News

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Long-term daily supplementation with moderate (1600 international units [IU]) or high (3200 IU) doses of vitamin D3 doesn’t reduce the risk for type 2 diabetes (T2D) among generally healthy older adults who have serum vitamin D levels sufficient for bone health.

 

METHODOLOGY:

• Observational studies have consistently linked low vitamin D levels with an increased risk for T2D, and short-term randomized trials have shown a protective effect of vitamin D supplementation for those with impaired glucose metabolism but not in populations of average risk-taking low doses.
• The Finnish Vitamin D Trial, conducted from 2012 to 2018 in generally healthy men (≥ 60 years) and women (≥ 65 years) without a history of cardiovascular disease or cancer, assessed the effects of 5 years of moderate and high vitamin D3 supplementation on the incidence of major chronic diseases.
• This analysis of T2D incidence included 2271 older participants (mean age, 68.2 years; 43.9% women) without self-reported use of diabetes medications at baseline.
• Participants were randomly assigned to receive placebo (n = 760), 1600 IU/d of vitamin D3 (n = 744), or 3200 IU/d of vitamin D3 (n = 767) and followed for a mean duration of 4.2 years, with T2D incidence assessed by diagnostic code from health registries.
• A representative subcohort of 505 participants underwent detailed investigations including blood sampling at months 0, 6, 12, and 24 for serum 25-hydroxyvitamin D3 [25(OH)D3], plasma glucose, and insulin concentrations.

TAKEAWAY:

• No significant difference in T2D incidence was observed between groups: Placebo (5.0%; 38 people), 1600 IU/d (4.2%; 31 people), and 3200 IU/d (4.7%; 36 people; P = .731 for trend), with no appreciable sex differences.
• When stratified by body mass index (BMI), a lower incidence of T2D with vitamin D supplementation was observed among those with a BMI < 25 (with wide CIs), but not among those with a higher BMI.
• In the subcohort, no significant differences in changes in plasma glucose, insulin concentrations, BMI, or waist circumference with vitamin D3 were observed between the three treatment groups during the 24-month follow-up (P ≥ .19).
• In an analysis excluding T2D from the first 2 years, researchers observed a potentially increased risk for T2D with increasing vitamin D dose (with wide CIs).

IN PRACTICE:

“Our findings do not suggest benefits of long-term moderate- or high-dose vitamin D3 supplementation for incidence of type 2 diabetes or glucose metabolism or body size among generally healthy older vitamin D–sufficient men and women who were not at high risk for type 2 diabetes,” the authors wrote.

SOURCE:

The study was led by Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and was published online in Diabetologia.

LIMITATIONS:

The study relied on national health registries to collect data on incident T2D events, which may have led to some T2D cases being missed. Data on serum 25(OH)D3 concentrations were available for the subcohort only, which prevented the investigation of whether vitamin D–deficient participants would have benefited from supplementation. The study was not specifically designed or powered for diabetes prevention, and information on participants’ diabetes history at baseline was not available. Wide CIs suggest uncertainty around some of the findings. Study participants were White and older, so caution is needed in generalizing results to groups of other ages, races and ethnicities, and different vitamin D levels.

DISCLOSURES:

The study received funding from the Academy of Finland, University of Eastern Finland, Juho Vainio Foundation, and other sources. Some authors reported receiving grants or travel support from pharmaceutical companies and certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“Specifically, the exclusion of patients with a current major depressive episode is both a strength (to show a specific effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“Specifically, the exclusion of patients with a current major depressive episode is both a strength (to show a specific effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System in Alabama, said in an interview.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported in May 2024 as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

 

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, said in an interview. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was –19.2 points in the brexpiprazole plus sertraline group and –13.6 points in the sertraline plus placebo group (95% CI, –8.79 to –2.38; P < .001).

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was –33.8 with the combination vs –21.8 with sertraline plus placebo (95% CI, –19.4 to –4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment because of adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

 

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors noted.

“Specifically, the exclusion of patients with a current major depressive episode is both a strength (to show a specific effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD),” they added.

 

Kudos, Caveats

Reached for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair, department of psychiatry, Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Maryland, said the exclusion of these patients is a limitation but that the study was well designed and conducted in a large sample across the United States.

