Clinical Endocrinology News

TOPLINE:

Isotretinoin was effective in treating acne in individuals undergoing masculinizing gender-affirming hormone therapy in a case series, but more information is needed on dosing and barriers to treatment.

METHODOLOGY:

• Acne can be a side effect of masculinizing hormone therapy for transmasculine individuals. While isotretinoin is an effective treatment option for acne, its effectiveness and safety in transgender and gender-diverse individuals are not well understood.
• This retrospective case series included 55 patients (mean age, 25.4 years) undergoing masculinizing hormone therapy at four medical centers, who were prescribed isotretinoin for acne associated with treatment.
• Isotretinoin treatment was started a median of 22.1 months after hormone therapy was initiated and continued for a median of 6 months with a median cumulative dose of 132.7 mg/kg.
• Researchers assessed acne improvement, clearance, recurrence, adverse effects, and reasons for treatment discontinuation.

TAKEAWAY:

• Overall, 48 patients (87.3%) experienced improvement, and 26 (47.3%) achieved clearance during treatment. A higher proportion of patients experienced improvement (97% vs 72.7%) and achieved clearance (63.6% vs 22.7%) with cumulative doses of ≥ 120 mg/kg than those who received cumulative doses < 120 mg/kg.
• The risk for recurrence was 20% (in four patients) among 20 patients who achieved clearance and had any subsequent health care encounters, with a mean follow-up time of 734.3 days.
• Common adverse effects included dryness (80%), joint pain (14.5%), and headaches (10.9%). Other adverse effects included nose bleeds (9.1%) and depression (5.5%).
• Of the 22 patients with a cumulative dose < 120 mg/kg, 14 (63.6%) were lost to follow-up; among those not lost to follow-up, 2 patients discontinued treatment because of transfer of care, 1 because of adverse effects, and 1 because of gender-affirming surgery, with concerns about wound healing.

IN PRACTICE:

“Although isotretinoin appears to be an effective treatment option for acne among individuals undergoing masculinizing hormone therapy, further efforts are needed to understand optimal dosing and treatment barriers to improve outcomes in transgender and gender-diverse individuals receiving testosterone,” the authors concluded.

SOURCE:

The study, led by James Choe, BS, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, was published online in JAMA Dermatology.

LIMITATIONS:

The study population was limited to four centers, and variability in clinician- and patient-reported acne outcomes and missing information could affect the reliability of data. Because of the small sample size, the association of masculinizing hormone therapy regimens with outcomes could not be evaluated.

DISCLOSURES:

One author is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Three authors reported receiving grants or personal fees from various sources. The other authors declared no conflicts of interest.

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

TOPLINE:

Isotretinoin was effective in treating acne in individuals undergoing masculinizing gender-affirming hormone therapy in a case series, but more information is needed on dosing and barriers to treatment.

METHODOLOGY:

• Acne can be a side effect of masculinizing hormone therapy for transmasculine individuals. While isotretinoin is an effective treatment option for acne, its effectiveness and safety in transgender and gender-diverse individuals are not well understood.
• This retrospective case series included 55 patients (mean age, 25.4 years) undergoing masculinizing hormone therapy at four medical centers, who were prescribed isotretinoin for acne associated with treatment.
• Isotretinoin treatment was started a median of 22.1 months after hormone therapy was initiated and continued for a median of 6 months with a median cumulative dose of 132.7 mg/kg.
• Researchers assessed acne improvement, clearance, recurrence, adverse effects, and reasons for treatment discontinuation.

TAKEAWAY:

• Overall, 48 patients (87.3%) experienced improvement, and 26 (47.3%) achieved clearance during treatment. A higher proportion of patients experienced improvement (97% vs 72.7%) and achieved clearance (63.6% vs 22.7%) with cumulative doses of ≥ 120 mg/kg than those who received cumulative doses < 120 mg/kg.
• The risk for recurrence was 20% (in four patients) among 20 patients who achieved clearance and had any subsequent health care encounters, with a mean follow-up time of 734.3 days.
• Common adverse effects included dryness (80%), joint pain (14.5%), and headaches (10.9%). Other adverse effects included nose bleeds (9.1%) and depression (5.5%).
• Of the 22 patients with a cumulative dose < 120 mg/kg, 14 (63.6%) were lost to follow-up; among those not lost to follow-up, 2 patients discontinued treatment because of transfer of care, 1 because of adverse effects, and 1 because of gender-affirming surgery, with concerns about wound healing.

IN PRACTICE:

“Although isotretinoin appears to be an effective treatment option for acne among individuals undergoing masculinizing hormone therapy, further efforts are needed to understand optimal dosing and treatment barriers to improve outcomes in transgender and gender-diverse individuals receiving testosterone,” the authors concluded.

SOURCE:

The study, led by James Choe, BS, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, was published online in JAMA Dermatology.

LIMITATIONS:

The study population was limited to four centers, and variability in clinician- and patient-reported acne outcomes and missing information could affect the reliability of data. Because of the small sample size, the association of masculinizing hormone therapy regimens with outcomes could not be evaluated.

DISCLOSURES:

One author is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Three authors reported receiving grants or personal fees from various sources. The other authors declared no conflicts of interest.

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

TOPLINE:

Isotretinoin was effective in treating acne in individuals undergoing masculinizing gender-affirming hormone therapy in a case series, but more information is needed on dosing and barriers to treatment.

METHODOLOGY:

• Acne can be a side effect of masculinizing hormone therapy for transmasculine individuals. While isotretinoin is an effective treatment option for acne, its effectiveness and safety in transgender and gender-diverse individuals are not well understood.
• This retrospective case series included 55 patients (mean age, 25.4 years) undergoing masculinizing hormone therapy at four medical centers, who were prescribed isotretinoin for acne associated with treatment.
• Isotretinoin treatment was started a median of 22.1 months after hormone therapy was initiated and continued for a median of 6 months with a median cumulative dose of 132.7 mg/kg.
• Researchers assessed acne improvement, clearance, recurrence, adverse effects, and reasons for treatment discontinuation.

TAKEAWAY:

• Overall, 48 patients (87.3%) experienced improvement, and 26 (47.3%) achieved clearance during treatment. A higher proportion of patients experienced improvement (97% vs 72.7%) and achieved clearance (63.6% vs 22.7%) with cumulative doses of ≥ 120 mg/kg than those who received cumulative doses < 120 mg/kg.
• The risk for recurrence was 20% (in four patients) among 20 patients who achieved clearance and had any subsequent health care encounters, with a mean follow-up time of 734.3 days.
• Common adverse effects included dryness (80%), joint pain (14.5%), and headaches (10.9%). Other adverse effects included nose bleeds (9.1%) and depression (5.5%).
• Of the 22 patients with a cumulative dose < 120 mg/kg, 14 (63.6%) were lost to follow-up; among those not lost to follow-up, 2 patients discontinued treatment because of transfer of care, 1 because of adverse effects, and 1 because of gender-affirming surgery, with concerns about wound healing.

IN PRACTICE:

“Although isotretinoin appears to be an effective treatment option for acne among individuals undergoing masculinizing hormone therapy, further efforts are needed to understand optimal dosing and treatment barriers to improve outcomes in transgender and gender-diverse individuals receiving testosterone,” the authors concluded.

