Endocrinology

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

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

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

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

A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.

Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.

“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
 

Getting the balance right: a tricky task

Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.

“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.

In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.

For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.

They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.

The mean age of participants was 67 years and 88.7% were male.

Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.

Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.

In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.

Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.

The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.

“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.

Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.

Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.

Addressing over- and under-treatment will avoid harm

The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.

And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.

“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.

Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.

“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.

“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.

“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”

The authors have reported no relevant financial relationships.

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

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

Exposure to per- and polyfluoroalkyl substances (PFAS) - a class of widely used synthetic chemicals dubbed “forever chemicals” - can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible contributor to growing NAFLD epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase were significantly associated with exposure to three of the older chemicals – PFOA, PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals, PFOA, was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, department of population and public health sciences, University of Southern California, Los Angeles, told this news organization.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Ms. Costello explained.

People widely exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways – through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Ms. Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Ms. Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

Dr. VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” Dr. VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” Dr. VanWagner added.

Further research needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, MD. MSc, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, PhD, MS, with the National Institute of Environmental Health Sciences, Research Triangle Park, N.C.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Dr. Ducatman and Dr. Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the U.S. Department of Agriculture National Institute of Food and Agriculture. Dr. Costello, Dr. VanWagner, Dr. Ducatman, and Dr. Fenton report no relevant financial relationships.

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

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

Approximately 7% of youth who chose gender identity social transition in early childhood had retransitioned 5 years later, based on data from 317 individuals.

“Increasing numbers of children are socially transitioning to live in line with their gender identity, rather than the gender assumed by their sex at birth – a process that typically involves changing a child’s pronouns, first name, hairstyle, and clothing,” wrote Kristina R. Olson, PhD, of Princeton (N.J.) University, and colleagues.

The question of whether early childhood social transitions will result in high rates of retransition continues to be a subject for debate, and long-term data on retransition rates and identity outcomes in children who transition are limited, they said.

To examine retransition in early-transitioning children, the researchers identified 317 binary socially transitioned transgender children to participate in a longitudinal study known as the Trans Youth Project (TYP) between July 2013 and December 2017. The study was published in Pediatrics. The mean age at baseline was 8 years. At study entry, participants had to have made a complete binary social transition, including changing their pronouns from those used at birth. During the 5-year follow-up period, children and parents were asked about use of puberty blockers and/or gender-affirming hormones. At study entry, 37 children had begun some type of puberty blockers. A total of 124 children initially socially transitioned before 6 years of age, and 193 initially socially transitioned at 6 years or older.

The study did not evaluate whether the participants met the DSM-5 criteria for gender dysphoria in childhood, the researchers noted. “Based on data collected at their initial visit, we do know that these participants showed signs of gender identification and gender-typed preferences commonly associated with their gender, not their sex assigned at birth,” they wrote.

Participants were classified as binary transgender, nonbinary, or cisgender based on their pronouns at follow-up. Binary transgender pronouns were associated with the other binary assigned sex, nonbinary pronouns were they/them or a mix of they/them and binary pronouns, and cisgender pronouns were those associated with assigned sex.

Overall, 7.3% of the participants had retransitioned at least once by 5 years after their initial binary social transition. The majority (94%) were living as binary transgender youth, including 1.3% who retransitioned to cisgender or nonbinary and then back to binary transgender during the follow-up period. A total of 2.5% were living as cisgender youth and 3.5% were living as nonbinary youth. These rates were similar across the initial population, as well as the 291 participants who continue to be in contact with the researchers, the 200 who had gone at least 5 years since their initial social transition, and the 280 participants who began the study before starting puberty blockers.

The researchers found no differences in retransition rates related to participant sex at birth. Rates of retransition were slightly higher among participants who made their initial social transition before 6 years of age, but these rates were low, the researchers noted.

The study findings were limited by several factors including the use of a volunteer community sample, with the potential for bias that may not generalize to the population at large, the researchers noted. Other limitations included the use of pronouns as the main criteria for retransition, and the classification of a change from binary transgender to nonbinary as a transition, they said. “Many nonbinary people consider themselves to be transgender,” they noted.

“If we had used a stricter criterion of retransition, more similar to the common use of terms like “detransition” or “desistence,” referring only to youth who are living as cisgender, then our retransition rate would have been lower (2.5%),” the researchers explained. Another limitation was the disproportionate number of trans girls, the researchers said. However, because no significant gender effect appeared in terms of retransition rates, “we do not predict any change in pattern of results if we had a different ratio of participants by sex at birth,” they said.

The researchers stated that they intend to follow the cohort through adolescence and into adulthood.

“As more youth are coming out and being supported in their transitions early in development, it is increasingly critical that clinicians understand the experiences of this cohort and not make assumptions about them as a function of older data from youth who lived under different circumstances,” the researchers emphasized. “Though we can never predict the exact gender trajectory of any child, these data suggest that many youth who identify as transgender early, and are supported through a social transition, will continue to identify as transgender 5 years after initial social transition.” They concluded that more research is needed to determine how best to support initial and later gender transitions in youth.
 

