Cardiology

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

TOPLINE:

Metformin cuts the risk for diabetic nephropathy (DN) and major kidney and cardiovascular events in patients with newly diagnosed type 2 diabetes (T2D) across various renal function states.

METHODOLOGY:

Metformin is a first-line treatment in US and South Korean T2D management guidelines, except for patients with advanced chronic kidney disease (CKD) (stage, ≥ 4; estimated glomerular filtration rate [eGFR], < 30).

The study used data from the databases of three tertiary hospitals in South Korea to assess the effect of metformin on long-term renal and cardiovascular outcomes across various renal function states in patients with newly diagnosed T2D.

Four groups of treatment-control comparative cohorts were identified at each hospital: Patients who had not yet developed DN at T2D diagnosis (mean age in treatment and control cohorts, 61-65 years) and those with reduced renal function (CKD stages 3A, 3B, and 4).

Patients who continuously received metformin after T2D diagnosis and beyond the observation period were 1:1 propensity score matched with controls who were prescribed oral hypoglycemic agents other than metformin.

Primary outcomes were net major adverse cardiovascular events including strokes (MACEs) or in-hospital death and a composite of major adverse kidney events (MAKEs) or in-hospital death.

TAKEAWAY:

Among patients without DN at T2D diagnosis, the continuous use of metformin vs other oral hypoglycemic agents was associated with a lower risk for:

Overt DN (incidence rate ratio [IRR], 0.82; 95% CI, 0.71-0.95),

MACEs (IRR, 0.76; 95% CI, 0.64-0.92), and

MAKEs (IRR, 0.45; 95% CI, 0.33-0.62).

Compared with non-metformin or discontinued metformin use, the continuous use of metformin was associated with a lower risk for MACE across CKD stages 3A (IRR, 0.70; 95% CI, 0.57-0.87), 3B (IRR, 0.83; 95% CI, 0.74-0.93), and 4 (IRR, 0.71; 95% CI, 0.60-0.85).

Similarly, the risk for MAKE was lower among continuous metformin users than in nonusers or discontinuous metformin users across CKD stage 3A (IRR, 0.39; 95% CI, 0.35-0.43), 3B (IRR, 0.44; 95% CI, 0.40-0.48), and 4 (IRR, 0.45; 95% CI, 0.39-0.51).

IN PRACTICE:

“The significance of the current study is highlighted by its integration of real-world clinical data, which encompasses patients diagnosed with CDK4 [eGRF, 15-29 mL/min/1.73 m2], a group currently considered contraindicated,” the authors wrote.

SOURCE:

The study, led by Yongjin Yi, MD, PhD, Department of Internal Medicine, Dankook University College of Medicine, Cheonan-si, Republic of Korea, was published in Scientific Reports.

LIMITATIONS:

There may be a possibility of selection bias because of the retrospective and observational nature of this study. Despite achieving a 1:1 propensity score matching to address the confounding factors, some variables, such as serum albumin and A1c levels, remained unbalanced after matching. The paper did not include observation length or patient numbers, but in response to an email query from Medscape, Yi notes that in one hospital, the mean duration of observation for the control and treatment groups was about 6.5 years, and the total number in the treatment groups across data from three hospitals was 11,675, with the same number of matched controls.

DISCLOSURES:

This study was supported by a Young Investigator Research Grant from the Korean Society of Nephrology, a grant from the Seoul National University Bundang Hospital Research Fund, and the Bio&Medical Technology Development Program of the National Research Foundation funded by the Korean government. The authors disclosed no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Metformin cuts the risk for diabetic nephropathy (DN) and major kidney and cardiovascular events in patients with newly diagnosed type 2 diabetes (T2D) across various renal function states.

METHODOLOGY:

Metformin is a first-line treatment in US and South Korean T2D management guidelines, except for patients with advanced chronic kidney disease (CKD) (stage, ≥ 4; estimated glomerular filtration rate [eGFR], < 30).

The study used data from the databases of three tertiary hospitals in South Korea to assess the effect of metformin on long-term renal and cardiovascular outcomes across various renal function states in patients with newly diagnosed T2D.

Four groups of treatment-control comparative cohorts were identified at each hospital: Patients who had not yet developed DN at T2D diagnosis (mean age in treatment and control cohorts, 61-65 years) and those with reduced renal function (CKD stages 3A, 3B, and 4).

Patients who continuously received metformin after T2D diagnosis and beyond the observation period were 1:1 propensity score matched with controls who were prescribed oral hypoglycemic agents other than metformin.

Primary outcomes were net major adverse cardiovascular events including strokes (MACEs) or in-hospital death and a composite of major adverse kidney events (MAKEs) or in-hospital death.

TAKEAWAY:

Among patients without DN at T2D diagnosis, the continuous use of metformin vs other oral hypoglycemic agents was associated with a lower risk for:

Overt DN (incidence rate ratio [IRR], 0.82; 95% CI, 0.71-0.95),

MACEs (IRR, 0.76; 95% CI, 0.64-0.92), and

MAKEs (IRR, 0.45; 95% CI, 0.33-0.62).

Compared with non-metformin or discontinued metformin use, the continuous use of metformin was associated with a lower risk for MACE across CKD stages 3A (IRR, 0.70; 95% CI, 0.57-0.87), 3B (IRR, 0.83; 95% CI, 0.74-0.93), and 4 (IRR, 0.71; 95% CI, 0.60-0.85).

Similarly, the risk for MAKE was lower among continuous metformin users than in nonusers or discontinuous metformin users across CKD stage 3A (IRR, 0.39; 95% CI, 0.35-0.43), 3B (IRR, 0.44; 95% CI, 0.40-0.48), and 4 (IRR, 0.45; 95% CI, 0.39-0.51).

IN PRACTICE:

“The significance of the current study is highlighted by its integration of real-world clinical data, which encompasses patients diagnosed with CDK4 [eGRF, 15-29 mL/min/1.73 m2], a group currently considered contraindicated,” the authors wrote.

SOURCE:

The study, led by Yongjin Yi, MD, PhD, Department of Internal Medicine, Dankook University College of Medicine, Cheonan-si, Republic of Korea, was published in Scientific Reports.

LIMITATIONS:

There may be a possibility of selection bias because of the retrospective and observational nature of this study. Despite achieving a 1:1 propensity score matching to address the confounding factors, some variables, such as serum albumin and A1c levels, remained unbalanced after matching. The paper did not include observation length or patient numbers, but in response to an email query from Medscape, Yi notes that in one hospital, the mean duration of observation for the control and treatment groups was about 6.5 years, and the total number in the treatment groups across data from three hospitals was 11,675, with the same number of matched controls.