SOURCE:

The study, led by James Choe, BS, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, was published online in JAMA Dermatology.

LIMITATIONS:

The study population was limited to four centers, and variability in clinician- and patient-reported acne outcomes and missing information could affect the reliability of data. Because of the small sample size, the association of masculinizing hormone therapy regimens with outcomes could not be evaluated.

DISCLOSURES:

One author is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Three authors reported receiving grants or personal fees from various sources. The other authors declared no conflicts of interest.

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

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

Do drugs work better if taken by the clock?

A new analysis published in The Lancet journal’s eClinicalMedicine suggests: Yes, they do — if you consider the patient’s individual body clock. The study is the first to find that timing blood pressure drugs to a person’s personal “chronotype” — that is, whether they are a night owl or an early bird — may reduce the risk for a heart attack.

The findings represent a significant advance in the field of circadian medicine or “chronotherapy” — timing drug administration to circadian rhythms. A growing stack of research suggests this approach could reduce side effects and improve the effectiveness of a wide range of therapies, including vaccines, cancer treatments, and drugs for depression, glaucoma, pain, seizures, and other conditions. Still, despite decades of research, time of day is rarely considered in writing prescriptions.

“We are really just at the beginning of an exciting new way of looking at patient care,” said Kenneth A. Dyar, PhD, whose lab at Helmholtz Zentrum München’s Institute for Diabetes and Cancer focuses on metabolic physiology. Dr. Dyar is co-lead author of the new blood pressure analysis.

“Chronotherapy is a rapidly growing field,” he said, “and I suspect we are soon going to see more and more studies focused on ‘personalized chronotherapy,’ not only in hypertension but also potentially in other clinical areas.”
 

The ‘Missing Piece’ in Chronotherapy Research

Blood pressure drugs have long been chronotherapy’s battleground. After all, blood pressure follows a circadian rhythm, peaking in the morning and dropping at night.

That healthy overnight dip can disappear in people with diabetes, kidney disease, and obstructive sleep apnea. Some physicians have suggested a bed-time dose to restore that dip. But studies have had mixed results, so “take at bedtime” has become a less common recommendation in recent years.

But the debate continued. After a large 2019 Spanish study found that bedtime doses had benefits so big that the results drew questions, an even larger, 2022 randomized, controlled trial from the University of Dundee in Dundee, Scotland — called the TIME study — aimed to settle the question.

Researchers assigned over 21,000 people to take morning or night hypertension drugs for several years and found no difference in cardiovascular outcomes.

“We did this study thinking nocturnal blood pressure tablets might be better,” said Thomas MacDonald, MD, professor emeritus of clinical pharmacology and pharmacoepidemiology at the University of Dundee and principal investigator for the TIME study and the recent chronotype analysis. “But there was no difference for heart attacks, strokes, or vascular death.”

So, the researchers then looked at participants’ chronotypes, sorting outcomes based on whether the participants were late-to-bed, late-to-rise “night owls” or early-to-bed, early-to-rise “morning larks.”

Their analysis of these 5358 TIME participants found the following results: Risk for hospitalization for a heart attack was at least 34% lower for “owls” who took their drugs at bedtime. By contrast, owls’ heart attack risk was at least 62% higher with morning doses. For “larks,” the opposite was true. Morning doses were associated with an 11% lower heart attack risk and night doses with an 11% higher risk, according to supplemental data.

The personalized approach could explain why some previous chronotherapy studies have failed to show a benefit. Those studies did not individualize drug timing as this one did. But personalization could be key to circadian medicine’s success.

“Our ‘internal personal time’ appears to be an important variable to consider when dosing antihypertensives,” said co-lead author Filippo Pigazzani, MD, PhD, clinical senior lecturer and honorary consultant cardiologist at the University of Dundee School of Medicine. “Chronotherapy research has been going on for decades. We knew there was something important with time of day. But researchers haven’t considered the internal time of individual people. I think that is the missing piece.”

The analysis has several important limitations, the researchers said. A total of 95% of participants were White. And it was an observational study, not a true randomized comparison. “We started it late in the original TIME study,” Dr. MacDonald said. “You could argue we were reporting on those who survived long enough to get into the analysis.” More research is needed, they concluded.
 

Looking Beyond Blood Pressure

What about the rest of the body? “Almost all the cells of our body contain ‘circadian clocks’ that are synchronized by daily environmental cues, including light-dark, activity-rest, and feeding-fasting cycles,” said Dr. Dyar.

An estimated 50% of prescription drugs hit targets in the body that have circadian patterns. So, experts suspect that syncing a drug with a person’s body clock might increase effectiveness of many drugs.

A handful of US Food and Drug Administration–approved drugs already have time-of-day recommendations on the label for effectiveness or to limit side effects, including bedtime or evening for the insomnia drug Ambien, the HIV antiviral Atripla, and cholesterol-lowering Zocor. Others are intended to be taken with or after your last meal of the day, such as the long-acting insulin Levemir and the cardiovascular drug Xarelto. A morning recommendation comes with the proton pump inhibitor Nexium and the attention-deficit/hyperactivity disorder drug Ritalin.

Interest is expanding. About one third of the papers published about chronotherapy in the past 25 years have come out in the past 5 years. The May 2024 meeting of the Society for Research on Biological Rhythms featured a day-long session aimed at bringing clinicians up to speed. An organization called the International Association of Circadian Health Clinics is trying to bring circadian medicine findings to clinicians and their patients and to support research.

Moreover, while recent research suggests minding the clock could have benefits for a wide range of treatments, ignoring it could cause problems.

In a Massachusetts Institute of Technology study published in April in Science Advances, researchers looked at engineered livers made from human donor cells and found more than 300 genes that operate on a circadian schedule, many with roles in drug metabolism. They also found that circadian patterns affected the toxicity of acetaminophen and atorvastatin. Identifying the time of day to take these drugs could maximize effectiveness and minimize adverse effects, the researchers said.
 

Timing and the Immune System

Circadian rhythms are also seen in immune processes. In a 2023 study in The Journal of Clinical Investigation of vaccine data from 1.5 million people in Israel, researchers found that children and older adults who got their second dose of the Pfizer mRNA COVID vaccine earlier in the day were about 36% less likely to be hospitalized with SARS-CoV-2 infection than those who got an evening shot.

“The sweet spot in our data was somewhere around late morning to late afternoon,” said lead researcher Jeffrey Haspel, MD, PhD, associate professor of medicine in the division of pulmonary and critical care medicine at Washington University School of Medicine in St. Louis.

In a multicenter, 2024 analysis of 13 studies of immunotherapy for advanced cancers in 1663 people, researchers found treatment earlier in the day was associated with longer survival time and longer survival without cancer progression.

“Patients with selected metastatic cancers seemed to largely benefit from early [time of day] infusions, which is consistent with circadian mechanisms in immune-cell functions and trafficking,” the researchers noted. But “retrospective randomized trials are needed to establish recommendations for optimal circadian timing.”