Study offers support for family discussions

“This study is important to help provide more data regarding the experiences of gender-diverse youth,” M. Brett Cooper, MD, of UT Southwestern Medical Center, Dallas, said in an interview. “The results of a study like this can be used by clinicians to help provide advice and guidance to parents and families as they support their children through their gender journey,” said Dr. Cooper, who was not involved in the study. The current study “also provides evidence to support that persistent, insistent, and consistent youth have an extremely low rate of retransition to a gender that aligns with their sex assigned at birth. This refutes suggestions by politicians and others that those who seek medical care have a high rate of regret or retransition,” Dr. Cooper emphasized.

“I was not surprised at all by their findings,” said Dr. Cooper. “These are very similar to what I have seen in my own panel of gender-diverse patients and what has been seen in other studies,” he noted.

The take-home message of the current study does not suggest any change in clinical practice, Dr. Cooper said. “Guidance already suggests supporting these youth on their gender journey and that for some youth, this may mean retransitioning to identify with their sex assigned at birth,” he explained.

The study was supported in part by grants to the researchers from the National Institutes of Health, the National Science Foundation, the Arcus Foundation, and the MacArthur Foundation. The researchers had no financial conflicts to disclose.

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

New research suggests physicians face a Herculean task to get Americans with atherosclerotic cardiovascular disease (ASCVD) to take high-intensity statins, despite multiple professional guidelines giving the therapy their highest level recommendation.

Results from more 600,000 commercially insured patients with established ASCVD showed:

• Only one in five patients (22.5%) were taking a high-intensity statin.
• 27.6% were taking a low- or moderate-intensity statin.
• One-half (49.9%) were not taking any statin.

“It’s embarrassing,” senior author Christopher B. Granger, MD, Duke Clinical Research Institute, Durham, N.C., told this news organization. “It should be embarrassing for anybody in health care that we do such a terrible job with something so simple and effective.”

The results were published in the Journal of the American College of Cardiology.

Statins have been shown to reduce the risk for ASCVD events by about 30%, with an added 15% reduction with a high-intensity formulation. The class I recommendation for high-intensity statin use in ASCVD patients younger than 75 years in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines prompted a jump in prescriptions that plateaued by 2017.

A class II recommendation was added to the 2018 guideline update for high-intensity statins in adults older than 75 years with ASCVD. But underuse persists, despite falling prices with generic availability and initiatives to improve statin adoption, the authors noted.

“There are a lot of barriers for patients to statin use, including the misinformation on the Internet and elsewhere that statins have all kinds of side effects,” Dr. Granger said. “They have uncommon side effects, but when we look at it carefully, only about 10% of patients, even with statin intolerance, have true intolerance.”

Efforts are needed to better understand and address these barriers, particularly for younger and female patients, he noted.

In multivariate analyses, patients who were middle-aged (odds ratio, 2.66) or at least 75 years of age (OR, 2.09) were more than twice as likely as patients younger than 45 years to be on any statin.

Not surprisingly, women were 30% less likely than men to receive a statin (OR, 0.70), Dr. Granger said. A high Charlson comorbidity score (OR, 0.72) and peripheral artery disease (OR, 0.55) also reduced the odds of a statin prescription.

Among statin users, middle-aged (OR, 0.83) and older (OR, 0.44) patients were less likely to be on a high-intensity statin, as were women (OR, 0.68) and patients with peripheral artery disease (OR, 0.43).

Visiting a cardiologist in the previous 12 months, however, increased the odds a patient was on a high-intensity statin (OR, 1.21), as did the use of other LDL-cholesterol-lowering drugs (OR, 1.44).

“With no evidence of heterogeneity in efficacy by sex, ongoing work must not only address misperceptions and barriers to the prescription of high-intensity statins in women, but also further understand (and address) differences in tolerability, which may be related to sex-based variation in statin metabolism,” wrote the authors, led by Adam J. Nelson, MBBS, MBA, MPH, also from Duke.

The study involved 601,934 patients (mean age, 67.5 years) who had a diagnosis of ASCVD between Jan. 31, 2018, and an index date of Jan. 31, 2019, and were enrolled in the HealthCore Integrated Research Environment database.

Two-thirds (70.9%) of patients visited a cardiologist in the 12 months prior to the index date, and three-fourths (81.3%) visited a primary care provider.

Pharmacy claims for the 12 months after the index date showed 82.8% of high-intensity users at index achieved coverage for at least 75% of days. Those with the least adherence (< 50% of days covered) included younger patients, as well as those with chronic kidney disease or depression.

“We need implementation research. What are the tools and the methods that we can use to improve the proportion of patients who are having the life-saving benefits from statins?” Dr. Granger said.

He noted that the team has submitted a National Institutes of Health grant to try to use pharmacists, as a mechanism within the context of health systems and payer systems, to improve the appropriate use of statins in a randomized trial. “I think that’s a win.”