DISCLOSURES:

This study was supported by a Young Investigator Research Grant from the Korean Society of Nephrology, a grant from the Seoul National University Bundang Hospital Research Fund, and the Bio&Medical Technology Development Program of the National Research Foundation funded by the Korean government. The authors disclosed no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Metformin cuts the risk for diabetic nephropathy (DN) and major kidney and cardiovascular events in patients with newly diagnosed type 2 diabetes (T2D) across various renal function states.

METHODOLOGY:

Metformin is a first-line treatment in US and South Korean T2D management guidelines, except for patients with advanced chronic kidney disease (CKD) (stage, ≥ 4; estimated glomerular filtration rate [eGFR], < 30).

The study used data from the databases of three tertiary hospitals in South Korea to assess the effect of metformin on long-term renal and cardiovascular outcomes across various renal function states in patients with newly diagnosed T2D.

Four groups of treatment-control comparative cohorts were identified at each hospital: Patients who had not yet developed DN at T2D diagnosis (mean age in treatment and control cohorts, 61-65 years) and those with reduced renal function (CKD stages 3A, 3B, and 4).

Patients who continuously received metformin after T2D diagnosis and beyond the observation period were 1:1 propensity score matched with controls who were prescribed oral hypoglycemic agents other than metformin.

Primary outcomes were net major adverse cardiovascular events including strokes (MACEs) or in-hospital death and a composite of major adverse kidney events (MAKEs) or in-hospital death.

TAKEAWAY:

Among patients without DN at T2D diagnosis, the continuous use of metformin vs other oral hypoglycemic agents was associated with a lower risk for:

Overt DN (incidence rate ratio [IRR], 0.82; 95% CI, 0.71-0.95),

MACEs (IRR, 0.76; 95% CI, 0.64-0.92), and

MAKEs (IRR, 0.45; 95% CI, 0.33-0.62).

Compared with non-metformin or discontinued metformin use, the continuous use of metformin was associated with a lower risk for MACE across CKD stages 3A (IRR, 0.70; 95% CI, 0.57-0.87), 3B (IRR, 0.83; 95% CI, 0.74-0.93), and 4 (IRR, 0.71; 95% CI, 0.60-0.85).

Similarly, the risk for MAKE was lower among continuous metformin users than in nonusers or discontinuous metformin users across CKD stage 3A (IRR, 0.39; 95% CI, 0.35-0.43), 3B (IRR, 0.44; 95% CI, 0.40-0.48), and 4 (IRR, 0.45; 95% CI, 0.39-0.51).

IN PRACTICE:

“The significance of the current study is highlighted by its integration of real-world clinical data, which encompasses patients diagnosed with CDK4 [eGRF, 15-29 mL/min/1.73 m2], a group currently considered contraindicated,” the authors wrote.

SOURCE:

The study, led by Yongjin Yi, MD, PhD, Department of Internal Medicine, Dankook University College of Medicine, Cheonan-si, Republic of Korea, was published in Scientific Reports.

LIMITATIONS:

There may be a possibility of selection bias because of the retrospective and observational nature of this study. Despite achieving a 1:1 propensity score matching to address the confounding factors, some variables, such as serum albumin and A1c levels, remained unbalanced after matching. The paper did not include observation length or patient numbers, but in response to an email query from Medscape, Yi notes that in one hospital, the mean duration of observation for the control and treatment groups was about 6.5 years, and the total number in the treatment groups across data from three hospitals was 11,675, with the same number of matched controls.

DISCLOSURES:

This study was supported by a Young Investigator Research Grant from the Korean Society of Nephrology, a grant from the Seoul National University Bundang Hospital Research Fund, and the Bio&Medical Technology Development Program of the National Research Foundation funded by the Korean government. The authors disclosed no competing interests.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) announced the removal of the endocrine-disrupting chemicals (EDCs) per- and polyfluoroalkyl substances (PFAS) from food packaging.

Issued on February 28, 2024, “this means the major source of dietary exposure to PFAS from food packaging like fast-food wrappers, microwave popcorn bags, take-out paperboard containers, and pet food bags is being eliminated,” the FDA said in a statement.

In 2020, the FDA had secured commitments from manufacturers to stop selling products containing PFAS used in the food packaging for grease-proofing. “Today’s announcement marks the fulfillment of these voluntary commitments,” according to the agency.

PFAS, a class of thousands of chemicals also called “forever chemicals” are widely used in consumer and industrial products. People may be exposed via contaminated food packaging (although perhaps no longer in the United States) or occupationally. Studies have found that some PFAS disrupt hormones including estrogen and testosterone, whereas others may impair thyroid function.
 

Endocrine Society Report Sounds the Alarm About PFAS and Others

The FDA’s announcement came just 2 days after the Endocrine Society issued a new alarm about the human health dangers from environmental EDCs including PFAS in a report covering the latest science.

“Endocrine disrupting chemicals” are individual substances or mixtures that can interfere with natural hormonal function, leading to disease or even death. Many are ubiquitous in the modern environment and contribute to a wide range of human diseases.

The new report Endocrine Disrupting Chemicals: Threats to Human Health was issued jointly with the International Pollutants Elimination Network (IPEN), a global advocacy organization. It’s an update to the Endocrine Society’s 2015 report, providing new data on the endocrine-disrupting substances previously covered and adding four EDCs not discussed in that document: Pesticides, plastics, PFAS, and children’s products containing arsenic.

At a briefing held during the United Nations Environment Assembly meeting in Nairobi, Kenya, last week, the new report’s lead author Andrea C. Gore, PhD, of the University of Texas at Austin, noted, “A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions.”

Added Dr. Gore, who is also a member of the Endocrine Society’s Board of Directors, “These chemicals pose particularly serious risks to pregnant women and children. Now is the time for the UN Environment Assembly and other global policymakers to take action to address this threat to public health.”

While the science has been emerging rapidly, global and national chemical control policies haven’t kept up, the authors said. Of particular concern is that EDCs behave differently from other chemicals in many ways, including that even very low-dose exposures can pose health threats, but policies thus far haven’t dealt with that aspect.

Moreover, “the effects of low doses cannot be predicted by the effects observed at high doses. This means there may be no safe dose for exposure to EDCs,” according to the report.

Exposures can come from household products, including furniture, toys, and food packages, as well as electronics building materials and cosmetics. These chemicals are also in the outdoor environment, via pesticides, air pollution, and industrial waste.