Other research suggests or is investigating possible chronotherapy benefits for depression, glaucoma, respiratory diseases, stroke treatment, epilepsy, and sedatives used in surgery. So why aren’t healthcare providers adding time of day to more prescriptions? “What’s missing is more reliable data,” Dr. Dyar said.
 

Should You Use Chronotherapy Now?

Experts emphasize that more research is needed before doctors use chronotherapy and before medical organizations include it in treatment recommendations. But for some patients, circadian dosing may be worth a try:

Night owls whose blood pressure isn’t well controlled. Dr. Dyar and Dr. Pigazzani said night-time blood pressure drugs may be helpful for people with a “late chronotype.” Of course, patients shouldn’t change their medication schedule on their own, they said. And doctors may want to consider other concerns, like more overnight bathroom visits with evening diuretics.

In their study, the researchers determined participants’ chronotype with a few questions from the Munich Chronotype Questionnaire about what time they fell asleep and woke up on workdays and days off and whether they considered themselves “morning types” or “evening types.” (The questions can be found in supplementary data for the study.)

If a physician thinks matching the timing of a dose with chronotype would help, they can consider it, Dr. Pigazzani said. “However, I must add that this was an observational study, so I would advise healthcare practitioners to wait for our data to be confirmed in new RCTs of personalized chronotherapy of hypertension.”

Children and older adults getting vaccines. Timing COVID shots and possibly other vaccines from late morning to mid-afternoon could have a small benefit for individuals and a bigger public-health benefit, Dr. Haspel said. But the most important thing is getting vaccinated. “If you can only get one in the evening, it’s still worthwhile. Timing may add oomph at a public-health level for more vulnerable groups.”
 

A version of this article appeared on Medscape.com.

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

High levels of xylitol, a low-calorie sweetener used in many reduced-sugar foods as well as gum and toothpaste, are linked to an increased risk of heart attacks, strokes, and death, says a new study published in the European Heart Journal.

The research team studied more than 3000 people in the US and Europe over 3 years and found that people with the highest amount of xylitol in their plasma were more likely to have a problem with their heart or blood vessels.

To show the early effects of xylitol, researchers studied platelet activity in volunteers who consumed a xylitol-sweetened drink and a glucose-sweetened drink. The xylitol levels went up by 1000 times in people after the xylitol drink but not after the glucose-sweetened drink.

Xylitol is naturally found in small amounts in fruit and vegetables, and it’s been used more as a sugar substitute over the past decade in processed foods, toothpaste, chewing gum, and other products.

“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combating conditions like obesity or diabetes,” Stanley Hazen, MD, chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, Cleveland, Ohio, said in a news release.

“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot-related events.”

A similar link between erythritol, another sugar substance, and problems with the heart and blood vessels was found last year by the same research team, the release said.

In a response to the study, the Calorie Control Council, a trade association representing the low- and reduced-calorie food and beverage industry, said xylitol has been approved for decades by government agencies. The study results may not apply to the general population because some people in the study already had a higher risk of having problems with their heart and blood vessels, it said.

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

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest. 

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)–secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed. ... Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, associate professor of medicine, endocrinology and molecular medicine, and the endocrine fellowship program director at Medical College of Wisconsin in Milwaukee, told this news organization. 

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

 

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said, “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma ... we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test … [i]f you have autonomous secretion by the adrenal, you don’t suppress as much. ... When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]. ... Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.” 

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules ... I don’t think we’re missing florid Cushing.” 

However, Dr. Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”
 

Is Wisconsin Representative of Cushing Everywhere?

Dr. Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%. 

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded. 

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Dr. Carroll said. 

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So ... that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said. 

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders. 

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Dr. Carroll noted. 

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded. 

Dr. Carroll reported consulting and investigator fees from Corcept Therapeutics. Dr. Wardlaw has no disclosures. 
 

A version of this article appeared on Medscape.com.

Some vitamin D tests may give misleading results despite progress made in recent years to improve the quality of these assays, according to the US Centers for Disease Control and Prevention (CDC).

Otoe Sugahara manager of the CDC Vitamin D Standardization-Certification Program (VDSCP), presented an update of her group’s work at ENDO 2024, the Endocrine Society’s annual meeting in Boston. 

“Though most vitamin D tests in our program have improved, there still remain some sample-specific inaccuracies. The CDC is working with program participants to address these situations,” Ms. Sugahara said in a statement released by the Endocrine Society.

For example, some assays measure other compounds besides 25-hydroxyvitamin D, which can falsely elevate results of some blood samples, Ms. Sugahara reported. Thus, some tests may be misclassified, with results seen as sufficient from samples that should have indicated a vitamin D deficiency.

“While most vitamin D tests are effective, it is important for healthcare providers to be aware of the potential inconsistencies associated with vitamin D tests to avoid misclassification of the patients,” Ms. Sugahara and coauthors said in an abstract provided by the Endocrine Society.

Ms. Sugahara’s report provided a snapshot of the state of longstanding efforts to improve the quality of a widely performed service in US healthcare: testing vitamin D levels.

These include an international collaboration that gave rise in 2010 to a vitamin D standardization program, from which the CDC’s VDSCP certification emerged. Among the leaders of these efforts was Christopher Sempos, PhD, then with the Office of Dietary Supplements at the National Institutes of Health.

Many clinicians may not be aware of the concerns about the accuracy of vitamin D tests that led to the drive for standardization, Dr. Sempos, now retired, said in an interview. And, in his view, it’s something that busy practitioners should not have to consider.

“They have literally thousands of diseases they have to be able to recognize and diagnose,” Dr. Sempos said. “They should be able to count on the laboratory system to give them accurate and precise data.”
 

‘Nudging’ Toward Better Results

The CDC’s certification program gives labs and companies detailed information about the analytical accuracy and precision of their vitamin D tests. 

This feedback has paid off with improved results, Andy Hoofnagle, MD, PhD, professor of laboratory medicine and pathology at the University of Washington in Seattle, told this news organization. It helps by “nudging manufacturers in the right direction,” he said.

“Some manufacturers reformulated, others recalibrated, which is a lot of effort on their part, so that when the patient get a number, it actually means the right thing,” said Dr. Hoofnagle, who is also chair of the Accuracy-Based Programs Committee of the College of American Pathologists.

“There are still many immunoassays on the market that aren’t giving the correct results, unfortunately, but the standardization certification program has really pushed the field in the right direction,” he said.

US scientists use two main types of technologies to measure vitamin D in the blood, Ms. Sugahara said. One is mass spectrometry, which separately measures 25-hydroxyvitamin D2 and D3 and sums the values. The other type, immunoassay, measures both compounds at the same time and reports one result for total 25-hydroxyvitamin D.

At the ENDO 2024 meeting, Ms. Sugahara reported generally positive trends seen in the VDSCP. For example, the program looks at specific tests’ bias, or the deviation of test results from the true value, as determined with the CDC’s reference method for vitamin D.

Average calibration bias was less than 1% for all assays in the VDSCP in 2022, Ms. Sugahara said. The average calibration bias for immunoassays was 0.86%, and for assays using mass spectrometry, it was 0.55%, Ms. Sugahara reported. 