Salim S. Virani, MD, PhD, Baylor College of Medicine, and Michael DeBakey VA Medical Center, Houston, and colleagues point out in a related editorial that the rates of statin usage in the study are “considerably lower” than in other contemporary studies, where about 80% and 50% of ASCVD patients are receiving statins and high-intensity statins, respectively.

Possible explanations are the use of rule-out codes, a short medication fill window from the index date, or issues with medication capture, they said. “Nevertheless, the findings are largely consistent with other work highlighting low use of statin therapy.”

The editorialists said social media, statin-related adverse effects, and therapeutic inertia are key drivers of non–guideline-concordant statin use. Possible solutions include improving guideline dissemination, leveraging team-based care, using smart clinical decision-support tools at the point of care, and identifying trustworthy and easily understood sources of information for patients.

“We can only hope that the fate of statin therapy is not repeated with sodium-glucose cotranspoerter-2 inhibitors or glucagon-like peptide-1 receptor agonists in another 30 years, or worse yet, that continued gaps in statin therapy use in patients with ASCVD persist 30 years from now,” Dr. Virani and colleagues concluded.

A sliver of optimism?

A research letter by Colantonio et al. in the same issue of JACC points to some positive steps, at least among patients having a myocardial infarction (MI). It reported that the percentage of patients who received a high-intensity statin as their first statin prescription 30 days after MI jumped from 30.7% in the first quarter of 2011 to 78.6% in the fourth quarter of 2019.

Similar increases were reported by race/ethnicity, despite statin use previously shown to be lower among non-Hispanic Black patients with ASCVD. In each calendar year, however, high-intensity statin therapy was lower among patients older than 75 years and among women.

Dr. Granger disclosed ties with Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, AKROS, Apple, AstraZeneca, Daiichi Sankyo, Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceuticals, AbbVie, Bayer, Boston Scientific, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Virani disclosed ties with the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, and the Jooma and Tahir Family, and the American College of Cardiology.

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

CHICAGO – Recent research has changed at least one physician’s understanding of obesity and boosted her hope for fighting it.

Caroline Apovian, MD, codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, described some of the new insights about obesity she has gained during her talk at the annual meeting of the American College of Physicians.

“When I was a medical student a while back, I learned that fat tissue just sat there and stored fat,” she said. “Now we know it’s an endocrine organ.”

This tissue secretes hormones, such as leptin, and other factors that have an array of effects on the brain, pancreas, heart, liver, and muscles. Moreover, it has plasticity, with the ability to change, constantly adjusting our metabolism as nutrient supply and demand changes, she continued.

Obesity leads to a decline in this plasticity, leading to fibrosis and inflammation and other problems. These changes can further impair the function of adipose tissue, leading to metabolic disease. But the central role of adipose tissue, and its dynamic nature, presents an opportunity for treatment, Dr. Apovian said, during her talk.
 

Hints to why obesity has become more common

More than 42% of the U.S. population – “unbelievably,” Dr. Apovian said – is obese, meaning they have a BMI over 30, according to the Centers for Disease Control and Prevention. That’s up by about 25% since 1960, although calories eaten hasn’t increased, and physical activity has increased somewhat, she said.

The root cause is still a bit of a mystery, but according to “good hints and clues” from animal models that are starting to be translated to the study of human obesity, “it has to do with epigenetics and how our brains and our bodies are perceiving the environment,” she noted, during her presentation.

“Our genes haven’t changed. Our environment has changed,” she said.

The industrialization of the food supply, the use of pesticides and preservatives, the dawn of fast food have all combined, most likely, to do “a number on our bodies,” Dr. Apovian said.

But not all hope is lost thanks to new research, Dr. Apovian suggested.
 

New treatments show promise for helping patients’ obesity

New research that has increased Dr. Apovian’s understanding of the sophisticated role of adipose tissue may be helpful for treating patients with obesity, offering more targets for intervention, she told the audience.

Some treatment avenues already identified have started producing results, Dr. Apovian noted.

Gastric bypass surgery typically leads to a loss of 25% of body weight, but is often shunned by patients, she said. “With such a great surgical procedure, we still only do 256,000 procedures and we have millions of Americans with a BMI over 30.”

Weight control with obsessive dieting, meal-planning and calorie-counting, “can be done, but it’s really hard,” Dr. Apovian noted.

More appealing therapies targeting hormones and appetite suppression have produced impressive results. Recently approved semaglutide produced 14% weight loss, compared with about 2% for placebo, she said.

Results just released for tirzepatide, a dual agonist of gut hormones GLP-1 and GIP, show a 22% total weight loss, compared with about 2% for placebo, with about 56% of patients losing more than 20% of their body weight, Dr. Apovian said.

Referencing studies finding that several hormones are altered during weight loss, she predicted that targeting multiple hormones with drug treatment will also be necessary for best results.

But, she noted, “we’re treating obesity now with one- or two-drug combos.”
 