“IPEN and the Endocrine Society call for chemical regulations based on the most modern scientific understanding of how hormones act and how EDCs can perturb these actions. We work to educate policy makers in global, regional, and national government assemblies and help ensure that regulations correlate with current scientific understanding,” they said in the report.
 

New Data on Four Classes of EDCs

Chapters of the report summarized the latest information about the science of EDCs and their links to endocrine disease and real-world exposure. It included a special section about “EDCs throughout the plastics life cycle” and a summary of the links between EDCs and climate change.

The report reviewed three pesticides, including the world’s most heavily applied herbicide, glycophosphate. Exposures can occur directly from the air, water, dust, and food residues. Recent data linked glycophosphate to adverse reproductive health outcomes.

Two toxic plastic chemicals, phthalates and bisphenols, are present in personal care products, among others. Emerging evidence links them with impaired neurodevelopment, leading to impaired cognitive function, learning, attention, and impulsivity.

Arsenic has long been linked to human health conditions including cancer, but more recent evidence finds it can disrupt multiple endocrine systems and lead to metabolic conditions including diabetes, reproductive dysfunction, and cardiovascular and neurocognitive conditions.

The special section about plastics noted that they are made from fossil fuels and chemicals, including many toxic substances that are known or suspected EDCs. People who live near plastic production facilities or waste dumps may be at greatest risk, but anyone can be exposed using any plastic product. Plastic waste disposal is increasingly problematic and often foisted on lower- and middle-income countries.
 

‘Additional Education and Awareness-Raising Among Stakeholders Remain Necessary’

Policies aimed at reducing human health risks from EDCs have included the 2022 Plastics Treaty, a resolution adopted by 175 countries at the United Nations Environmental Assembly that “may be a significant step toward global control of plastics and elimination of threats from exposures to EDCs in plastics,” the report said.

The authors added, “While significant progress has been made in recent years connecting scientific advances on EDCs with health-protective policies, additional education and awareness-raising among stakeholders remain necessary to achieve a safer and more sustainable environment that minimizes exposure to these harmful chemicals.”

The document was produced with financial contributions from the Government of Sweden, the Tides Foundation, Passport Foundation, and other donors.

A version of this article appeared on Medscape.com.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

A 73-year-old man with hypertension is evaluated for right great toe pain. A tap of the toe reveals uric acid crystals. He has a history of hypertension and hyperlipidemia. His current medications are hydrochlorothiazide, amlodipine, and atorvastatin.

Which blood pressure medication would you recommend to replace his hydrochlorothiazide?

A. Furosemide

B. Chlorthalidone

C. Lisinopril

D. Losartan

E. Irbesartan

Losartan

Diuretics should be avoided if possible in a patient with gout, as they increase uric acid levels. Of the other three options, losartan offers the added benefit of lowering uric acid levels. Losartan has uricosuric effects — a property that is unique to losartan of the angiotensin receptor blockers (ARBs) that have been studied.^1,2 The uric acid lowering appears to be a probenecid-like effect.

Losartan has also been evaluated to see whether using it in combination with a thiazide diuretic can reduce the rise in uric acid that occurs with thiazides. Matsumura and colleagues looked at data from the COMFORT trial, focusing on the effect of combining losartan with hydrochlorothiazide on uric acid levels.³ They looked at a group of 118 patients on an ARB other than losartan plus a diuretic, who were then randomly assigned to losartan 50 mg/hydrochlorothiazide 12.5 mg or continuation of another ARB plus a diuretic. Blood pressure control was the same between groups, but the patients who received the losartan combination had lower uric acid levels (P = .01).

Ferreira and colleagues looked at the difference in uric acid lowering between high-dose (150 mg/day) vs low-dose losartan (50 mg/day).⁴ Compared with low-dose, high-dose losartan reduced serum uric acid by 0.27 (0.34 to 0.21) mg/dL, P < .001.
 

SGLT2 inhibitors

SGLT2 inhibitors also lower uric acid. Suijik and colleagues conducted an analysis of two randomized trials of SGLT2 inhibitors (empagliflozin and dapagliflozin), and concluded that SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion.⁵

Metformin

Metformin is used as a firstline drug for the treatment of diabetes. It also has evidence for decreasing colonic polyps. Cho and colleagues looked at over 12,000 patients with diabetes over a 12-year period; 3775 underwent colonoscopies.⁶ They compared frequency of polyps in patients who were using metformin with those who were not treated with metformin. The polyp detection rate was lower in the metformin group than in the no metformin group (39.4% vs. 62.4%, P < .01).

Higurashi and colleagues performed a double-blind, placebo-controlled trial of metformin in nondiabetic patients for the prevention of colon polyps.⁷ The dose of metformin used in this study was very low (250 mg/day). There were significantly fewer adenomas in the metformin group (22 of 71 patients) than in the placebo group (32 of 62) (relative risk, 0.60; 95% confidence interval, 0.39-0.92, P = .016).
 

Thiazide diuretics

Thiazide diuretics have long been used to help prevent kidney stones in addition to treating hypertension. They decrease urinary calcium excretion, which may reduce kidney stones. Could this reduction in calcium excretion be good for bones?

Xiao and colleagues did a meta-analysis of 11 prospective studies involving 2,193,160 participants.⁸ Thiazide diuretic users had a significant 14% reduction in the risk of all fractures (RR, 0.86; 95% CI, 0.80-0.93; P = .009) and an 18% reduction in the risk of hip fracture (RR, 0.82; 95% CI, 0.80-0.93; P = .009). Kruse and colleagues found that long duration and continuity of thiazide exposure seemed to be important to obtain this protective effect on fracture risk.⁹

Pearls:

• Losartan, but not other ARBs, lowers uric acid levels and may be helpful in managing hypertension in gout patients; higher doses lower uric acid more.
• Metformin use appears to decrease colon polyp formation.
• Thiazide diuretics may reduce fracture risk while patients are taking them.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Würzner G et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60.

2. Puig JG et al. Effect of eprosartan and losartan on uric acid metabolism in patients with essential hypertension. J Hypertens. 1999 Jul;17(7):1033-9.

3. Matsumura K et al. Effect of losartan on serum uric acid in hypertension treated with a diuretic: The COMFORT study. Clin Exp Hypertens. 2015;37(3):192-6.

4. Ferreira JP et al. High- versus low-dose losartan and uric acid: An analysis from HEAAL. J Cardiol. 2023 Jul;82(1):57-61.

5. Suijk DLS et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Soc Nephrol. 2022 May;17(5):663-71.

6. Youn Hee Cho et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intestinal Res. 2014 Apr;12(2):139-45.

7. Higurashi T et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: A multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475-83.