These are improved results compared with 2019 data, in which mass spectrometry–based assays had a mean bias of 1.9% and immunoassays had a mean bias of 2.4%, the CDC told this news organization in an email exchange.

The CDC said the VDSCP supports laboratories and researchers from around the world, including ones based in the US, China, Australia, Japan, and Korea.
 

Call for Research

Vitamin D tests are widely administered despite questions about their benefit for people who do not appear likely to be deficient of it. 

The Endocrine Society’s newly released practice guideline recommends against routine testing of blood vitamin D levels in the general population.

Laboratory testing has increased over the years owing to studies reporting associations between blood vitamin D [25(OH)D] levels and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases, wrote Marie B. Demay, MD, of Harvard Medical School in Boston, and coauthors in the new guideline. It was published on June 3 in The Journal of Clinical Endocrinology & Metabolism.

‘”Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population,” they wrote.

It’s uncertain that “any putative benefits of screening would outweigh the increased burden and cost, and whether implementation of universal 25(OH)D screening would be feasible from a societal perspective,” Dr. Demay and coauthors added.

They noted that the influential US Preventive Services Task Force also has raised doubts about widespread use of vitamin D tests. 

The USPSTF has a somewhat different take from the Endocrine Society. The task force in 2021 reiterated its view that there is not enough evidence to recommend for or against widespread vitamin D testing for adults. The task force gave this test an I grade, meaning there is insufficient evidence to weigh the risks and benefits. That’s the same grade the task force gave it in 2014.

The USPSTF uses a grade of D to recommend against use of a test or service.

In an interview with this news organization, John Wong, MD, vice chair of the USPSTF, reiterated his group’s call for more research into the potential benefits and harms of vitamin D screening. 

One of the challenges in addressing this issue, Dr. Wong noted, has been the variability of test results. Therefore, efforts such as the CDC’s VDSCP in improving test quality may help in eventually building up the kind of evidence base needed for the task force to offer a more definitive judgment on the tests, he said.

Wong acknowledged it must be frustrating for clinicians and patients to hear that experts don’t have the evidence needed to make a broad call about whether routine vitamin D tests are beneficial.

“We really would like to have that evidence because we recognize that it’s an important health question to help everybody in this nation stay healthy and live longer,” Dr. Wong said.

A version of this article appeared on Medscape.com.

Some vitamin D tests may give misleading results despite progress made in recent years to improve the quality of these assays, according to the US Centers for Disease Control and Prevention (CDC).

Otoe Sugahara manager of the CDC Vitamin D Standardization-Certification Program (VDSCP), presented an update of her group’s work at ENDO 2024, the Endocrine Society’s annual meeting in Boston. 

“Though most vitamin D tests in our program have improved, there still remain some sample-specific inaccuracies. The CDC is working with program participants to address these situations,” Ms. Sugahara said in a statement released by the Endocrine Society.

For example, some assays measure other compounds besides 25-hydroxyvitamin D, which can falsely elevate results of some blood samples, Ms. Sugahara reported. Thus, some tests may be misclassified, with results seen as sufficient from samples that should have indicated a vitamin D deficiency.

“While most vitamin D tests are effective, it is important for healthcare providers to be aware of the potential inconsistencies associated with vitamin D tests to avoid misclassification of the patients,” Ms. Sugahara and coauthors said in an abstract provided by the Endocrine Society.

Ms. Sugahara’s report provided a snapshot of the state of longstanding efforts to improve the quality of a widely performed service in US healthcare: testing vitamin D levels.

These include an international collaboration that gave rise in 2010 to a vitamin D standardization program, from which the CDC’s VDSCP certification emerged. Among the leaders of these efforts was Christopher Sempos, PhD, then with the Office of Dietary Supplements at the National Institutes of Health.

Many clinicians may not be aware of the concerns about the accuracy of vitamin D tests that led to the drive for standardization, Dr. Sempos, now retired, said in an interview. And, in his view, it’s something that busy practitioners should not have to consider.

“They have literally thousands of diseases they have to be able to recognize and diagnose,” Dr. Sempos said. “They should be able to count on the laboratory system to give them accurate and precise data.”
 

‘Nudging’ Toward Better Results

The CDC’s certification program gives labs and companies detailed information about the analytical accuracy and precision of their vitamin D tests. 

This feedback has paid off with improved results, Andy Hoofnagle, MD, PhD, professor of laboratory medicine and pathology at the University of Washington in Seattle, told this news organization. It helps by “nudging manufacturers in the right direction,” he said.

“Some manufacturers reformulated, others recalibrated, which is a lot of effort on their part, so that when the patient get a number, it actually means the right thing,” said Dr. Hoofnagle, who is also chair of the Accuracy-Based Programs Committee of the College of American Pathologists.

“There are still many immunoassays on the market that aren’t giving the correct results, unfortunately, but the standardization certification program has really pushed the field in the right direction,” he said.

US scientists use two main types of technologies to measure vitamin D in the blood, Ms. Sugahara said. One is mass spectrometry, which separately measures 25-hydroxyvitamin D2 and D3 and sums the values. The other type, immunoassay, measures both compounds at the same time and reports one result for total 25-hydroxyvitamin D.

At the ENDO 2024 meeting, Ms. Sugahara reported generally positive trends seen in the VDSCP. For example, the program looks at specific tests’ bias, or the deviation of test results from the true value, as determined with the CDC’s reference method for vitamin D.

Average calibration bias was less than 1% for all assays in the VDSCP in 2022, Ms. Sugahara said. The average calibration bias for immunoassays was 0.86%, and for assays using mass spectrometry, it was 0.55%, Ms. Sugahara reported. 

These are improved results compared with 2019 data, in which mass spectrometry–based assays had a mean bias of 1.9% and immunoassays had a mean bias of 2.4%, the CDC told this news organization in an email exchange.

The CDC said the VDSCP supports laboratories and researchers from around the world, including ones based in the US, China, Australia, Japan, and Korea.
 

Call for Research

Vitamin D tests are widely administered despite questions about their benefit for people who do not appear likely to be deficient of it. 

The Endocrine Society’s newly released practice guideline recommends against routine testing of blood vitamin D levels in the general population.

Laboratory testing has increased over the years owing to studies reporting associations between blood vitamin D [25(OH)D] levels and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases, wrote Marie B. Demay, MD, of Harvard Medical School in Boston, and coauthors in the new guideline. It was published on June 3 in The Journal of Clinical Endocrinology & Metabolism.

‘”Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population,” they wrote.

It’s uncertain that “any putative benefits of screening would outweigh the increased burden and cost, and whether implementation of universal 25(OH)D screening would be feasible from a societal perspective,” Dr. Demay and coauthors added.

They noted that the influential US Preventive Services Task Force also has raised doubts about widespread use of vitamin D tests. 

The USPSTF has a somewhat different take from the Endocrine Society. The task force in 2021 reiterated its view that there is not enough evidence to recommend for or against widespread vitamin D testing for adults. The task force gave this test an I grade, meaning there is insufficient evidence to weigh the risks and benefits. That’s the same grade the task force gave it in 2014.