Medication costs are too high for many patients

Isis Smith, MD, an internist at University Medical Center in New Orleans, said in an interview that the cost of the most effective medications – which are not covered by Medicaid – means that many of her patients don’t have access to these treatments.

“We’re talking about $1,000 a month. And so there is no way they can afford [them]. I can prescribe phentermine [but] unless a patient has another indication, Medicaid will not pay for it,” she explained.

“I love hearing about all of the new developments. ... It’s interesting to hear, but we need to get insurance to pay so that I can actually prescribe,” Dr. Smith noted.

Dr. Apovian reports financial relationships with Xeno Biosciences, Cowen, Allergan, Novo Nordisk, Abbott Nutrition, and other companies.

CHICAGO – Recent research has changed at least one physician’s understanding of obesity and boosted her hope for fighting it.

Caroline Apovian, MD, codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, described some of the new insights about obesity she has gained during her talk at the annual meeting of the American College of Physicians.

“When I was a medical student a while back, I learned that fat tissue just sat there and stored fat,” she said. “Now we know it’s an endocrine organ.”

This tissue secretes hormones, such as leptin, and other factors that have an array of effects on the brain, pancreas, heart, liver, and muscles. Moreover, it has plasticity, with the ability to change, constantly adjusting our metabolism as nutrient supply and demand changes, she continued.

Obesity leads to a decline in this plasticity, leading to fibrosis and inflammation and other problems. These changes can further impair the function of adipose tissue, leading to metabolic disease. But the central role of adipose tissue, and its dynamic nature, presents an opportunity for treatment, Dr. Apovian said, during her talk.
 

Hints to why obesity has become more common

More than 42% of the U.S. population – “unbelievably,” Dr. Apovian said – is obese, meaning they have a BMI over 30, according to the Centers for Disease Control and Prevention. That’s up by about 25% since 1960, although calories eaten hasn’t increased, and physical activity has increased somewhat, she said.

The root cause is still a bit of a mystery, but according to “good hints and clues” from animal models that are starting to be translated to the study of human obesity, “it has to do with epigenetics and how our brains and our bodies are perceiving the environment,” she noted, during her presentation.

“Our genes haven’t changed. Our environment has changed,” she said.

The industrialization of the food supply, the use of pesticides and preservatives, the dawn of fast food have all combined, most likely, to do “a number on our bodies,” Dr. Apovian said.

But not all hope is lost thanks to new research, Dr. Apovian suggested.
 

New treatments show promise for helping patients’ obesity

New research that has increased Dr. Apovian’s understanding of the sophisticated role of adipose tissue may be helpful for treating patients with obesity, offering more targets for intervention, she told the audience.

Some treatment avenues already identified have started producing results, Dr. Apovian noted.

Gastric bypass surgery typically leads to a loss of 25% of body weight, but is often shunned by patients, she said. “With such a great surgical procedure, we still only do 256,000 procedures and we have millions of Americans with a BMI over 30.”

Weight control with obsessive dieting, meal-planning and calorie-counting, “can be done, but it’s really hard,” Dr. Apovian noted.

More appealing therapies targeting hormones and appetite suppression have produced impressive results. Recently approved semaglutide produced 14% weight loss, compared with about 2% for placebo, she said.

Results just released for tirzepatide, a dual agonist of gut hormones GLP-1 and GIP, show a 22% total weight loss, compared with about 2% for placebo, with about 56% of patients losing more than 20% of their body weight, Dr. Apovian said.

Referencing studies finding that several hormones are altered during weight loss, she predicted that targeting multiple hormones with drug treatment will also be necessary for best results.

But, she noted, “we’re treating obesity now with one- or two-drug combos.”
 

Medication costs are too high for many patients

Isis Smith, MD, an internist at University Medical Center in New Orleans, said in an interview that the cost of the most effective medications – which are not covered by Medicaid – means that many of her patients don’t have access to these treatments.

“We’re talking about $1,000 a month. And so there is no way they can afford [them]. I can prescribe phentermine [but] unless a patient has another indication, Medicaid will not pay for it,” she explained.

“I love hearing about all of the new developments. ... It’s interesting to hear, but we need to get insurance to pay so that I can actually prescribe,” Dr. Smith noted.

Dr. Apovian reports financial relationships with Xeno Biosciences, Cowen, Allergan, Novo Nordisk, Abbott Nutrition, and other companies.

CHICAGO – Recent research has changed at least one physician’s understanding of obesity and boosted her hope for fighting it.

Caroline Apovian, MD, codirector of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, described some of the new insights about obesity she has gained during her talk at the annual meeting of the American College of Physicians.

“When I was a medical student a while back, I learned that fat tissue just sat there and stored fat,” she said. “Now we know it’s an endocrine organ.”

This tissue secretes hormones, such as leptin, and other factors that have an array of effects on the brain, pancreas, heart, liver, and muscles. Moreover, it has plasticity, with the ability to change, constantly adjusting our metabolism as nutrient supply and demand changes, she continued.