8. Xiao X et al. Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies. Osteoporos Int. 2018 Jul;29(7):1515-24.

9. Kruse C et al. Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk. J Intern Med. 2016 Jan;279(1):110-22.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

People with gout are 58% more likely to develop cardiovascular disease (CVD), according to a new analysis. This increased risk was observed across 12 different cardiovascular conditions, including heart failure, arrhythmias, and valve diseases.

“These findings suggest that the organ damage associated with gout is likely to be much broader than originally thought,” Nathalie Conrad, PhD, senior author of the research and cardiovascular epidemiologist at KU Leuven, Leuven, Belgium, said in an email. This could be useful for future research on underlying biological mechanisms driving CVD risk in gout, she added.

While previous research has tied gout to increased cardiovascular risk, these studies “largely focused on coronary heart disease, stroke, and thromboembolic outcomes,” she explained, and have been smaller in size.

This new study included more than 862,000 individuals, which permitted researchers to investigate rarer CVD outcomes such as myocarditis and pericarditis.

For the study, researchers used electronic health records from the UK Clinical Practice Research Datalink, a primary care database that contains anonymized health data for about 22 million individuals. Using these data, they identified more than 152,600 individuals with gout. Patients included in the analysis were diagnosed between 2000 and 2017, younger than 80 years at diagnosis, and free of CVD for at least 12 months after their gout diagnosis.

Patients with gout were compared with nearly 710,000 controls, matched on demographic factors such as age, sex, and geographic region.

Researchers then investigated the incidence of 12 CVDs, including atherosclerotic diseases, degenerative and thromboembolic diseases, and arrythmias, between the two groups from January 1, 2000, to June 30, 2019.

The findings were published in the March 2024 issue of The Lancet Rheumatology. Overall, patients with gout were 58% more likely to develop any CVD than their matched comparators without gout. There was a higher disease incidence among patients with gout for each of the 12 conditions. This association was more pronounced in women (hazard ratio [HR], 1.88) than in men (HR, 1.49), and gout amplified the risk for CVD in younger individuals to a greater extent.

Individuals younger than 45 years with gout were more than twice as likely to develop CVD compared with similarly aged individuals without gout. For comparison, individuals aged 45-54 years with gout were 84% more likely to develop CVD, and individuals aged 55-64 years were 57% more likely to develop CVD than matched controls.

Conduction system disease had the highest incident risk (HR, 1.88), followed by heart failure and valve disease (HR, 1.85 for both).

Individuals with gout had higher rates of comorbidities than the controls, including hypertension, obesity, and dyslipidemia. Overall, CVD risk was slightly attenuated after adjustment for traditional CVD risk factors such as smoking, blood pressure, and body mass index but still significant: Patients with gout had a 31% higher risk for CVD than comparators.

This shows “that known CVD risk factors only explain part of the CVD risks seen in patients with gout,” Dr. Conrad said. Other factors such as inflammation and other disease activity factors could be at play, she explained, which would need to be explored in future research.

The study “shows the whole landscape” of CVD and gout, Michael H. Pillinger, MD, rheumatologist and professor of medicine, biochemistry, and molecular pharmacology at NYU Grossman School of Medicine in New York City, said in an interview. He was not involved with the research.

“Every possible cardiovascular disease that they could think of was something that gout patients had more of than the non-gout patients,” he added. “I think this is going to be a paper that gets cited a lot, at minimum when describing the background of risk when we look at gout patients.”

The study had some limitations, including that researchers were unable to account for how medications such as nonsteroidal anti-inflammatory drugs, corticosteroids, colchicine, or allopurinol may have affected the association between gout and CVD.

“This is because analyses of nonrandomized treatment can be confounded by indication, wherein it is difficult to differentiate the effects of the treatment from underlying disease severity,” the authors wrote.

There was also a large amount of missing data on blood pressure, body mass index, smoking status, and other health information relevant to cardiovascular risk, so sensitivity analyses adjusting for these factors “should be interpreted with caution,” they added.

Dr. Pillinger also noted that the rates of comorbidities in the gout study population were lower than what have been found in US study populations. For example, about 40% of patients with gout in the analysis had hypertension, while other studies have suggested higher rates of 60%-70%, he said. However, it’s not clear if these differences could have affected outcomes. He added that these limitations do not “in any way weaken [the authors’] conclusion.”

The findings call for better strategies to reduce CVD risk in patients with gout, Dr. Conrad noted.

“Further improvements could come from better recognition and intervention on CVD risk factors (eg, through lifestyle changes or drug therapies where they are indicated), as well as proactive screening for heart disease in patients with gout, which could allow early diagnosis and interventions to delay more severe outcomes,” she added.

This study was funded by Research Foundation Flanders. Dr. Conrad was funded by a personal fellowship from the Research Foundation Flanders and a European Society of Cardiology research grant. She received royalties from Oxford University Innovation. Four of Dr. Conrad’s eight coauthors also reported financial relationships with pharmaceutical companies. Dr. Pillinger served as a consultant to Amgen, Federation Bio, Fortress Biotech, and Scilex, and he holds an investigator-initiated grant from Hikma.

A version of this article appeared on Medscape.com.

For many, stretching is the fitness equivalent of awkward small talk. It’s the opening act, the thing you tolerate because you know it will be over soon. 

Others have challenged the practice, suggesting that stretching isn’t necessary at all. Some research has found that a preworkout stretch may even be disadvantageous, weakening muscles and hindering performance.

To put it plainly, no one seems terribly enthusiastic about touching their toes. 

That’s why a 2020 study on exercise and mortality was such a head-scratcher. The study found that stretching was uniquely associated with a lower risk for all-cause mortality among American adults. That’s after controlling for participation in other types of exercise. 

The finding seemed like a fluke, until a 2023 study found essentially the same thing. 

Among Korean adults, those who did flexibility exercise at least five times a week had a 20% lower risk of dying during the follow-up period than those who didn’t stretch at all. That was slightly better than the risk reduction associated with high volumes of aerobic exercise and resistance training. 

How can that be ? It turns out, stretching is linked to several health benefits that you might not expect.
 

The Surprising Benefits of Stretching

When we talk about stretching, we usually mean static stretching — getting into and holding a position that challenges a muscle, with the goal of improving range of motion around a joint. 

It doesn’t need to be a big challenge. “Research shows you can get increases in flexibility by stretching to the initial point of discomfort,” said David Behm, PhD, an exercise scientist at Memorial University of Newfoundland in Canada who’s published dozens of studies on stretching over the past quarter-century. 

That brings us to the first benefit.
 