“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he said. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”

Additionally, the significant improvement in psychosocial functioning at week 12 “is important because PTSD is known to cause significant social and occupational disability, as well as quality-of-life issues,” he said.

Capaldi pointed out, however, that the study was conducted only at US sites and did not specifically target military/veteran persons, which may limit applicability to these unique populations.

“While subgroup analyses were generally consistent with the primary analysis, the study was not powered to detect differences between subgroups,” he added. “These subgroup analyses are quite important when considering military and veteran populations.”

Further research is needed to explore whether certain traumas are more responsive to combination treatment, the efficacy of augmenting existing sertraline therapy, and the specific mechanisms of brexpiprazole driving the improved outcomes, Capaldi said.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several coauthors are employees of Otsuka. Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.

A version of this article appeared on Medscape.com.

TOPLINE:

Ivarmacitinib, a novel Janus kinase 1 inhibitor, alleviates symptoms, reduces disease activity, and improves physical function and quality of life in patients with moderate to severe rheumatoid arthritis (RA) who have an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

METHODOLOGY:

• This phase 3 trial, conducted across 59 sites in China, evaluated the efficacy and safety of ivarmacitinib in patients with moderate to severe active RA despite treatment with one or more csDMARDs.
• The patients were randomly assigned to receive either placebo (n = 188; mean age, 50.9 years; 85.6% women) or 4 mg ivarmacitinib (n = 189; mean age, 49.7 years; 91% women) or 8 mg ivarmacitinib (n = 189; mean age, 49.8 years; 83.6% women) once daily for 24 weeks, alongside background csDMARDs.
• After 24 weeks, the patients receiving placebo were switched to receive 4 mg ivarmacitinib for the additional 28-week extension period, whereas those receiving ivarmacitinib continued their initial dosage.
• Secondary endpoints included the proportion of patients achieving American College of Rheumatology (ACR) 50/70 responses and, Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP)) score < 2.6 or ≤ 3.2, as well as measures of other patient-reported outcomes such as pain, physical function, and quality of life at 24 and 52 weeks.

TAKEAWAY:

• At 24 weeks, the proportion of patients achieving a 20% improvement in the ACR20 response — the primary endpoint — was higher among those receiving 4 mg ivarmacitinib (70.4%) or 8 mg ivarmacitinib (75.1%) than among those receiving placebo (40.4%; P < .0001 for both comparisons), with the efficacy either maintained or improved through 52 weeks.
• The proportion of patients achieving ACR50/70 responses or a DAS28(CRP) score < 2.6 or ≤ 3.2 was higher in the ivarmacitinib groups than in the placebo group (P < .0001 for all comparisons).
• Compared with the placebo group, both the ivarmacitinib groups showed improvements in patient-reported outcomes such as pain, physical function, quality of life, and duration and severity of morning stiffness.
• The overall rates of treatment discontinuation caused by adverse events were low across all the groups, with no deaths, tuberculosis or gastrointestinal perforations reported throughout the 52 weeks.
•  

IN PRACTICE:

“Based on these findings, ivarmacitinib with background csDMARDs allowed, could be considered a treatment option in patients with moderate to severe active RA who have an inadequate response to csDMARDs,” the authors wrote.

SOURCE:

This study was led by Jinjing Liu and Xiaofeng Zeng, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, China. It was published online on November 27, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

As the study was conducted in a Chinese population, the findings may have limited applicability across diverse global populations. Additionally, as the placebo-controlled period was limited to 24 weeks because of ethical concerns, comparisons between placebo and ivarmacitinib beyond that period were restricted. Lastly, this study was not powered to compare efficacy and safety between the two active dose regimens.

DISCLOSURES:

This study was funded by Jiangsu Hengrui Pharmaceuticals. Two authors declared being employees of the company. The other authors reported no competing interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Ivarmacitinib, a novel Janus kinase 1 inhibitor, alleviates symptoms, reduces disease activity, and improves physical function and quality of life in patients with moderate to severe rheumatoid arthritis (RA) who have an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

METHODOLOGY:

• This phase 3 trial, conducted across 59 sites in China, evaluated the efficacy and safety of ivarmacitinib in patients with moderate to severe active RA despite treatment with one or more csDMARDs.
• The patients were randomly assigned to receive either placebo (n = 188; mean age, 50.9 years; 85.6% women) or 4 mg ivarmacitinib (n = 189; mean age, 49.7 years; 91% women) or 8 mg ivarmacitinib (n = 189; mean age, 49.8 years; 83.6% women) once daily for 24 weeks, alongside background csDMARDs.
• After 24 weeks, the patients receiving placebo were switched to receive 4 mg ivarmacitinib for the additional 28-week extension period, whereas those receiving ivarmacitinib continued their initial dosage.
• Secondary endpoints included the proportion of patients achieving American College of Rheumatology (ACR) 50/70 responses and, Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP)) score < 2.6 or ≤ 3.2, as well as measures of other patient-reported outcomes such as pain, physical function, and quality of life at 24 and 52 weeks.

TAKEAWAY:

• At 24 weeks, the proportion of patients achieving a 20% improvement in the ACR20 response — the primary endpoint — was higher among those receiving 4 mg ivarmacitinib (70.4%) or 8 mg ivarmacitinib (75.1%) than among those receiving placebo (40.4%; P < .0001 for both comparisons), with the efficacy either maintained or improved through 52 weeks.
• The proportion of patients achieving ACR50/70 responses or a DAS28(CRP) score < 2.6 or ≤ 3.2 was higher in the ivarmacitinib groups than in the placebo group (P < .0001 for all comparisons).
• Compared with the placebo group, both the ivarmacitinib groups showed improvements in patient-reported outcomes such as pain, physical function, quality of life, and duration and severity of morning stiffness.
• The overall rates of treatment discontinuation caused by adverse events were low across all the groups, with no deaths, tuberculosis or gastrointestinal perforations reported throughout the 52 weeks.
•  

IN PRACTICE:

“Based on these findings, ivarmacitinib with background csDMARDs allowed, could be considered a treatment option in patients with moderate to severe active RA who have an inadequate response to csDMARDs,” the authors wrote.

SOURCE:

This study was led by Jinjing Liu and Xiaofeng Zeng, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, China. It was published online on November 27, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

As the study was conducted in a Chinese population, the findings may have limited applicability across diverse global populations. Additionally, as the placebo-controlled period was limited to 24 weeks because of ethical concerns, comparisons between placebo and ivarmacitinib beyond that period were restricted. Lastly, this study was not powered to compare efficacy and safety between the two active dose regimens.

DISCLOSURES:

This study was funded by Jiangsu Hengrui Pharmaceuticals. Two authors declared being employees of the company. The other authors reported no competing interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Ivarmacitinib, a novel Janus kinase 1 inhibitor, alleviates symptoms, reduces disease activity, and improves physical function and quality of life in patients with moderate to severe rheumatoid arthritis (RA) who have an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

METHODOLOGY:

• This phase 3 trial, conducted across 59 sites in China, evaluated the efficacy and safety of ivarmacitinib in patients with moderate to severe active RA despite treatment with one or more csDMARDs.
• The patients were randomly assigned to receive either placebo (n = 188; mean age, 50.9 years; 85.6% women) or 4 mg ivarmacitinib (n = 189; mean age, 49.7 years; 91% women) or 8 mg ivarmacitinib (n = 189; mean age, 49.8 years; 83.6% women) once daily for 24 weeks, alongside background csDMARDs.
• After 24 weeks, the patients receiving placebo were switched to receive 4 mg ivarmacitinib for the additional 28-week extension period, whereas those receiving ivarmacitinib continued their initial dosage.
• Secondary endpoints included the proportion of patients achieving American College of Rheumatology (ACR) 50/70 responses and, Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP)) score < 2.6 or ≤ 3.2, as well as measures of other patient-reported outcomes such as pain, physical function, and quality of life at 24 and 52 weeks.