Obesity leads to a decline in this plasticity, leading to fibrosis and inflammation and other problems. These changes can further impair the function of adipose tissue, leading to metabolic disease. But the central role of adipose tissue, and its dynamic nature, presents an opportunity for treatment, Dr. Apovian said, during her talk.
 

Hints to why obesity has become more common

More than 42% of the U.S. population – “unbelievably,” Dr. Apovian said – is obese, meaning they have a BMI over 30, according to the Centers for Disease Control and Prevention. That’s up by about 25% since 1960, although calories eaten hasn’t increased, and physical activity has increased somewhat, she said.

The root cause is still a bit of a mystery, but according to “good hints and clues” from animal models that are starting to be translated to the study of human obesity, “it has to do with epigenetics and how our brains and our bodies are perceiving the environment,” she noted, during her presentation.

“Our genes haven’t changed. Our environment has changed,” she said.

The industrialization of the food supply, the use of pesticides and preservatives, the dawn of fast food have all combined, most likely, to do “a number on our bodies,” Dr. Apovian said.

But not all hope is lost thanks to new research, Dr. Apovian suggested.
 

New treatments show promise for helping patients’ obesity

New research that has increased Dr. Apovian’s understanding of the sophisticated role of adipose tissue may be helpful for treating patients with obesity, offering more targets for intervention, she told the audience.

Some treatment avenues already identified have started producing results, Dr. Apovian noted.

Gastric bypass surgery typically leads to a loss of 25% of body weight, but is often shunned by patients, she said. “With such a great surgical procedure, we still only do 256,000 procedures and we have millions of Americans with a BMI over 30.”

Weight control with obsessive dieting, meal-planning and calorie-counting, “can be done, but it’s really hard,” Dr. Apovian noted.

More appealing therapies targeting hormones and appetite suppression have produced impressive results. Recently approved semaglutide produced 14% weight loss, compared with about 2% for placebo, she said.

Results just released for tirzepatide, a dual agonist of gut hormones GLP-1 and GIP, show a 22% total weight loss, compared with about 2% for placebo, with about 56% of patients losing more than 20% of their body weight, Dr. Apovian said.

Referencing studies finding that several hormones are altered during weight loss, she predicted that targeting multiple hormones with drug treatment will also be necessary for best results.

But, she noted, “we’re treating obesity now with one- or two-drug combos.”
 

Medication costs are too high for many patients

Isis Smith, MD, an internist at University Medical Center in New Orleans, said in an interview that the cost of the most effective medications – which are not covered by Medicaid – means that many of her patients don’t have access to these treatments.

“We’re talking about $1,000 a month. And so there is no way they can afford [them]. I can prescribe phentermine [but] unless a patient has another indication, Medicaid will not pay for it,” she explained.

“I love hearing about all of the new developments. ... It’s interesting to hear, but we need to get insurance to pay so that I can actually prescribe,” Dr. Smith noted.

Dr. Apovian reports financial relationships with Xeno Biosciences, Cowen, Allergan, Novo Nordisk, Abbott Nutrition, and other companies.

Mild traumatic brain injury (TBI) is linked to a significantly increased risk for a host of subsequent cardiovascular, endocrine, neurologic, and psychiatric disorders, new research shows.

Incidence of hypertension, coronary heart disease, diabetes, stroke, depression, and dementia all began to increase soon after the brain injury and persisted over a decade in both mild and moderate to severe TBI.

Researchers found the multisystem comorbidities in all age groups, including in patients as young as 18. They also found that patients who developed multiple postinjury problems had higher mortality during the decade-long follow-up.

The findings suggest patients with TBI may require longer follow-up and proactive screening for multisystem disease, regardless of age or injury severity.

“The fact that both patients with mild and moderate to severe injuries both had long-term ongoing associations with comorbidities that continued over time and that they are cardiovascular, endocrine, neurologic, and behavioral health oriented was pretty striking,” study author Ross Zafonte, DO, PhD, president of Spaulding Rehab Hospital and professor and chair of physical medicine and rehab at Harvard Medical School, both in Boston, told this news organization.

The study was published online in JAMA Network Open.
 

Injury severity not a factor

An estimated 2.8 million individuals in the United States experience TBI every year. Worldwide, the figure may be as high as 74 million.

Studies have long suggested a link between brain injury and subsequent neurologic disorders, but research suggesting a possible link to cardiovascular and endocrine problems has recently gained attention.

Building on a 2021 study that showed increased incidence of cardiovascular issues following a concussion, the researchers examined medical records of previously healthy patients treated for TBI between 2000 and 2015 who also had at least 1 follow-up visit between 6 months and 10 years after the initial injury.

Researchers analyzed data from 13,053 individuals – 4,351 with mild injury (mTBI), 4351 with moderate to severe injury (msTBI), and 4351 with no TBI. The most common cause of injury was a fall. Patients with sports-related injuries were excluded.