Stretching Benefit #1: More Strength

At first glance, flexibility training and strength training have little in common. You lengthen muscles in the former and contract them in the latter. 

But in both cases, Dr. Behm said, you’re applying tension to muscles and connective tissues. Tension activates proteins called integrins, which send and receive signals across cellular membranes. Those signals are the start of a cascade that leads to protein synthesis. That’s how muscles get bigger and stronger when you lift weights. 

That mechanism could explain the small gains in muscle strength and size associated with static stretching, Dr. Behm said. 

But can you really stretch your way to muscle growth? Theoretically, yes. But strength training is far more time-efficient, Dr. Behm says. Studies showing increases in muscle mass have typically stretched a single muscle (usually the calves, using a specialized device) for > 30 min/session, 6 d/wk for 6 weeks. And that’s for just one leg.

Still, stretching may be more accessible for some patients — research suggested that older and more sedentary people are most likely to benefit from stretching-induced gains in strength.

 

Stretching Benefit #2: Reduced Arterial Stiffness

“Most people don’t think about the cardiovascular benefits of stretching,” Dr. Behm said. There are some big ones. 

If your body doesn’t move well, it’s not unreasonable to assume your blood doesn’t flow well. That is indeed the case: Poor flexibility is associated with arterial stiffness. 

Stretching is associated not only with improved arterial function but also with reductions in resting heart rate and blood pressure and increased vasodilation.

Mobility improvements may have an indirect benefit on cardiovascular health as well. 

“Studies show runners are more economical when they’re more flexible,” Dr. Behm said. If your movement is more efficient, you’ll probably do more of it. Doing more, in turn, would lead to improved fitness. 
 

Stretching Benefit #3: Improved Performance

Research is equivocal on whether stretching improves athletic performance, said Joe Yoon, a sports massage therapist in Orlando, Florida, and author of Better Stretching. 

“But I’ve always taken the approach that if you can improve your range of motion and get into positions” required for your sport, you’ll probably perform better, with less risk for injury, Mr. Yoon said. 

It’s worth noting that some research over the past 30 years has linked pre-exercise static stretching with a loss of strength, power, and/or speed. 

But consider this: In a 2016 review, Dr. Behm and his coauthors showed that performance reductions were most likely to occur in two situations: 

When participants did extremely long stretches (duration, ≥ 60 sec per muscle).

When researchers tested the participants’ strength, power, or speed immediately after they stretched.

Avoiding those problems is easy, Dr. Behm said: Stretch each muscle for < 60 sec, and combine static stretches with more active warm-up exercises. 

“Stretching can impair your performance but only if you do it wrong,” he said.
 

Stretching Benefit #4: Fewer Injuries

When you stretch, the point where you feel tension is where the muscle is most vulnerable. “That’s where injuries usually happen,” Dr. Behm said. 

More flexibility in those areas allows your muscles to safely generate force at longer lengths. For an athlete, that means fewer injuries when they’re doing explosive movements or changing direction. 

For nonathletes, flexibility reduces injuries by improving balance. Better balance reduces the risk of falling and helps mitigate the damage if you do take a tumble.
 

Help Your Patients Get the Benefits of Stretching

Stretching, like training for endurance or strength, can be as complex as you want to make it. But Mr. Yoon advocates a simpler approach. 

“You see this flashy stuff online,” he said. “But if you see those trainers in real life or you book a session with them, they go right back to the basics.” 

Ideally, Mr. Yoon said, a flexibility routine will work the entire body. But if that’s too big a stretch for your patient, he recommends starting with one or two stretches for the most problematic area. 

For example, for a stiff back, try doing the puppy pose at least once a day, although twice is better. Hold the position for 30 seconds to 2 minutes, said Mr. Yoon. Even if you combine it with a dynamic movement like the cat-cow, the two exercises would take just a few minutes a day. 

“There’s this misconception that you have to do a lot of it to be successful,” Mr. Yoon said. 

Consistency is far more important than volume. Mr. Yoon recommends “a little bit every day — the minimum viable dose.” 

As a bonus, stretching an area like your upper back will probably improve your shoulder mobility, Mr. Yoon said. Same with your lower body: Stretches for your hips, over time, should also benefit your knees and lower back. 

And thanks to a phenomenon called nonlocal flexibility transfer, lower-body stretches should improve upper-body flexibility, at least temporarily. Shoulder stretches can also have an immediate effect on hip mobility. 

“It’s all connected,” Mr. Yoon said, which brings us back to where we started. 

If stretching can indeed reduce mortality risk, it’s probably because of interconnected pathways, rather than any single mechanism. 

Most obviously, stretching improves flexibility, which makes movement easier, improves balance, and reduces the risk for falls and other types of injuries. It can also lead to small improvements in strength. Less obviously, stretching improves several aspects of cardiovascular function, including circulation. 

“There seems to be a global effect in everything we do,” Dr. Behm said. “Whether you’re stretching or weight training, the message is sent throughout your body."

A version of this article appeared on Medscape.com.

For many, stretching is the fitness equivalent of awkward small talk. It’s the opening act, the thing you tolerate because you know it will be over soon. 

Others have challenged the practice, suggesting that stretching isn’t necessary at all. Some research has found that a preworkout stretch may even be disadvantageous, weakening muscles and hindering performance.

To put it plainly, no one seems terribly enthusiastic about touching their toes. 

That’s why a 2020 study on exercise and mortality was such a head-scratcher. The study found that stretching was uniquely associated with a lower risk for all-cause mortality among American adults. That’s after controlling for participation in other types of exercise. 

The finding seemed like a fluke, until a 2023 study found essentially the same thing. 

Among Korean adults, those who did flexibility exercise at least five times a week had a 20% lower risk of dying during the follow-up period than those who didn’t stretch at all. That was slightly better than the risk reduction associated with high volumes of aerobic exercise and resistance training. 

How can that be ? It turns out, stretching is linked to several health benefits that you might not expect.
 

The Surprising Benefits of Stretching

When we talk about stretching, we usually mean static stretching — getting into and holding a position that challenges a muscle, with the goal of improving range of motion around a joint. 

It doesn’t need to be a big challenge. “Research shows you can get increases in flexibility by stretching to the initial point of discomfort,” said David Behm, PhD, an exercise scientist at Memorial University of Newfoundland in Canada who’s published dozens of studies on stretching over the past quarter-century. 

That brings us to the first benefit.
 

Stretching Benefit #1: More Strength

At first glance, flexibility training and strength training have little in common. You lengthen muscles in the former and contract them in the latter. 