TAKEAWAY:

• At 24 weeks, the proportion of patients achieving a 20% improvement in the ACR20 response — the primary endpoint — was higher among those receiving 4 mg ivarmacitinib (70.4%) or 8 mg ivarmacitinib (75.1%) than among those receiving placebo (40.4%; P < .0001 for both comparisons), with the efficacy either maintained or improved through 52 weeks.
• The proportion of patients achieving ACR50/70 responses or a DAS28(CRP) score < 2.6 or ≤ 3.2 was higher in the ivarmacitinib groups than in the placebo group (P < .0001 for all comparisons).
• Compared with the placebo group, both the ivarmacitinib groups showed improvements in patient-reported outcomes such as pain, physical function, quality of life, and duration and severity of morning stiffness.
• The overall rates of treatment discontinuation caused by adverse events were low across all the groups, with no deaths, tuberculosis or gastrointestinal perforations reported throughout the 52 weeks.
•  

IN PRACTICE:

“Based on these findings, ivarmacitinib with background csDMARDs allowed, could be considered a treatment option in patients with moderate to severe active RA who have an inadequate response to csDMARDs,” the authors wrote.

SOURCE:

This study was led by Jinjing Liu and Xiaofeng Zeng, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Beijing, China. It was published online on November 27, 2024, in Annals of the Rheumatic Diseases.

LIMITATIONS:

As the study was conducted in a Chinese population, the findings may have limited applicability across diverse global populations. Additionally, as the placebo-controlled period was limited to 24 weeks because of ethical concerns, comparisons between placebo and ivarmacitinib beyond that period were restricted. Lastly, this study was not powered to compare efficacy and safety between the two active dose regimens.

DISCLOSURES:

This study was funded by Jiangsu Hengrui Pharmaceuticals. Two authors declared being employees of the company. The other authors reported no competing interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

This story was translated from Univadis France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

This story was translated from Univadis France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Estimation of cardiovascular risk (CVR) in individuals living with type 1 diabetes (T1D) was a key topic presented by Sophie Borot, MD, from Besançon University Hospital, Besançon, France, at the 40th congress of the French Society of Endocrinology. Borot highlighted the complexities of this subject, outlining several factors that contribute to its challenges.

A Heterogeneous Disease

T1D is a highly heterogeneous condition, and the patients included in studies reflect this diversity:

• The impact of blood glucose levels on CVR changes depending on diabetes duration, its history, the frequency of hypoglycemic episodes, average A1c levels over several years, and the patient’s age at diagnosis.
• A T1D diagnosis from the 1980s involved different management strategies compared with a diagnosis today.
• Patient profiles also vary based on complications such as nephropathy or cardiac autonomic neuropathy.
• Diffuse and distal arterial damage in T1D leads to more subtle and delayed pathologic events than in type 2 diabetes (T2D).
• Most clinical studies assess CVR over 10 years, but a 20- or 30-year evaluation would be more relevant.
• Patients may share CVR factors with the general population (eg, family history, smoking, sedentary lifestyle, obesity, hypertension, or elevated low-density lipoprotein [LDL] levels), raising questions about possible overlap with metabolic syndrome.
• Study criteria differ, with a focus on outcomes such as cardiovascular death, major adverse cardiovascular events like myocardial infarction and stroke, or other endpoints.
• CVR is measured using either absolute or relative values, with varying units of measurement.

A Recent Awareness

The concept of CVR in T1D is relatively new. Until the publication of the prospective Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study in 2005, it was believed that T1D control had no impact on CVR. However, follow-up results from the same cohort of 50,000 patients, published in 2022 after 30 years of observation, revealed that CVR was 20% higher in patients who received conventional hyperglycemia-targeted treatment than those undergoing intensive treatment. The CVR increases in conjunction with diabetes duration. The study also showed that even well-controlled glycemia in T1D carries CVR (primarily due to microangiopathy), and that the most critical factor for CVR is not A1c control but rather LDL cholesterol levels.

These findings were corroborated by a Danish prospective study, which demonstrated that while CVR increased in conjunction with the number of risk factors, it was 82% higher in patients with T1D than in a control group — even in the absence of risk factors.
 

Key Takeaways

At diagnosis, a fundamental difference exists between T1D and T2D in terms of the urgency to address CVR. In T2D, diabetes may have progressed for years before diagnosis, necessitating immediate CVR reduction efforts. In contrast, T1D is often diagnosed in younger patients with initially low CVR, raising questions about the optimal timing for interventions such as statin prescriptions.

Recommendations

The American Diabetes Association/European Association for the Study of Diabetes guidelines (2024) include the following recommendations:

For adults with T1D, treatment should mirror that for T2D:

• Between ages 20 and 40, statins are recommended if at least one CVR factor is present.
• For children 10 years of age or older with T1D, the LDL target is < 1.0 g/L. Statins are prescribed if LDL exceeds 1.6 g/L without CVR factors or 1.3 g/L with at least one CVR factor.