The USPSTF uses a grade of D to recommend against use of a test or service.

In an interview with this news organization, John Wong, MD, vice chair of the USPSTF, reiterated his group’s call for more research into the potential benefits and harms of vitamin D screening. 

One of the challenges in addressing this issue, Dr. Wong noted, has been the variability of test results. Therefore, efforts such as the CDC’s VDSCP in improving test quality may help in eventually building up the kind of evidence base needed for the task force to offer a more definitive judgment on the tests, he said.

Wong acknowledged it must be frustrating for clinicians and patients to hear that experts don’t have the evidence needed to make a broad call about whether routine vitamin D tests are beneficial.

“We really would like to have that evidence because we recognize that it’s an important health question to help everybody in this nation stay healthy and live longer,” Dr. Wong said.

A version of this article appeared on Medscape.com.

Some vitamin D tests may give misleading results despite progress made in recent years to improve the quality of these assays, according to the US Centers for Disease Control and Prevention (CDC).

Otoe Sugahara manager of the CDC Vitamin D Standardization-Certification Program (VDSCP), presented an update of her group’s work at ENDO 2024, the Endocrine Society’s annual meeting in Boston. 

“Though most vitamin D tests in our program have improved, there still remain some sample-specific inaccuracies. The CDC is working with program participants to address these situations,” Ms. Sugahara said in a statement released by the Endocrine Society.

For example, some assays measure other compounds besides 25-hydroxyvitamin D, which can falsely elevate results of some blood samples, Ms. Sugahara reported. Thus, some tests may be misclassified, with results seen as sufficient from samples that should have indicated a vitamin D deficiency.

“While most vitamin D tests are effective, it is important for healthcare providers to be aware of the potential inconsistencies associated with vitamin D tests to avoid misclassification of the patients,” Ms. Sugahara and coauthors said in an abstract provided by the Endocrine Society.

Ms. Sugahara’s report provided a snapshot of the state of longstanding efforts to improve the quality of a widely performed service in US healthcare: testing vitamin D levels.

These include an international collaboration that gave rise in 2010 to a vitamin D standardization program, from which the CDC’s VDSCP certification emerged. Among the leaders of these efforts was Christopher Sempos, PhD, then with the Office of Dietary Supplements at the National Institutes of Health.

Many clinicians may not be aware of the concerns about the accuracy of vitamin D tests that led to the drive for standardization, Dr. Sempos, now retired, said in an interview. And, in his view, it’s something that busy practitioners should not have to consider.

“They have literally thousands of diseases they have to be able to recognize and diagnose,” Dr. Sempos said. “They should be able to count on the laboratory system to give them accurate and precise data.”
 

‘Nudging’ Toward Better Results

The CDC’s certification program gives labs and companies detailed information about the analytical accuracy and precision of their vitamin D tests. 

This feedback has paid off with improved results, Andy Hoofnagle, MD, PhD, professor of laboratory medicine and pathology at the University of Washington in Seattle, told this news organization. It helps by “nudging manufacturers in the right direction,” he said.

“Some manufacturers reformulated, others recalibrated, which is a lot of effort on their part, so that when the patient get a number, it actually means the right thing,” said Dr. Hoofnagle, who is also chair of the Accuracy-Based Programs Committee of the College of American Pathologists.

“There are still many immunoassays on the market that aren’t giving the correct results, unfortunately, but the standardization certification program has really pushed the field in the right direction,” he said.

US scientists use two main types of technologies to measure vitamin D in the blood, Ms. Sugahara said. One is mass spectrometry, which separately measures 25-hydroxyvitamin D2 and D3 and sums the values. The other type, immunoassay, measures both compounds at the same time and reports one result for total 25-hydroxyvitamin D.

At the ENDO 2024 meeting, Ms. Sugahara reported generally positive trends seen in the VDSCP. For example, the program looks at specific tests’ bias, or the deviation of test results from the true value, as determined with the CDC’s reference method for vitamin D.

Average calibration bias was less than 1% for all assays in the VDSCP in 2022, Ms. Sugahara said. The average calibration bias for immunoassays was 0.86%, and for assays using mass spectrometry, it was 0.55%, Ms. Sugahara reported. 

These are improved results compared with 2019 data, in which mass spectrometry–based assays had a mean bias of 1.9% and immunoassays had a mean bias of 2.4%, the CDC told this news organization in an email exchange.

The CDC said the VDSCP supports laboratories and researchers from around the world, including ones based in the US, China, Australia, Japan, and Korea.
 

Call for Research

Vitamin D tests are widely administered despite questions about their benefit for people who do not appear likely to be deficient of it. 

The Endocrine Society’s newly released practice guideline recommends against routine testing of blood vitamin D levels in the general population.

Laboratory testing has increased over the years owing to studies reporting associations between blood vitamin D [25(OH)D] levels and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases, wrote Marie B. Demay, MD, of Harvard Medical School in Boston, and coauthors in the new guideline. It was published on June 3 in The Journal of Clinical Endocrinology & Metabolism.

‘”Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population,” they wrote.

It’s uncertain that “any putative benefits of screening would outweigh the increased burden and cost, and whether implementation of universal 25(OH)D screening would be feasible from a societal perspective,” Dr. Demay and coauthors added.

They noted that the influential US Preventive Services Task Force also has raised doubts about widespread use of vitamin D tests. 

The USPSTF has a somewhat different take from the Endocrine Society. The task force in 2021 reiterated its view that there is not enough evidence to recommend for or against widespread vitamin D testing for adults. The task force gave this test an I grade, meaning there is insufficient evidence to weigh the risks and benefits. That’s the same grade the task force gave it in 2014.

The USPSTF uses a grade of D to recommend against use of a test or service.

In an interview with this news organization, John Wong, MD, vice chair of the USPSTF, reiterated his group’s call for more research into the potential benefits and harms of vitamin D screening. 

One of the challenges in addressing this issue, Dr. Wong noted, has been the variability of test results. Therefore, efforts such as the CDC’s VDSCP in improving test quality may help in eventually building up the kind of evidence base needed for the task force to offer a more definitive judgment on the tests, he said.

Wong acknowledged it must be frustrating for clinicians and patients to hear that experts don’t have the evidence needed to make a broad call about whether routine vitamin D tests are beneficial.

“We really would like to have that evidence because we recognize that it’s an important health question to help everybody in this nation stay healthy and live longer,” Dr. Wong said.

A version of this article appeared on Medscape.com.

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

TOPLINE:

Long-term exposure to fine particulate matter is associated with higher fasting blood glucose (FBG) levels and an increased type 2 diabetes risk, significantly contributing to the diabetes-related health burden among women of reproductive age.