Incidence of hypertension was significantly higher among patients with mTBI (hazard ratio, 2.5; 95% confidence interval, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9), compared with the unaffected group. Risk for other cardiovascular problems, including hyperlipidemia, obesity, and coronary artery disease, were also higher in the affected groups.

TBI patients also reported higher incidence of endocrine diseases, including diabetes (mTBI: HR, 1.9; 95% CI, 1.4-2.7; msTBI: HR, 1.9; 95% CI, 1.4-2.6). Elevated risk for ischemic stroke or transient ischemic attack was also increased (mTBI: HR, 2.2; 95% CI, 1.4-3.3; msTBI: HR, 3.6; 95% CI, 2.4-5.3).

Regardless of injury severity, patients with TBI had a higher risk for neurologic and psychiatric diseases, particularly depression, dementia, and psychotic disorders. “This tells us that mild TBI is not clean of events,” Dr. Zafonte said.

Surprising rate of comorbidity in youth

Investigators found increased risk for posttrauma comorbidities in all age groups, but researchers were struck by the high rates in younger patients, aged 18-40. Compared with age-matched individuals with no TBI history, hypertension risk was nearly six times higher in those with mTBI (HR, 5.9; 95% CI, 3.9-9.1) and nearly four times higher in patients with msTBI (HR, 3.9; 95% CI, 2.5-6.1).

Rates of hyperlipidemia and diabetes were also higher in younger patients in the mTBI group and posttraumatic seizures and psychiatric disorders were elevated regardless of TBI severity.

Overall, patients with msTBI, but not those with mTBI, were at higher risk for mortality, compared with the unexposed group (432 deaths [9.9%] vs. 250 deaths [5.7%]; P < .001).

“It’s clear that what we may be dealing with is that it holds up even for the younger people,” Dr. Zafonte said. “We used to think brain injury risk is worse in the severe cases, which it is, and it’s worse later on among those who are older, which it is. But our younger folks don’t get away either.”

While the study offers associations between TBI and multisystem health problems, Dr. Zafonte said it’s impossible to say at this point whether the brain injury caused the increased risk for cardiovascular or endocrine problems. Other organ injuries sustained in the trauma may be a contributing factor.

“Further data is needed to elucidate the mechanism and the causative relationships, which we do not have here,” he said.

Many of the postinjury comorbidities emerged a median of 3.5 years after TBI, regardless of severity. But some of the cardiovascular and psychiatric conditions emerged far sooner than that.

That’s important because research suggests less than half of patients with TBI receive follow-up care.

“It does make sense for folks who are interacting with people who’ve had a TBI to be suspicious of medical comorbidities relatively early on, within the first couple of years,” Dr. Zafonte said.

In an invited commentary, Vijay Krishnamoorthy, MD, MPH, PhD, Duke University, Durham, N.C., and Monica S. Vavilala, MD, University of Washington, Seattle, highlight some of the study’s limitations, including a lack of information on comorbidity severity and the lack of a matched group of patients who experienced non-head trauma.

Despite those limitations, the study offers important information on how TBI may affect organs beyond the brain, they noted.

“These observations, if replicated in future studies, raise intriguing implications in the future care of patients with TBI, including heightened chronic disease-screening measures and possibly enhanced guidelines for chronic extracranial organ system care for patients who experience TBI,” Dr. Krishnamoorthy and Dr. Vavilala wrote.

The study received no specific funding. Dr. Zafonte reported having received personal fees from Springer/Demos, serving on scientific advisory boards for Myomo and OnCare and has received funding from the Football Players Health Study at Harvard, funded in part by the National Football League Players Association. Dr. Krishnamoorthy and Dr. Vavilala disclosed no relevant financial relationships.

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

Mild traumatic brain injury (TBI) is linked to a significantly increased risk for a host of subsequent cardiovascular, endocrine, neurologic, and psychiatric disorders, new research shows.

Incidence of hypertension, coronary heart disease, diabetes, stroke, depression, and dementia all began to increase soon after the brain injury and persisted over a decade in both mild and moderate to severe TBI.

Researchers found the multisystem comorbidities in all age groups, including in patients as young as 18. They also found that patients who developed multiple postinjury problems had higher mortality during the decade-long follow-up.

The findings suggest patients with TBI may require longer follow-up and proactive screening for multisystem disease, regardless of age or injury severity.

“The fact that both patients with mild and moderate to severe injuries both had long-term ongoing associations with comorbidities that continued over time and that they are cardiovascular, endocrine, neurologic, and behavioral health oriented was pretty striking,” study author Ross Zafonte, DO, PhD, president of Spaulding Rehab Hospital and professor and chair of physical medicine and rehab at Harvard Medical School, both in Boston, told this news organization.

The study was published online in JAMA Network Open.
 

Injury severity not a factor

An estimated 2.8 million individuals in the United States experience TBI every year. Worldwide, the figure may be as high as 74 million.