The European Society of Cardiology guidelines (2023) include the following:

• For the first time, a dedicated chapter addresses T1D. Like the American guidelines, routine statin use after age 40 is recommended.
• Before age 40, statins are prescribed if there is at least one CVR factor (microangiopathy) or a 10-year CVR ≥ 10% (based on a CVR calculator).

The International Society for Pediatric and Adolescent Diabetes guidelines (2022) recommend:

• For children 10 years of age or older, the LDL target is < 1.0 g/L. Statins are recommended if LDL exceeds 1.3 g/L.

CAC Score in High CVR

The French Society of Cardiology and the French-speaking Society of Diabetology recommend incorporating the coronary artery calcium (CAC) score to refine CVR classification in high-risk patients. For those without prior cardiovascular events, LDL targets vary based on CAC and age. For example:

• High-risk patients with a CAC of 0-10 are reclassified as moderate risk, with an LDL target of < 1 g/L.
• A CAC ≥ 400 indicates very high risk, warranting coronary exploration.
• Patients under 50 years of age with a CAC of 11-100 remain high risk, with an LDL target of 0.7 g/L.

Conclusion

CVR in patients with T1D remains challenging to define. However, it is essential to consider long-term outcomes, planning for 30 or 40 years into the future. This involves educating patients about the importance of prevention, even when reassuring numbers are seen in their youth.

This story was translated from Univadis France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

A new evidence-based guideline recommends prescribing metformin when initiating antipsychotic treatment to help mitigate weight gain in certain instances.

There is “good evidence” that metformin can prevent weight gain caused by antipsychotics, first author Aoife Carolan, MPharm, with Saint John of God Hospital and the Royal College of Surgeons, Dublin, Ireland, said in an interview.

“While there have been some general recommendations to use metformin for this purpose, until now, clear guidance on how to prevent this side effect of treatment has been lacking,” Carolan said. “At present, it is likely that metformin is underused and when used, it is likely to be started after the weight gain occurs. Therefore, this guideline will reflect a new practice for most clinicians.” 

The guideline was published online on December 9 in Schizophrenia Bulletin.

It offers three key recommendations:

• Initiate metformin when prescribing a high-risk weight-inducing antipsychotic, such as olanzapine or clozapine.
• Initiate metformin with a medium-risk antipsychotic (quetiapine, paliperidone, or risperidone) in patients with one or more cardiometabolic risk factors; in patients aged 10-25 years; or in patients with a body mass index (BMI) between 25 and 30.
• Initiate metformin with any antipsychotic if > 3% increase in baseline body weight is observed during the first 12 months of treatment.

The guideline authors noted that a recent Cochrane review of pharmacological interventions for the prevention of antipsychotic-induced weight gain showed that metformin is the only pharmacological agent that may be effective for preventing weight gain.

The review showed that starting metformin with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg, compared with controls.

In terms of dose, the guideline recommends escalating from 500 mg daily to 500 mg twice daily over 2 weeks, followed by biweekly increases of 500 mg as tolerated up to 1 g twice daily at week 6.

Metformin should be discontinued if risks for lactic acidosis are present, or the condition is suspected; if BMI falls below 20; or if the antipsychotic medicine is discontinued. Metformin should be avoided where there is harmful use of alcohol.

While the guideline focused on metformin, it also recommends that, if available, glucagon-like peptide 1 (GLP-1) agonists, should be considered for patients with a BMI > 30, certain cardiometabolic diseases, or obstructive sleep apnea.

“At present, there is insufficient evidence for the risk benefit calculation for GLP-1 agonists as a preventative agent, but we will continue to monitor the evidence and update the guideline if it is needed,” Carolan said.

 

Experts Weigh In

This news organization asked several psychiatrists not involved in the guideline development for their thoughts on it.

Ipsit Vahia, MD, McLean Hospital, Belmont, and Harvard Medical School, Boston, both in Massachusetts, said: “There is an urgent need for evidence to guide treatments that can mitigate the metabolic side effects of antipsychotics.”

While metformin has shown some potential based on preliminary studies, this paper offers more substantial evidence to guide clinicians in using these medications and marks a significant step forward in clinical psychiatry, Vahia said.