METHODOLOGY:

• Exposure to fine particulate matter < 2.5 µm (PM2.5) is a known risk factor for type 2 diabetes, but its effect on women of reproductive age, who undergo hormonal fluctuations during reproductive events, is not well studied.
• Researchers evaluated the association of long-term exposure to PM2.5 with FBG levels and diabetes risk in 20,076,032 eligible women of reproductive age (average age, 27.04 years) across 350 cities in China between 2010 and 2015.
• They assessed PM2.5 exposure at the participants’ residential addresses and calculated average long-term exposure at 1 (lag 1 year), 2 (lag 2 years), and 3 years (lag 3 years) before the survey date, as defined by the World Health Organization (WHO).
• The primary outcomes were FBG levels and diabetes prevalence (FBG, ≥ 7 mmol/L, classified as diabetes; FBG, 6.1-7 mmol/L, classified as prediabetes).
• The study also evaluated the diabetes burden attributed to long-term PM2.5 exposure as per the Chinese National Ambient Air Quality Standards (annual mean PM2.5 exposure limit, > 35 µg/m³) and the WHO air quality guideline (annual mean PM2.5 exposure limit, > 5 µg/m³).

TAKEAWAY:

• The median PM2.5 exposure levels over lag periods of 1, 2, and 3 years were 67, 67, and 66 µg/m³, respectively, exceeding the WHO limit by more than 13-fold.
• Each interquartile range increase in the 3-year average PM2.5 exposure by 27 μg/m³ raised FBG levels by 0.078 mmol/L (P < .05), risk for diabetes by 18% (odds ratio [OR], 1.18; 95% CI, 1.16-1.19), and risk for prediabetes by 5% (OR, 1.05; 95% CI, 1.04-1.05).
• Long-term exposure to PM2.5 > 5 µg/m³ and 35 µg/m³ in the previous 3 years corresponded to an additional 41.7 (95% CI, 39.3-44.0) and 78.6 (95% CI, 74.5-82.6) thousand cases of diabetes nationwide, respectively.
• A higher PM2.5 exposure increased FBG levels and risk for diabetes in women with overweight or obesity vs those without and in those aged ≥ 35 years vs < 35 years (P < .001).

IN PRACTICE:

“These findings carry significant public health implications for formulating effective intervention strategies and environmental policies to better protect women’s health, particularly in countries with relatively high levels of air pollution and a large population with diabetes, such as China,” the authors wrote.

SOURCE:

The study, led by Yang Shen, Key Laboratory of Public Health Safety of the Ministry of Education and National Health Commission Key Laboratory of Health Technology Assessment, School of Public Health, Fudan University, Shanghai, China, was published online in Diabetes Care.

LIMITATIONS:

An error in the measurement of particulate matter exposure may have been possible as residential address estimates were used as a proxy for actual personal exposure. Questionnaires were used to retrospectively collect information on parameters such as smoking and alcohol consumption, which may have introduced recall bias. Data on potential confounders, such as diet and physical activity, were not included. Distinction between type 1 and type 2 diabetes was not reported owing to data collection–related limitations.

DISCLOSURES:

The study was supported by the National Key Research and Development Program of China, Henan Key Research and Development Program, State Key Laboratory of Resources and Environmental Information System, and Three-Year Public Health Action Plan of Shanghai. The authors declared no conflicts of interest.

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

Richard* was a master-of-the-universe type. He went to Wharton, ran a large hedge fund, and lived in Greenwich, Connecticut. His three children attended Ivy League schools. He played golf on the weekends and ate three healthy meals per day. There was just one issue: He had gained 90 pounds since the 1990s from consuming six to seven alcoholic beverages per day. He already had one DUI under his belt, and his marriage was on shaky ground. He had tried to address his alcohol abuse disorder on multiple occasions: He went to a yearlong class on alcoholism, saw a psychologist for cognitive-behavioral therapy, and joined Alcoholics Anonymous, all to no avail. 

When I met him in December 2023, he had hit rock bottom and was willing to try anything.

At our first visit, I prescribed him weekly tirzepatide (Zepbound) off label, along with a small dose of naltrexone. 

Richard shared some feedback after his first 2 weeks:

The naltrexone works great and is strong ... small dose for me effective ... I haven’t wanted to drink and when I do I can’t finish a glass over 2 hours … went from 25 drinks a week to about 4 … don’t notice other side effects … sleeping better too.

And after 6 weeks:

Some more feedback … on week 6-7 and all going well ... drinking very little alcohol and still on half tab of naltrexone ... that works well and have no side effects ... the Zepbound works well too. I do get hungry a few days after the shot but still don’t crave sugar or bad snacks … weight down 21 pounds since started … 292 to 271.

And finally, after 8 weeks:

Looking at my last text to you I see the progress … been incredible ... now down 35 pounds and at 257 … continue to feel excellent with plenty of energy … want to exercise more ... and no temptation to eat or drink unhealthy stuff ... I’m very happy this has surpassed my expectations on how fast it’s worked and I don’t feel any side effects. Marriage has never been better … all thanks to you. 

Tirzepatide contains two hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), that are naturally produced by our bodies after meals. Scientists recently learned that the GLP-1 system contributes to the feedback loop of addictive behaviors. Increasing synthetic GLP-1, through medications like tirzepatide, appears to minimize addictive behaviors by limiting their ability to upregulate the brain’s production of dopamine. 

Dopamine is a neurotransmitter produced in the brain’s reward center, which regulates how people experience pleasure and control impulses. Dopamine reinforces the pleasure experienced by certain behaviors like drinking, smoking, and eating sweets. These new medications reduce the amount of dopamine released after these activities and thereby lower the motivation to repeat these behaviors. 

Contrary to some reports in the news, the vast majority of my male patients using these medications for alcohol abuse disorder experience concurrent increases in testosterone, for two reasons: (1) testosterone increases as body mass index decreases and (2) chronic alcohol use can damage the cells in the testicles that produce testosterone and also decrease the brain’s ability to stimulate the testicles to produce testosterone. 

At his most recent checkup last month, Richard’s testosterone had risen from borderline to robust levels, his libido and sleep had improved, and he reported never having felt so healthy or confident. Fingers crossed that the US Food and Drug Administration won’t wait too long before approving this class of medications for more than just diabetes, heart disease, and obesity. 

*Patient’s name has been changed.
 

Dr. Messer is clinical assistant professor, Icahn School of Medicine at Mount Sinai, New York, and associate professor, Zucker School of Medicine at Hofstra University, Hempstead, New York. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Richard* was a master-of-the-universe type. He went to Wharton, ran a large hedge fund, and lived in Greenwich, Connecticut. His three children attended Ivy League schools. He played golf on the weekends and ate three healthy meals per day. There was just one issue: He had gained 90 pounds since the 1990s from consuming six to seven alcoholic beverages per day. He already had one DUI under his belt, and his marriage was on shaky ground. He had tried to address his alcohol abuse disorder on multiple occasions: He went to a yearlong class on alcoholism, saw a psychologist for cognitive-behavioral therapy, and joined Alcoholics Anonymous, all to no avail. 

When I met him in December 2023, he had hit rock bottom and was willing to try anything.

At our first visit, I prescribed him weekly tirzepatide (Zepbound) off label, along with a small dose of naltrexone. 

Richard shared some feedback after his first 2 weeks:

The naltrexone works great and is strong ... small dose for me effective ... I haven’t wanted to drink and when I do I can’t finish a glass over 2 hours … went from 25 drinks a week to about 4 … don’t notice other side effects … sleeping better too.