Studies have long suggested a link between brain injury and subsequent neurologic disorders, but research suggesting a possible link to cardiovascular and endocrine problems has recently gained attention.

Building on a 2021 study that showed increased incidence of cardiovascular issues following a concussion, the researchers examined medical records of previously healthy patients treated for TBI between 2000 and 2015 who also had at least 1 follow-up visit between 6 months and 10 years after the initial injury.

Researchers analyzed data from 13,053 individuals – 4,351 with mild injury (mTBI), 4351 with moderate to severe injury (msTBI), and 4351 with no TBI. The most common cause of injury was a fall. Patients with sports-related injuries were excluded.

Incidence of hypertension was significantly higher among patients with mTBI (hazard ratio, 2.5; 95% confidence interval, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9), compared with the unaffected group. Risk for other cardiovascular problems, including hyperlipidemia, obesity, and coronary artery disease, were also higher in the affected groups.

TBI patients also reported higher incidence of endocrine diseases, including diabetes (mTBI: HR, 1.9; 95% CI, 1.4-2.7; msTBI: HR, 1.9; 95% CI, 1.4-2.6). Elevated risk for ischemic stroke or transient ischemic attack was also increased (mTBI: HR, 2.2; 95% CI, 1.4-3.3; msTBI: HR, 3.6; 95% CI, 2.4-5.3).

Regardless of injury severity, patients with TBI had a higher risk for neurologic and psychiatric diseases, particularly depression, dementia, and psychotic disorders. “This tells us that mild TBI is not clean of events,” Dr. Zafonte said.

Surprising rate of comorbidity in youth

Investigators found increased risk for posttrauma comorbidities in all age groups, but researchers were struck by the high rates in younger patients, aged 18-40. Compared with age-matched individuals with no TBI history, hypertension risk was nearly six times higher in those with mTBI (HR, 5.9; 95% CI, 3.9-9.1) and nearly four times higher in patients with msTBI (HR, 3.9; 95% CI, 2.5-6.1).

Rates of hyperlipidemia and diabetes were also higher in younger patients in the mTBI group and posttraumatic seizures and psychiatric disorders were elevated regardless of TBI severity.

Overall, patients with msTBI, but not those with mTBI, were at higher risk for mortality, compared with the unexposed group (432 deaths [9.9%] vs. 250 deaths [5.7%]; P < .001).

“It’s clear that what we may be dealing with is that it holds up even for the younger people,” Dr. Zafonte said. “We used to think brain injury risk is worse in the severe cases, which it is, and it’s worse later on among those who are older, which it is. But our younger folks don’t get away either.”

While the study offers associations between TBI and multisystem health problems, Dr. Zafonte said it’s impossible to say at this point whether the brain injury caused the increased risk for cardiovascular or endocrine problems. Other organ injuries sustained in the trauma may be a contributing factor.

“Further data is needed to elucidate the mechanism and the causative relationships, which we do not have here,” he said.

Many of the postinjury comorbidities emerged a median of 3.5 years after TBI, regardless of severity. But some of the cardiovascular and psychiatric conditions emerged far sooner than that.

That’s important because research suggests less than half of patients with TBI receive follow-up care.

“It does make sense for folks who are interacting with people who’ve had a TBI to be suspicious of medical comorbidities relatively early on, within the first couple of years,” Dr. Zafonte said.

In an invited commentary, Vijay Krishnamoorthy, MD, MPH, PhD, Duke University, Durham, N.C., and Monica S. Vavilala, MD, University of Washington, Seattle, highlight some of the study’s limitations, including a lack of information on comorbidity severity and the lack of a matched group of patients who experienced non-head trauma.

Despite those limitations, the study offers important information on how TBI may affect organs beyond the brain, they noted.

“These observations, if replicated in future studies, raise intriguing implications in the future care of patients with TBI, including heightened chronic disease-screening measures and possibly enhanced guidelines for chronic extracranial organ system care for patients who experience TBI,” Dr. Krishnamoorthy and Dr. Vavilala wrote.

The study received no specific funding. Dr. Zafonte reported having received personal fees from Springer/Demos, serving on scientific advisory boards for Myomo and OnCare and has received funding from the Football Players Health Study at Harvard, funded in part by the National Football League Players Association. Dr. Krishnamoorthy and Dr. Vavilala disclosed no relevant financial relationships.

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

Mild traumatic brain injury (TBI) is linked to a significantly increased risk for a host of subsequent cardiovascular, endocrine, neurologic, and psychiatric disorders, new research shows.

Incidence of hypertension, coronary heart disease, diabetes, stroke, depression, and dementia all began to increase soon after the brain injury and persisted over a decade in both mild and moderate to severe TBI.

Researchers found the multisystem comorbidities in all age groups, including in patients as young as 18. They also found that patients who developed multiple postinjury problems had higher mortality during the decade-long follow-up.

The findings suggest patients with TBI may require longer follow-up and proactive screening for multisystem disease, regardless of age or injury severity.