Lynn DeLisi, MD, also with Harvard Medical School, emphasized that decisions about the use of metformin in patients taking antipsychotics should be made on an individual basis.

“It should not be used routinely with all antipsychotics, as metformin has its own set of side effects,” said DeLisi.

Xiaoduo Fan, MD, MPH, with UMass Chan Medical School, Worcester, Massachusetts, director of UMass MIND, noted that the evidence regarding metformin’s benefits to prevent or mitigate antipsychotic-induced weight gain and other metabolic disturbances is clear.

“It was somewhat controversial when psychiatrists started to prescribe metformin 15-20 years ago, but now many psychiatrists feel comfortable doing so. In many clinical settings, especially in academically affiliated hospitals, using metformin to address antipsychotic-associated metabolic concerns has become part of the routine practice,” said Fan.

“The guideline recommendations are generally consistent with what we have been doing clinically. The publication of the guideline may help promote wider use of metformin in the patient population we serve,” Fan added.

Fan also noted that a growing body of the literature has demonstrated the weight loss effect and other metabolic benefits of GLP-1 agonists. “Compared with metformin, GLP-1 agonists are more effective in inducing weight loss and mitigating cardiometabolic risks,” he said.

Fan said his group has completed a double-blind, placebo-controlled trial of 6-month weekly injection of the GLP-1 receptor agonist exenatide, as an adjunctive treatment in 70 patients with schizophrenia. “Preliminary data analysis suggests positive metabolic benefits,” he reported.

This research had no commercial funding. Carolan had no relevant disclosures. A complete list of disclosures for the guideline authors is available with the original article. DeLisi had no relevant disclosures. Fan had received research support from Alkermes, Eli Lilly, Janssen, Otsuka Pharmaceutical, Roche, Lundbeck, Boehringer Ingelheim, Neurocrine Biosciences, Intra-Cellular Therapies, Teva, and Bristol-Myers Squibb. He served on the BMJ Best Practice’s US Advisory Panel and as the contributor for the BMJ Best Practice — Schizophrenia Topic. Vahia had served as a consultant for Otsuka.

A version of this article appeared on Medscape.com.

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Adults aged 50 years who were born preterm have a higher risk for hypertension but lower risk for cardiovascular events than those born at term, with similar risks for diabetes, prediabetes, and dyslipidemia between groups.

METHODOLOGY:

• The researchers conducted a prospective cohort study of the Auckland Steroid Trial — the first randomized trial of antenatal corticosteroids (betamethasone) for women who were at risk for preterm birth, conducted in Auckland, New Zealand, between December 1969 and February 1974.
• They analyzed 470 participants, including 424 survivors recruited between January 2020 and May 2022 and 46 participants who died after infancy.
• The outcomes for 326 participants born preterm (mean age, 49.4 years) and 144 participants born at term (mean age, 49.2 years) were assessed using either a questionnaire, administrative datasets, or both.
• The primary outcome was a composite of cardiovascular events or risk factors, defined as a history of a major adverse cardiovascular event or the presence of at least one cardiovascular risk factor, including diabetes mellitus, prediabetes, treated dyslipidemia, and treated hypertension.
• The secondary outcomes included respiratory, mental health, educational, and other health outcomes, as well as components of the primary outcomes.

TAKEAWAY:

• The composite of cardiovascular events or risk factors occurred in 34.5% of participants born preterm and 29.9% of participants born at term, with no differences in the risk factor components.
• The risk for cardiovascular events was lower in participants born preterm than in those born at term (adjusted relative risk [aRR], 0.33; P = .013).
• The participants born preterm had a higher risk for high blood pressure (aRR, 1.74; P = .007) and the composite of treated hypertension or self-reported diagnosis of high blood pressure (aRR, 1.63; P = .010) than those born at term.
• From randomization to the 50-year follow-up, death from any cause was more common in those born preterm than in those born at term (aRR, 2.29; P < .0001), whereas the diagnosis or treatment of a mental health disorder was less common (P = .007); no differences were observed between the groups for other outcomes.

IN PRACTICE:

“Those aware of being born preterm also may be more likely to seek preventive treatments, potentially resulting in a reduced risk of cardiovascular disease but a greater prevalence of risk factors if defined by a treatment such as treated dyslipidemia or treated hypertension,” the authors wrote.