But in both cases, Dr. Behm said, you’re applying tension to muscles and connective tissues. Tension activates proteins called integrins, which send and receive signals across cellular membranes. Those signals are the start of a cascade that leads to protein synthesis. That’s how muscles get bigger and stronger when you lift weights. 

That mechanism could explain the small gains in muscle strength and size associated with static stretching, Dr. Behm said. 

But can you really stretch your way to muscle growth? Theoretically, yes. But strength training is far more time-efficient, Dr. Behm says. Studies showing increases in muscle mass have typically stretched a single muscle (usually the calves, using a specialized device) for > 30 min/session, 6 d/wk for 6 weeks. And that’s for just one leg.

Still, stretching may be more accessible for some patients — research suggested that older and more sedentary people are most likely to benefit from stretching-induced gains in strength.

 

Stretching Benefit #2: Reduced Arterial Stiffness

“Most people don’t think about the cardiovascular benefits of stretching,” Dr. Behm said. There are some big ones. 

If your body doesn’t move well, it’s not unreasonable to assume your blood doesn’t flow well. That is indeed the case: Poor flexibility is associated with arterial stiffness. 

Stretching is associated not only with improved arterial function but also with reductions in resting heart rate and blood pressure and increased vasodilation.

Mobility improvements may have an indirect benefit on cardiovascular health as well. 

“Studies show runners are more economical when they’re more flexible,” Dr. Behm said. If your movement is more efficient, you’ll probably do more of it. Doing more, in turn, would lead to improved fitness. 
 

Stretching Benefit #3: Improved Performance

Research is equivocal on whether stretching improves athletic performance, said Joe Yoon, a sports massage therapist in Orlando, Florida, and author of Better Stretching. 

“But I’ve always taken the approach that if you can improve your range of motion and get into positions” required for your sport, you’ll probably perform better, with less risk for injury, Mr. Yoon said. 

It’s worth noting that some research over the past 30 years has linked pre-exercise static stretching with a loss of strength, power, and/or speed. 

But consider this: In a 2016 review, Dr. Behm and his coauthors showed that performance reductions were most likely to occur in two situations: 

When participants did extremely long stretches (duration, ≥ 60 sec per muscle).

When researchers tested the participants’ strength, power, or speed immediately after they stretched.

Avoiding those problems is easy, Dr. Behm said: Stretch each muscle for < 60 sec, and combine static stretches with more active warm-up exercises. 

“Stretching can impair your performance but only if you do it wrong,” he said.
 

Stretching Benefit #4: Fewer Injuries

When you stretch, the point where you feel tension is where the muscle is most vulnerable. “That’s where injuries usually happen,” Dr. Behm said. 

More flexibility in those areas allows your muscles to safely generate force at longer lengths. For an athlete, that means fewer injuries when they’re doing explosive movements or changing direction. 

For nonathletes, flexibility reduces injuries by improving balance. Better balance reduces the risk of falling and helps mitigate the damage if you do take a tumble.
 

Help Your Patients Get the Benefits of Stretching

Stretching, like training for endurance or strength, can be as complex as you want to make it. But Mr. Yoon advocates a simpler approach. 

“You see this flashy stuff online,” he said. “But if you see those trainers in real life or you book a session with them, they go right back to the basics.” 

Ideally, Mr. Yoon said, a flexibility routine will work the entire body. But if that’s too big a stretch for your patient, he recommends starting with one or two stretches for the most problematic area. 

For example, for a stiff back, try doing the puppy pose at least once a day, although twice is better. Hold the position for 30 seconds to 2 minutes, said Mr. Yoon. Even if you combine it with a dynamic movement like the cat-cow, the two exercises would take just a few minutes a day. 

“There’s this misconception that you have to do a lot of it to be successful,” Mr. Yoon said. 

Consistency is far more important than volume. Mr. Yoon recommends “a little bit every day — the minimum viable dose.” 

As a bonus, stretching an area like your upper back will probably improve your shoulder mobility, Mr. Yoon said. Same with your lower body: Stretches for your hips, over time, should also benefit your knees and lower back. 

And thanks to a phenomenon called nonlocal flexibility transfer, lower-body stretches should improve upper-body flexibility, at least temporarily. Shoulder stretches can also have an immediate effect on hip mobility. 

“It’s all connected,” Mr. Yoon said, which brings us back to where we started. 

If stretching can indeed reduce mortality risk, it’s probably because of interconnected pathways, rather than any single mechanism. 

Most obviously, stretching improves flexibility, which makes movement easier, improves balance, and reduces the risk for falls and other types of injuries. It can also lead to small improvements in strength. Less obviously, stretching improves several aspects of cardiovascular function, including circulation. 

“There seems to be a global effect in everything we do,” Dr. Behm said. “Whether you’re stretching or weight training, the message is sent throughout your body."

A version of this article appeared on Medscape.com.

For many, stretching is the fitness equivalent of awkward small talk. It’s the opening act, the thing you tolerate because you know it will be over soon. 

Others have challenged the practice, suggesting that stretching isn’t necessary at all. Some research has found that a preworkout stretch may even be disadvantageous, weakening muscles and hindering performance.

To put it plainly, no one seems terribly enthusiastic about touching their toes. 

That’s why a 2020 study on exercise and mortality was such a head-scratcher. The study found that stretching was uniquely associated with a lower risk for all-cause mortality among American adults. That’s after controlling for participation in other types of exercise. 

The finding seemed like a fluke, until a 2023 study found essentially the same thing. 

Among Korean adults, those who did flexibility exercise at least five times a week had a 20% lower risk of dying during the follow-up period than those who didn’t stretch at all. That was slightly better than the risk reduction associated with high volumes of aerobic exercise and resistance training. 

How can that be ? It turns out, stretching is linked to several health benefits that you might not expect.
 

The Surprising Benefits of Stretching

When we talk about stretching, we usually mean static stretching — getting into and holding a position that challenges a muscle, with the goal of improving range of motion around a joint. 

It doesn’t need to be a big challenge. “Research shows you can get increases in flexibility by stretching to the initial point of discomfort,” said David Behm, PhD, an exercise scientist at Memorial University of Newfoundland in Canada who’s published dozens of studies on stretching over the past quarter-century. 

That brings us to the first benefit.
 

Stretching Benefit #1: More Strength

At first glance, flexibility training and strength training have little in common. You lengthen muscles in the former and contract them in the latter. 

But in both cases, Dr. Behm said, you’re applying tension to muscles and connective tissues. Tension activates proteins called integrins, which send and receive signals across cellular membranes. Those signals are the start of a cascade that leads to protein synthesis. That’s how muscles get bigger and stronger when you lift weights. 