“The fact that both patients with mild and moderate to severe injuries both had long-term ongoing associations with comorbidities that continued over time and that they are cardiovascular, endocrine, neurologic, and behavioral health oriented was pretty striking,” study author Ross Zafonte, DO, PhD, president of Spaulding Rehab Hospital and professor and chair of physical medicine and rehab at Harvard Medical School, both in Boston, told this news organization.

The study was published online in JAMA Network Open.
 

Injury severity not a factor

An estimated 2.8 million individuals in the United States experience TBI every year. Worldwide, the figure may be as high as 74 million.

Studies have long suggested a link between brain injury and subsequent neurologic disorders, but research suggesting a possible link to cardiovascular and endocrine problems has recently gained attention.

Building on a 2021 study that showed increased incidence of cardiovascular issues following a concussion, the researchers examined medical records of previously healthy patients treated for TBI between 2000 and 2015 who also had at least 1 follow-up visit between 6 months and 10 years after the initial injury.

Researchers analyzed data from 13,053 individuals – 4,351 with mild injury (mTBI), 4351 with moderate to severe injury (msTBI), and 4351 with no TBI. The most common cause of injury was a fall. Patients with sports-related injuries were excluded.

Incidence of hypertension was significantly higher among patients with mTBI (hazard ratio, 2.5; 95% confidence interval, 2.1-2.9) and msTBI (HR, 2.4; 95% CI, 2.0-2.9), compared with the unaffected group. Risk for other cardiovascular problems, including hyperlipidemia, obesity, and coronary artery disease, were also higher in the affected groups.

TBI patients also reported higher incidence of endocrine diseases, including diabetes (mTBI: HR, 1.9; 95% CI, 1.4-2.7; msTBI: HR, 1.9; 95% CI, 1.4-2.6). Elevated risk for ischemic stroke or transient ischemic attack was also increased (mTBI: HR, 2.2; 95% CI, 1.4-3.3; msTBI: HR, 3.6; 95% CI, 2.4-5.3).

Regardless of injury severity, patients with TBI had a higher risk for neurologic and psychiatric diseases, particularly depression, dementia, and psychotic disorders. “This tells us that mild TBI is not clean of events,” Dr. Zafonte said.

Surprising rate of comorbidity in youth

Investigators found increased risk for posttrauma comorbidities in all age groups, but researchers were struck by the high rates in younger patients, aged 18-40. Compared with age-matched individuals with no TBI history, hypertension risk was nearly six times higher in those with mTBI (HR, 5.9; 95% CI, 3.9-9.1) and nearly four times higher in patients with msTBI (HR, 3.9; 95% CI, 2.5-6.1).

Rates of hyperlipidemia and diabetes were also higher in younger patients in the mTBI group and posttraumatic seizures and psychiatric disorders were elevated regardless of TBI severity.

Overall, patients with msTBI, but not those with mTBI, were at higher risk for mortality, compared with the unexposed group (432 deaths [9.9%] vs. 250 deaths [5.7%]; P < .001).

“It’s clear that what we may be dealing with is that it holds up even for the younger people,” Dr. Zafonte said. “We used to think brain injury risk is worse in the severe cases, which it is, and it’s worse later on among those who are older, which it is. But our younger folks don’t get away either.”

While the study offers associations between TBI and multisystem health problems, Dr. Zafonte said it’s impossible to say at this point whether the brain injury caused the increased risk for cardiovascular or endocrine problems. Other organ injuries sustained in the trauma may be a contributing factor.

“Further data is needed to elucidate the mechanism and the causative relationships, which we do not have here,” he said.

Many of the postinjury comorbidities emerged a median of 3.5 years after TBI, regardless of severity. But some of the cardiovascular and psychiatric conditions emerged far sooner than that.

That’s important because research suggests less than half of patients with TBI receive follow-up care.

“It does make sense for folks who are interacting with people who’ve had a TBI to be suspicious of medical comorbidities relatively early on, within the first couple of years,” Dr. Zafonte said.

In an invited commentary, Vijay Krishnamoorthy, MD, MPH, PhD, Duke University, Durham, N.C., and Monica S. Vavilala, MD, University of Washington, Seattle, highlight some of the study’s limitations, including a lack of information on comorbidity severity and the lack of a matched group of patients who experienced non-head trauma.

Despite those limitations, the study offers important information on how TBI may affect organs beyond the brain, they noted.

“These observations, if replicated in future studies, raise intriguing implications in the future care of patients with TBI, including heightened chronic disease-screening measures and possibly enhanced guidelines for chronic extracranial organ system care for patients who experience TBI,” Dr. Krishnamoorthy and Dr. Vavilala wrote.

The study received no specific funding. Dr. Zafonte reported having received personal fees from Springer/Demos, serving on scientific advisory boards for Myomo and OnCare and has received funding from the Football Players Health Study at Harvard, funded in part by the National Football League Players Association. Dr. Krishnamoorthy and Dr. Vavilala disclosed no relevant financial relationships.

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

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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