And after 6 weeks:

Some more feedback … on week 6-7 and all going well ... drinking very little alcohol and still on half tab of naltrexone ... that works well and have no side effects ... the Zepbound works well too. I do get hungry a few days after the shot but still don’t crave sugar or bad snacks … weight down 21 pounds since started … 292 to 271.

And finally, after 8 weeks:

Looking at my last text to you I see the progress … been incredible ... now down 35 pounds and at 257 … continue to feel excellent with plenty of energy … want to exercise more ... and no temptation to eat or drink unhealthy stuff ... I’m very happy this has surpassed my expectations on how fast it’s worked and I don’t feel any side effects. Marriage has never been better … all thanks to you. 

Tirzepatide contains two hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), that are naturally produced by our bodies after meals. Scientists recently learned that the GLP-1 system contributes to the feedback loop of addictive behaviors. Increasing synthetic GLP-1, through medications like tirzepatide, appears to minimize addictive behaviors by limiting their ability to upregulate the brain’s production of dopamine. 

Dopamine is a neurotransmitter produced in the brain’s reward center, which regulates how people experience pleasure and control impulses. Dopamine reinforces the pleasure experienced by certain behaviors like drinking, smoking, and eating sweets. These new medications reduce the amount of dopamine released after these activities and thereby lower the motivation to repeat these behaviors. 

Contrary to some reports in the news, the vast majority of my male patients using these medications for alcohol abuse disorder experience concurrent increases in testosterone, for two reasons: (1) testosterone increases as body mass index decreases and (2) chronic alcohol use can damage the cells in the testicles that produce testosterone and also decrease the brain’s ability to stimulate the testicles to produce testosterone. 

At his most recent checkup last month, Richard’s testosterone had risen from borderline to robust levels, his libido and sleep had improved, and he reported never having felt so healthy or confident. Fingers crossed that the US Food and Drug Administration won’t wait too long before approving this class of medications for more than just diabetes, heart disease, and obesity. 

*Patient’s name has been changed.
 

Dr. Messer is clinical assistant professor, Icahn School of Medicine at Mount Sinai, New York, and associate professor, Zucker School of Medicine at Hofstra University, Hempstead, New York. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Richard* was a master-of-the-universe type. He went to Wharton, ran a large hedge fund, and lived in Greenwich, Connecticut. His three children attended Ivy League schools. He played golf on the weekends and ate three healthy meals per day. There was just one issue: He had gained 90 pounds since the 1990s from consuming six to seven alcoholic beverages per day. He already had one DUI under his belt, and his marriage was on shaky ground. He had tried to address his alcohol abuse disorder on multiple occasions: He went to a yearlong class on alcoholism, saw a psychologist for cognitive-behavioral therapy, and joined Alcoholics Anonymous, all to no avail. 

When I met him in December 2023, he had hit rock bottom and was willing to try anything.

At our first visit, I prescribed him weekly tirzepatide (Zepbound) off label, along with a small dose of naltrexone. 

Richard shared some feedback after his first 2 weeks:

The naltrexone works great and is strong ... small dose for me effective ... I haven’t wanted to drink and when I do I can’t finish a glass over 2 hours … went from 25 drinks a week to about 4 … don’t notice other side effects … sleeping better too.

And after 6 weeks:

Some more feedback … on week 6-7 and all going well ... drinking very little alcohol and still on half tab of naltrexone ... that works well and have no side effects ... the Zepbound works well too. I do get hungry a few days after the shot but still don’t crave sugar or bad snacks … weight down 21 pounds since started … 292 to 271.

And finally, after 8 weeks:

Looking at my last text to you I see the progress … been incredible ... now down 35 pounds and at 257 … continue to feel excellent with plenty of energy … want to exercise more ... and no temptation to eat or drink unhealthy stuff ... I’m very happy this has surpassed my expectations on how fast it’s worked and I don’t feel any side effects. Marriage has never been better … all thanks to you. 

Tirzepatide contains two hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), that are naturally produced by our bodies after meals. Scientists recently learned that the GLP-1 system contributes to the feedback loop of addictive behaviors. Increasing synthetic GLP-1, through medications like tirzepatide, appears to minimize addictive behaviors by limiting their ability to upregulate the brain’s production of dopamine. 

Dopamine is a neurotransmitter produced in the brain’s reward center, which regulates how people experience pleasure and control impulses. Dopamine reinforces the pleasure experienced by certain behaviors like drinking, smoking, and eating sweets. These new medications reduce the amount of dopamine released after these activities and thereby lower the motivation to repeat these behaviors. 

Contrary to some reports in the news, the vast majority of my male patients using these medications for alcohol abuse disorder experience concurrent increases in testosterone, for two reasons: (1) testosterone increases as body mass index decreases and (2) chronic alcohol use can damage the cells in the testicles that produce testosterone and also decrease the brain’s ability to stimulate the testicles to produce testosterone. 

At his most recent checkup last month, Richard’s testosterone had risen from borderline to robust levels, his libido and sleep had improved, and he reported never having felt so healthy or confident. Fingers crossed that the US Food and Drug Administration won’t wait too long before approving this class of medications for more than just diabetes, heart disease, and obesity. 

*Patient’s name has been changed.
 

Dr. Messer is clinical assistant professor, Icahn School of Medicine at Mount Sinai, New York, and associate professor, Zucker School of Medicine at Hofstra University, Hempstead, New York. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

Now that semaglutide (Wegovy), tirzepatide (Zepbound), and other injectables have created an insatiable market for weight loss drugs, biotech and pharmaceutical companies are roaring ahead with oral formulations, which promise a greater level of convenience, in line with patient preference.

One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.

Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD. 

“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”

He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”

Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.

Here’s a look at other promising oral drugs on the horizon.

Oral Semaglutide

The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.

A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.

“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.

Oral Amycretin

Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.

“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”

APH-012

As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity. 

The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.

The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”

Topline data from the first part of the study are expected to be released by the third quarter.

AZD5004

In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.

“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”

Ecnoglutide

In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.

The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.

Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.

The company is also developing an injectable formulation of ecnoglutide.

GSBR-1290

On May 9, Structure Therapeutics released highlights of the company›s evaluation of GSBR-1290, an oral small molecule selective GLP-1 receptor agonist. Topline data from the obesity cohort of the phase 2a study, including 12-week efficacy data for 40 participants and safety and tolerability for all 64 participants, are expected in June. 

In preparation for later stage clinical trials, the company said it is conducting a formulation bridging and titration study to evaluate capsule vs tablet pharmacokinetics and explore different titration regimens of the molecule. Pharmacokinetic study results are also expected in June.

A global phase 2b obesity study is planned for the fourth quarter of 2024.

Orforglipron

Orforglipron is an oral GLP-1 receptor agonist being developed by Eli Lilly and Co. A phase 3 study of the once-daily capsule is underway, and will run until mid-2027. 

Phase 2 data presented last year at the American Diabetes Association conference showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥ 15% of their body weight at 36 weeks. 

Additionally, a meta-analysis of randomized controlled trials of the drug was recently published.

A Lilly spokesperson told this news organization that phase 3 results from the ATTAIN-1 study are “expected to be to be available beginning in 2025, and we can expect a launch possibly a year after that.”