That mechanism could explain the small gains in muscle strength and size associated with static stretching, Dr. Behm said. 

But can you really stretch your way to muscle growth? Theoretically, yes. But strength training is far more time-efficient, Dr. Behm says. Studies showing increases in muscle mass have typically stretched a single muscle (usually the calves, using a specialized device) for > 30 min/session, 6 d/wk for 6 weeks. And that’s for just one leg.

Still, stretching may be more accessible for some patients — research suggested that older and more sedentary people are most likely to benefit from stretching-induced gains in strength.

 

Stretching Benefit #2: Reduced Arterial Stiffness

“Most people don’t think about the cardiovascular benefits of stretching,” Dr. Behm said. There are some big ones. 

If your body doesn’t move well, it’s not unreasonable to assume your blood doesn’t flow well. That is indeed the case: Poor flexibility is associated with arterial stiffness. 

Stretching is associated not only with improved arterial function but also with reductions in resting heart rate and blood pressure and increased vasodilation.

Mobility improvements may have an indirect benefit on cardiovascular health as well. 

“Studies show runners are more economical when they’re more flexible,” Dr. Behm said. If your movement is more efficient, you’ll probably do more of it. Doing more, in turn, would lead to improved fitness. 
 

Stretching Benefit #3: Improved Performance

Research is equivocal on whether stretching improves athletic performance, said Joe Yoon, a sports massage therapist in Orlando, Florida, and author of Better Stretching. 

“But I’ve always taken the approach that if you can improve your range of motion and get into positions” required for your sport, you’ll probably perform better, with less risk for injury, Mr. Yoon said. 

It’s worth noting that some research over the past 30 years has linked pre-exercise static stretching with a loss of strength, power, and/or speed. 

But consider this: In a 2016 review, Dr. Behm and his coauthors showed that performance reductions were most likely to occur in two situations: 

When participants did extremely long stretches (duration, ≥ 60 sec per muscle).

When researchers tested the participants’ strength, power, or speed immediately after they stretched.

Avoiding those problems is easy, Dr. Behm said: Stretch each muscle for < 60 sec, and combine static stretches with more active warm-up exercises. 

“Stretching can impair your performance but only if you do it wrong,” he said.
 

Stretching Benefit #4: Fewer Injuries

When you stretch, the point where you feel tension is where the muscle is most vulnerable. “That’s where injuries usually happen,” Dr. Behm said. 

More flexibility in those areas allows your muscles to safely generate force at longer lengths. For an athlete, that means fewer injuries when they’re doing explosive movements or changing direction. 

For nonathletes, flexibility reduces injuries by improving balance. Better balance reduces the risk of falling and helps mitigate the damage if you do take a tumble.
 

Help Your Patients Get the Benefits of Stretching

Stretching, like training for endurance or strength, can be as complex as you want to make it. But Mr. Yoon advocates a simpler approach. 

“You see this flashy stuff online,” he said. “But if you see those trainers in real life or you book a session with them, they go right back to the basics.” 

Ideally, Mr. Yoon said, a flexibility routine will work the entire body. But if that’s too big a stretch for your patient, he recommends starting with one or two stretches for the most problematic area. 

For example, for a stiff back, try doing the puppy pose at least once a day, although twice is better. Hold the position for 30 seconds to 2 minutes, said Mr. Yoon. Even if you combine it with a dynamic movement like the cat-cow, the two exercises would take just a few minutes a day. 

“There’s this misconception that you have to do a lot of it to be successful,” Mr. Yoon said. 

Consistency is far more important than volume. Mr. Yoon recommends “a little bit every day — the minimum viable dose.” 

As a bonus, stretching an area like your upper back will probably improve your shoulder mobility, Mr. Yoon said. Same with your lower body: Stretches for your hips, over time, should also benefit your knees and lower back. 

And thanks to a phenomenon called nonlocal flexibility transfer, lower-body stretches should improve upper-body flexibility, at least temporarily. Shoulder stretches can also have an immediate effect on hip mobility. 

“It’s all connected,” Mr. Yoon said, which brings us back to where we started. 

If stretching can indeed reduce mortality risk, it’s probably because of interconnected pathways, rather than any single mechanism. 

Most obviously, stretching improves flexibility, which makes movement easier, improves balance, and reduces the risk for falls and other types of injuries. It can also lead to small improvements in strength. Less obviously, stretching improves several aspects of cardiovascular function, including circulation. 

“There seems to be a global effect in everything we do,” Dr. Behm said. “Whether you’re stretching or weight training, the message is sent throughout your body."

A version of this article appeared on Medscape.com.

TOPLINE: 

Accelerometer-measured physical activity (PA), whether light, moderate, or vigorous, is associated with lower risk for heart failure (HF) in older women while more sedentary time is associated with higher HF risk in these women, results of a new study suggest. 

METHODOLOGY:

• The analysis included 5951 women aged 63-99 years (mean age, 78.6 years), including 33.7% Black, 17.2% Hispanic, and 49.2% White individuals without HF from the Objective Physical Activity and Cardiovascular Health (OPACH) study, an ancillary to the Women’s Health Initiative Long-Life Study.
• Participants wore an accelerometer on their hip 24 hours a day for up to 7 consecutive days except when in water, kept nightly sleep logs, completed questionnaires to provide information on medical history and sociodemographic and lifestyle factors, and self-rated their general health status.
• Researchers recorded their use of assistive walking devices; determined body mass index as well as blood pressure; obtained fasting serum glucose, total and high-density lipoprotein cholesterol, triglyceride, and high-sensitivity C-reactive protein concentrations; and scored participants’ multimorbidity.
• They determined intensity-specific PA using vector magnitude acceleration cut points (light PA, 19-518 counts/15 s; moderate to vigorous PA [MVPA], > 518) and steps per day using dedicated software, and they quantified sedentary time (total and mean bout duration).
• The primary outcome was overall self-reported HF later adjudicated by physicians using medical record reviews; secondary endpoints were heart failure with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), classified by an EF of < 45% or 45% or > 45%, respectively, after cardiac imaging.

