyses were performed using STATA v.15. We used t tests to examine changes within each group, along with paired t tests to compare the 2 groups. Two-sample t tests were used to analyze the continuous data at both the primary and secondary endpoints.

Results

Of the 1771 patients included in the initial data set, a randomized sample of 255 charts were reviewed, 155 were excluded, and 100 were included. Fifty patients, had stage 3a CKD and 50 had stage 3b CKD. Baseline demographics were similar between the stage 3a and 3b groups (Table 1). Both groups were predominantly White and male, with mean age > 70 years.

The primary endpoint was the differences in HbA_1c levels over time and between groups for patients with stage 3a and stage 3b CKD 1 year after initiation of empagliflozin. The starting doses of empagliflozin were either 12.5 mg or 25.0 mg. For both groups, the changes in HbA_1c levels were statistically significant (Table 2). HbA_1c levels dropped 0.65% for the stage 3a group and 0.48% for the 3b group. When compared to one another, the results were not statistically significant (P = .51).

Secondary Endpoint

There was no statistically significant difference in serum creatinine levels within each group between baselines and 1 year later for the stage 3a (P = .21) and stage 3b (P = .22) groups, or when compared to each other (P = .67). There were statistically significant changes in weight for patients in the stage 3a group (P < .05), but not for stage 3b group (P = .06) or when compared to each other (P = .41). A statistically significant change in systolic blood pressure was observed for the stage 3a group (P = .003), but not the stage 3b group (P = .16) or when compared to each other (P = .27). There were statistically significant changes in diastolic blood pressure within the stage 3a group (P = .04), but not within the stage 3b group (P = .61) or when compared to each other (P = .31).

Ten patients discontinued empagliflozin before the 1-year mark due to ADRs, including dizziness, increased incidence of urinary tract infections, rash, and tachycardia (Table 3). Additionally, 3 ADRs resulted in the empagliflozin discontinuation after 1 year (Table 3).

Discussion

This study showed a statistically significant change in HbA_1c levels for patients with stage 3a and stage 3b CKD. With eGFR levels in these 2 groups > 30 mL/min/1.73 m², patients were able to achieve glycemic benefits. There were no significant changes to the serum creatinine levels. Both groups saw statistically significant changes in weight loss within their own group; however, there were no statistically significant changes when compared to each other. With both systolic and diastolic blood pressure, the stage 3a group had statistically significant changes.

The EMPA-REG BP study demonstrated that empagliflozin was associated with significant and clinically meaningful reductions in blood pressure and HbA_1c levels compared with placebo and was well tolerated in patients with T2DM and hypertension.^6,7,8

Limitations

This study had a retrospective study design, which resulted in missing information for many patients and higher rates of exclusion. The population was predominantly older, White, and male and may not reflect other populations. The starting doses of empagliflozin varied between the groups. The VA employs tablet splitting for some patients, and the available doses were either 10.0 mg, 12.5 mg, or 25.0 mg. Some prescribers start veterans at lower doses and gradually increase to the higher dose of 25.0 mg, adding to the variability in starting doses.

Patients with eGFR < 30 mL/min/1.73 m² make it difficult to determine any potential benefit in this population. The EMPA-KIDNEY trial demonstrated that the benefits of empagliflozin treatment were consistent among patients with or without DM and regardless of eGFR at randomization.⁹ Furthermore, many veterans had an initial HbA_1c levels outside the inclusion criteria range, which was a factor in the smaller sample size.

Conclusions

While the reduction in HbA_1c levels was less in patients with stage 3b CKD compared to patients stage 3a CKD, all patients experienced a benefit. The overall incidence of ADRs was low in the study population, showing empagliflozin as a favorable choice for those with T2DM and CKD. Based on the findings of this study, empagliflozin is a potentially beneficial option for reducing HbA_1c levels in patients with CKD.

VIENNA — Researchers have determined a bidirectional relationship between inflammatory bowel disease (IBD) and type 1 diabetes (T1D), using both a cohort and case-control approach to analysis.

Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.

Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.

“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.

Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.

Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
 

Exploring the Bidirectional Relationship 

Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.

These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.

In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors. 

The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).

The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.

The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.

Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.

In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.

In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.

Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.

That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.

“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”

Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”

“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.

Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.

Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.

A version of this article appeared on Medscape.com.

VIENNA — Researchers have determined a bidirectional relationship between inflammatory bowel disease (IBD) and type 1 diabetes (T1D), using both a cohort and case-control approach to analysis.

Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.

Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.

“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.

Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.

Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
 

Exploring the Bidirectional Relationship 

Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.

These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.

In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors. 

The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).

The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.

The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.

Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.

In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.

In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.

Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.

That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.

“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”

Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”

“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.

Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.

Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.

A version of this article appeared on Medscape.com.

VIENNA — Researchers have determined a bidirectional relationship between inflammatory bowel disease (IBD) and type 1 diabetes (T1D), using both a cohort and case-control approach to analysis.

Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.

Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.

“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.

Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.

Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
 

Exploring the Bidirectional Relationship 

Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.

These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.

In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors. 

The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).

The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.

The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.

Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.

In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.

In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.

Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.

That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.

“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”

Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”

“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.

Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.

Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.

A version of this article appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

SAN ANTONIO, TEXAS — An upcoming document will entirely reframe obesity as a “condition of excess adiposity” that constitutes a disease called “clinical obesity” when related tissue and organ abnormalities are present.

The authors of the new framework are a Lancet Commission of 56 of the world’s leading obesity experts, including academic clinicians, scientists, public health experts, patient representatives, and officers from the World Health Organization. Following peer review, it will be launched via livestream and published in Lancet Diabetes & Endocrinology in mid-January 2025, with formal endorsement from more than 75 medical societies and other relevant stakeholder organizations.

On November 4, 2024, at the Obesity Society’s Obesity Week meeting, the publication’s lead author, Francesco Rubino, MD, Chair of Bariatric and Metabolic Surgery at King’s College London in England, gave a preview. He began by noting that, despite the declaration of obesity as a chronic disease over a decade ago, the concept is still debated and not widely accepted by the public or even by all in the medical community.

“The idea of obesity as a disease remains highly controversial,” Rubino noted, adding that the current body mass index (BMI)–based definition contributes to this because it doesn’t distinguish between people whose excess adiposity place them at excess risk for disease but they’re currently healthy vs those who already have undergone bodily harm from that adiposity.

“Having a framework that distinguishes at an individual level when you are in a condition of risk and when you have a condition of disease is fundamentally important. You don’t want to blur the picture in either direction, because obviously the consequence would be quite significant. ... So, the commission focused exactly on that point,” he said.

The new paper will propose a two-part clinical approach: First, assess whether the patient has excess adiposity, with methods that will be outlined. Next, assess on an organ-by-organ basis for the presence of abnormalities related to excess adiposity, or “clinical obesity.” The document will also provide those specific criteria, Rubino said, noting that those details are under embargo until January.

However, he did say that “We are going to propose a pragmatic approach to say that BMI alone is not enough in the clinic. It’s okay as a screening tool, but when somebody potentially has obesity, then you have to add additional measures of adiposity that makes sure you decrease the level of risk… Once you have obesity, then you need to establish if it’s clinical or nonclinical.”

Asked to comment, session moderator John D. Clark, MD, PhD, Chief Population Health Officer at Sharp Rees-Stealy Medical Group, San Diego, California, said in an interview, “I think it’ll help explain and move medicine as a whole in a direction to a greater understanding of obesity actually being a disease, how to define it, and how to identify it. And will, I think, lead to a greater understanding of the underlying disease.”

And, Clark said, it should also help target individuals with preventive vs therapeutic approaches. “I would describe it as matching the right tool to the right patient. If a person has clinical obesity, they likely can and would benefit from either different or additional tools, as opposed to otherwise healthy obesity.”

Rubino said he hopes the new framework will prompt improvements in reimbursement and public policy. “Policymakers scratch their heads when they have limited resources and you need to prioritize things. Having an obesity definition that is blurry doesn’t allow you to have a fair, human, and meaningful prioritization. ... Now that we have drugs that cannot be given to 100% of people, how do you decide who gets them first? I hope this will make it easier for people to access treatment. At the moment, it is not only difficult, but it’s also unfair. It’s random. Somebody gets access, while somebody else who is very, very sick has no access. I don’t think that’s what we want.”

A version of this article appeared on Medscape.com.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

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