VK2735

VK2735, a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, is being developed by Viking Therapeutics for the treatment of metabolic disorders, including obesity, in both subcutaneous and oral formulations.

In a phase 1, 28-day multiple ascending dose study, cohorts receiving oral formulation VK2735 had dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%, and also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥ 10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at day 34, 6 days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo.

Based on these phase 1 results, the company plans to initiate a phase 2 trial in obesity later this year.
 

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

BOSTON — Use of over-the-counter arthritis supplements containing undisclosed glucocorticoids can lead to iatrogenic adrenal dysfunction, Cushing syndrome, and/or adrenal insufficiency (AI). 

Patients who have been taking these supplements for prolonged periods must slowly taper off them with corticosteroid replacement, because abruptly stopping the supplement can precipitate AI, Kevin S. Wei, MD, said in a presentation of 12 cases — the largest such series to date of the phenomenon — at the annual meeting of the Endocrine Society.

The specific supplements used were Artri King in eight of the patients, Ardosons in two, and Ajo Rey in one. In April 2022, the US Food and Drug Administration issued a warning that Artri King contains diclofenac and dexamethasone not listed on the product label. In July 2023, the agency issued an expanded warning about that product and others including Ajo Rey.

The supplements are not believed to be sold in the United States, but they are available in Mexico and can be ordered online, said Dr. Wei, a second-year resident at the Keck School of Medicine at the University of California, Los Angeles.

“We found that quite a lot of patients after they’ve been on the Artri King or some other over the counter arthritis supplement, started developing these cushingoid features seen in the physical exam, such as rounded facial features or stretch marks of their abdomen,” he said.

And “when patients are abruptly taken off those supplements … sometimes this can cause them to go into signs or symptoms of adrenal insufficiency. That can occasionally be life-threatening if it’s not addressed in an inpatient setting,” Dr. Wei said.

In an interview, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University Irving Medical Center, New York, explained that when a person takes these drugs containing hidden glucocorticoids, “they won’t be picked up in a cortisol assay, but they’ll suppress the [adrenocorticotropic hormone] and the person’s own cortisol production. They look like they have Cushing, but when you measure their hormone levels, they’re undetectable. And then people wonder what’s going on. Well, their [hypothalamic-pituitary-adrenal] axis is suppressed.”

But if the product is suddenly stopped without cortisol replacement “If they get an infection they can die because they can’t mount a cortisol response.”

The takeaway message, she said, is “always ask patients to show you their supplements and look at them. In many cases, that’s why they work so well for pain relief because they have ingredients that people shouldn’t be taking.”

Twelve Patients Seen During 2022-2023

The 12 patients were seen during 2022-2023 at an endocrinology consult service in an urban safety net hospital. Their median age was 52 years, and one third were women. All had started using the supplements for joint pain, with a median of about 6 months of use prior to cessation.

Presenting symptoms included nausea/vomiting in 42%, fatigue in 42%, abdominal pain in 33%, and dizziness in 17%. Physical exam findings included moon facies in 66%, central adiposity in 66%, abdominal striae in 50%, dorsocervical fat pad in 33%, and bruising in 33%. Three required intensive care admission.

Cortisol testing was performed in 11 of the patients and was normal (≥ 16 mcg/dL) in just one. AI (≤ 3 mcg/dL) was found in three, while the rest had indeterminate results. Of those seven patients, subsequent cosyntropin-stimulation testing suggested AI (cortisol < 16 mcg/dL at 60 minutes post stimulation) in four patients, while the other two showed reduced but normal responses (cortisol 18.2-18.4 mcg/dL).

Ten of the 12 patients were prescribed glucocorticoid tapering replacements to avoid precipitating adrenal crisis, most commonly twice-daily hydrocortisone. Of those ten, eight continued to take the replacement steroids 1-2 years later, Dr. Wei said.

Dr. Wei and Dr. Wardlaw had no disclosures.

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report in the British Medical Journal on the regular use of omega-3 fish oil supplements and the course of cardiovascular disease (CVD).

This is an observational study from the large-scale UK Biobank. The authors divided the participants into those with and those without CVD. In participants without CVD at baseline, those using fish oil supplements regularly had an increased incidence of both atrial fibrillation (AF) and stroke, whereas those with prevalent CVD had a reduction in the progression to major adverse cardiovascular events, which offset any increase in the risk for AF.

Observational studies of omega-3 supplements have potential limitations and confounding, and correlation in these studies does not prove causation. What do the randomized clinical trials of omega-3 supplements show? At least seven randomized trials have looked at AF. A meta-analysis published in Circulation in 2021 showed a dose-response relationship. In trials testing > 1 g/d of marine omega-3 fatty acids, there was close to a 50% overall increase in risk for AF. In studies testing lower doses, there was a very modest 12% increase and a significant dose-response gradient.

For the relationship between omega-3 supplements and major cardiovascular events, at least 15 individual randomized trials have been conducted. There actually have been more meta-analyses of these randomized trials than individual trials. The meta-analyses tend to show a significant reduction of coronary events with omega-3 supplementation, but no reduction in stroke. This is true in both primary and secondary prevention trials.

The one exception to this finding is the REDUCE-IT trial testing high-dose eicosapentaenoic acid (EPA) (4 g/day of icosapent ethyl), and there was a 25%-30% reduction in both cardiovascular events and stroke. But there has been some criticism of the mineral oil placebo used in the REDUCE-IT trial that it may have had adverse effects on biomarkers and might have interfered with the absorption of statins in the placebo group. So, it will be important to have a replication trial of the high-dose EPA, findings in a trial using an inert placebo such as corn oil.

What should be done in the meantime? It’s important to think about prescription omega-3s vs over-the-counter fish oil. The US Food and Drug Administration (FDA) has approved prescription omega-3 medications for several indications, including severely elevated triglyceride levels (> 500 mg/dL). In the REDUCE-IT trial, those who had moderate elevations of triglycerides (≥ 150 mg/dL) or prevalent CVD or diabetes, plus two additional risk factors, were also considered to have indications based on the FDA labeling for icosapent ethyl.

What about patients who don’t meet these criteria for prescription omega-3s? In the VITAL trial (the large-scale primary prevention trial), there was a similar reduction in coronary events but no effect on stroke. Those who seemed to benefit the most in terms of at least 40% reduction in coronary events were participants who had low fish consumption at baseline, had two or more risk factors for cardiovascular disease, or were African American. 

Someone who rarely or never eats fish and has multiple risk factors for CVD, but doesn’t meet criteria for prescription omega-3 medication, may want to discuss with their clinician the use of over-the-counter fish oil supplements. But fish oil and other dietary supplements will never be a substitute for healthy diet and healthy lifestyle. There is a national recommendation for one to two servings of fish per week. For those planning to take fish oil, it’s important to use reputable sources of the supplement, and check the bottle for a quality control seal. It’s also really important to avoid megadoses of fish oil, because high doses have been linked to an increased risk for AF and bleeding.

Dr. Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, Boston, disclosed ties with Mars Symbioscience for the COSMOS trial.

A version of this article appeared on Medscape.com.