“In this cohort, the survival advantage of the term-born control group abated after infancy, with a higher all-cause mortality rate, compared with that of the group born preterm,” wrote Jonathan S. Litt, MD, MPH, ScD, and Henning Tiemeier, MD, PhD, in a related commentary published in Pediatrics.

SOURCE:

The study was led by Anthony G. B. Walters, MBChB, Liggins Institute, Auckland, New Zealand. It was published online on December 16, 2024, in Pediatrics .

LIMITATIONS:

The small sample size limited the ability to detect subtle differences between groups and the validity of subgroup analyses. Attrition bias may have occurred because of low follow-up rates among presumed survivors. Bias could have been introduced because of lack of consent for access to the administrative dataset or from missing data from the participants in the questionnaire. The lack of in-person assessments for blood pressure and blood tests, resulting from geographical dispersion over 50 years, may have led to underestimation of some outcomes. Additionally, as most participants were born moderately or late preterm, with a median gestational age of 34.1 weeks, findings may not be generalizable to those born preterm at earlier gestational ages.

DISCLOSURES:

The study was supported in part by the Aotearoa Foundation, the Auckland Medical Research Foundation, Cure Kids New Zealand, and the Health Research Council of New Zealand. The authors of both the study and the commentary reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

Children aged 5-12 years with concussion have similar recovery trajectories, regardless of whether the injury is linked to sports or to other causes, such as falls, new data indicated. 

“With that result, it means we don’t need to change management protocols” depending on the cause of the concussion, study author Andrée-Anne Ledoux, PhD, a scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Ontario, Canada, said in an interview. “That’s kind of good news. We’re applying the right management protocols with them.”

The data were published on December 4 in JAMA Network Open.

 

Secondary Analysis

The results stem from a planned secondary analysis of the prospective Predicting and Preventing Postconcussive Problems in Pediatrics study. Conducted from August 2013 to June 2015 at nine pediatric emergency departments in Canada, it included children of different ages (5 to < 18 years), genders, demographic characteristics, and comorbidities. All participants had a concussion.

The secondary analysis focused on study participants who were aged 5-12 years and had presented within 48 hours of injury. The primary outcome was symptom change, which was defined as current ratings minus preinjury ratings, across time (1, 2, 4, 8, and 12 weeks), measured using the Post-Concussion Symptom Inventory.

No significant differences in postinjury recovery curves were found between participants with sport-related concussions (SRC) and those with non-SRC. The latter injuries resulted from causes such as falls and objects dropped on heads. SRC and non-SRC showed a nonlinear association with time, with symptoms decreasing over time.

Perhaps surprisingly, the researchers also reported a higher rate of persisting symptoms after concussion (PSAC) following limited contact sports than following contact sports such as hockey, soccer, rugby, lacrosse, and football. Limited contact sports include activities such as bicycling, horseback riding, tobogganing, gymnastics, and cheerleading.

This finding suggests that the management of SRC may not require distinct strategies based on sports classification, the researchers wrote. “Instead, it may be more appropriate for clinicians to consider the specific dynamics of the activity, such as velocity and risk of falls from heights. This nuanced perspective can aid in assessing the likelihood of persisting symptoms.” The researchers urged more investigation of this question. “A larger sample with more information on injury height and velocity would be required to confirm whether an association exists.”

In addition, the researchers cited guidelines that include a recommendation for a gradual return to low to moderate physical and cognitive activity starting 24-48 hours after a concussion at a level that does not result in recurrence or exacerbation of symptoms.

“Children do need to return to their lives. They need to return to school,” said Ledoux. “They can have accommodations while they return to school, but just returning to school has huge benefits because you’re reintegrating the child into their typical lifestyle and socialization as well.”

A potential limitation of the study was its reliance on participants who had been seen in emergency departments and thus may have been experiencing more intense symptoms than those seen elsewhere.

The researchers also excluded cases of concussion resulting from assaults and motor vehicle crashes. This decision may explain why they didn’t reproduce the previous observation that patients with SRC tended to recover faster than those with concussions from other causes.

Injuries resulting from assaults and motor vehicle crashes can involve damage beyond concussions, Ledoux said. Including these cases would not allow for an apples-to-apples comparison of SRC and non-SRC.

 

‘Don’t Cocoon Kids’

The authors of an accompanying editorial wrote that the researchers had done “a beautiful job highlighting this important nuance.” Noncontact sports with seemingly little risk “actually carry substantial risks when one imagines the high-impact forces that can occur with a fall from height, albeit rare,” Scott Zuckerman, MD, MPH, assistant professor of neurological surgery at Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues wrote.

The new analysis suggests a need to rethink a “somewhat archaic way of classifying sport risk, which may oversimplify how we categorize risk of brain and spine injuries.”

The commentary also noted how the researchers used the term PSAC to describe lingering symptoms instead of more widely used terms like “persistent postconcussive symptoms” or “postconcussive syndrome.”

“These traditional terms often connote a permanent syndrome or assumption that the concussion itself is solely responsible for 100% of symptoms, which can be harmful to a patient’s recovery,” the editorialists wrote. “Conversely, PSAC offers room for the clinician to discuss how other causes may be maintaining, magnifying, or mimicking concussion symptoms.”

Commenting on the findings, Richard Figler, MD, an orthopedic surgeon at the Cleveland Clinic, Cleveland, praised the researchers for addressing concussion in younger children, a field in which little research has been conducted. The research supports the current approaches to treatment. The approach has shifted toward easing children quickly and safely back into normal routines. “We don’t cocoon kids. We don’t send them to dark rooms,” Figler added.

He also commended the researchers’ decision to examine data about concussions linked to limited contact sports. In contact sports, participants may be more likely to anticipate and prepare for a hit. That’s not the case with injuries sustained in limited contact sports.

“Dodgeball is basically a sucker punch. That’s why these kids have so many concussions,” said Figler. “They typically don’t see the ball coming, or they can’t get out of the way, and they can’t tense themselves to take that blow.”

The Predicting and Preventing Postconcussive Problems in Pediatrics study was funded by the Canadian Institutes of Health Research and the Canadian Institutes of Health Research-Ontario Neurotrauma Foundation Mild Traumatic Brain Injury Team. Ledoux reported receiving grants from the Children’s Hospital of Eastern Ontario Foundation, Ontario Brain Institute, and University of Ottawa Brain and Mind Research Institute. She received nonfinancial support from Mobio Interactive outside the submitted work. Zuckerman reported receiving personal fees from the National Football League and Medtronic outside the submitted work. Figler had no relevant financial disclosures.

A version of this article appeared on Medscape.com.

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.

PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”

In a study presented at the American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.

“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition. ... This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD — The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, said at the meeting.

During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Ohio, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”

In an interview with this news organization, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity. ... It just shows where the field is. We need better biomarkers.”

 

In Those With PEM, Exercise May Harm

Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told this news organization, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful. ... There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”

For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.

This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatologic conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”

Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”

Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told this news organization: “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse. ... Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”

There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.

Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.

Yellman commented: “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”

 

How Prevalent Is PEM in Rheumatologic Conditions?

For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January–June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.

Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).

A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.

Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.

The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July–December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.

By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.

Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.

 

Better Tools Are Available

The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, Illinois, told this news organization that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.

Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).

The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).

For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.

Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 

And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”

Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early in 2025. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

Yellman is also working to define minimum quality of care standards for infection-associated chronic conditions for state medical boards and to provide continuing medical education for clinicians on those standards. These would include recognizing and evaluating patients for PEM, as well as orthostatic intolerance, cognitive impairment, and other associated comorbidities.

Importantly, he said, the standards will include the principles of teaching people with PEM how to pace and will emphasize not prescribing them graded exercise as first- or even second-line therapy. “We need people to do some basic things. And the first thing is do no harm.”

None of the individuals quoted for this article had relevant financial disclosures.

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

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.

METHODOLOGY:

• Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
• They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
• The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
• The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.

TAKEAWAY:

• At the 5-year follow-up, the incidence and risk for MACE were higher in patients with anorexia than in those without (4.82% vs 0.85% and adjusted hazard ratio [aHR], 3.78; 95% CI, 2.83-5.05, respectively).
• Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
• Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
• The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.

IN PRACTICE:

“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.

“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
 

SOURCE:

The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.

LIMITATIONS:

The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.

DISCLOSURES:

This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.