TAKEAWAY:

• A total of 407 HF cases (including 257 HFpEF and 110 HFrEF) were identified during a mean of 7.5 years of follow-up.
• HFrEF was not associated with PA measures in the fully adjusted model (which controlled extensively for health and physical functioning status), but overall HF and HFpEF were inversely associated with total PA (per 1-standard deviation [SD] increment: hazard ratio [HR] 0.85; 95% CI, 0.75-0.95 and HR, 0.78; 95% CI, 0.67-0.91, respectively), light PA (HR, 0.88; 95% CI, 0.78-0.98 and HR, 0.80; 95% CI, 0.70-0.93, respectively) and MVPA (HR, 0.84; 95% CI, 0.73-0.97 and HR, 0.85; 95% CI, 0.72-1.01, respectively).
• With regard to daily steps, each 1-SD increment was associated with a significant 26% lower risk for overall HF (HR 0.74; 95% CI, 0.63-0.88) and 29% lower risk for HFpEF (HR, 0.71; 95% CI, 0.57-0.88), with these inverse risks becoming significant at about 2000 steps/d, “far less than the often touted 10,000 steps/d for promoting health benefits,” noted the authors.
• Total sedentary time was positively associated (per 1 SD in the fully adjusted model) with risks of overall HF (HR, 1.17; 95% CI, 1.04-1.33) and HFpEF (HR, 1.29; 95% CI, 1.10-1.51) but not HFrEF; mean sedentary bout duration was significantly inversely associated with HFrEF (per 1 SD: HR, 0.76; 95% CI, 0.61-0.97), although the relatively small number of cases at the extremes of bout duration may contribute to this unexpected inverse association, said the authors.

IN PRACTICE:

The implications of promoting PA, regardless of intensity, for primary HFpEF prevention in later life, “has profound public health and clinical relevance,” the authors concluded. They noted that HFpEF is a “burgeoning epidemic” that disproportionately affects women and minorities with limited available therapies.

STUDY DETAILS:

The study, led by Michael J. LaMonte, PhD, MPH, University at Buffalo-SUNY, Buffalo, New York, was published online on February 21, 2024, in JAMA Cardiology.

LIMITATIONS:

There was only a single accelerometer assessment of PA and sedentary exposures and relatively small numbers of HFrEF cases, which restricted analytic precision. Although researchers controlled for several established vascular biomarkers, they did not have HF-specific measures such as cardiac troponin or N-terminal pro–brain natriuretic peptide. It’s unknown if the findings can be generalized to men and populations dissimilar to women in OPACH.

DISCLOSURES:

The study was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services. LaMonte reported receiving grants from the National Institutes of Health during the conduct of the study; see paper for disclosures of the other authors.
 

A version of this article appeared on Medscape.com.

TOPLINE: 

Accelerometer-measured physical activity (PA), whether light, moderate, or vigorous, is associated with lower risk for heart failure (HF) in older women while more sedentary time is associated with higher HF risk in these women, results of a new study suggest. 

METHODOLOGY:

• The analysis included 5951 women aged 63-99 years (mean age, 78.6 years), including 33.7% Black, 17.2% Hispanic, and 49.2% White individuals without HF from the Objective Physical Activity and Cardiovascular Health (OPACH) study, an ancillary to the Women’s Health Initiative Long-Life Study.
• Participants wore an accelerometer on their hip 24 hours a day for up to 7 consecutive days except when in water, kept nightly sleep logs, completed questionnaires to provide information on medical history and sociodemographic and lifestyle factors, and self-rated their general health status.
• Researchers recorded their use of assistive walking devices; determined body mass index as well as blood pressure; obtained fasting serum glucose, total and high-density lipoprotein cholesterol, triglyceride, and high-sensitivity C-reactive protein concentrations; and scored participants’ multimorbidity.
• They determined intensity-specific PA using vector magnitude acceleration cut points (light PA, 19-518 counts/15 s; moderate to vigorous PA [MVPA], > 518) and steps per day using dedicated software, and they quantified sedentary time (total and mean bout duration).
• The primary outcome was overall self-reported HF later adjudicated by physicians using medical record reviews; secondary endpoints were heart failure with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), classified by an EF of < 45% or 45% or > 45%, respectively, after cardiac imaging.

TAKEAWAY:

• A total of 407 HF cases (including 257 HFpEF and 110 HFrEF) were identified during a mean of 7.5 years of follow-up.
• HFrEF was not associated with PA measures in the fully adjusted model (which controlled extensively for health and physical functioning status), but overall HF and HFpEF were inversely associated with total PA (per 1-standard deviation [SD] increment: hazard ratio [HR] 0.85; 95% CI, 0.75-0.95 and HR, 0.78; 95% CI, 0.67-0.91, respectively), light PA (HR, 0.88; 95% CI, 0.78-0.98 and HR, 0.80; 95% CI, 0.70-0.93, respectively) and MVPA (HR, 0.84; 95% CI, 0.73-0.97 and HR, 0.85; 95% CI, 0.72-1.01, respectively).
• With regard to daily steps, each 1-SD increment was associated with a significant 26% lower risk for overall HF (HR 0.74; 95% CI, 0.63-0.88) and 29% lower risk for HFpEF (HR, 0.71; 95% CI, 0.57-0.88), with these inverse risks becoming significant at about 2000 steps/d, “far less than the often touted 10,000 steps/d for promoting health benefits,” noted the authors.
• Total sedentary time was positively associated (per 1 SD in the fully adjusted model) with risks of overall HF (HR, 1.17; 95% CI, 1.04-1.33) and HFpEF (HR, 1.29; 95% CI, 1.10-1.51) but not HFrEF; mean sedentary bout duration was significantly inversely associated with HFrEF (per 1 SD: HR, 0.76; 95% CI, 0.61-0.97), although the relatively small number of cases at the extremes of bout duration may contribute to this unexpected inverse association, said the authors.

IN PRACTICE:

The implications of promoting PA, regardless of intensity, for primary HFpEF prevention in later life, “has profound public health and clinical relevance,” the authors concluded. They noted that HFpEF is a “burgeoning epidemic” that disproportionately affects women and minorities with limited available therapies.

STUDY DETAILS:

The study, led by Michael J. LaMonte, PhD, MPH, University at Buffalo-SUNY, Buffalo, New York, was published online on February 21, 2024, in JAMA Cardiology.

LIMITATIONS:

There was only a single accelerometer assessment of PA and sedentary exposures and relatively small numbers of HFrEF cases, which restricted analytic precision. Although researchers controlled for several established vascular biomarkers, they did not have HF-specific measures such as cardiac troponin or N-terminal pro–brain natriuretic peptide. It’s unknown if the findings can be generalized to men and populations dissimilar to women in OPACH.

DISCLOSURES:

The study was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services. LaMonte reported receiving grants from the National Institutes of Health during the conduct of the study; see paper for disclosures of the other authors.
 

A version of this article appeared on Medscape.com.

TOPLINE: 

Accelerometer-measured physical activity (PA), whether light, moderate, or vigorous, is associated with lower risk for heart failure (HF) in older women while more sedentary time is associated with higher HF risk in these women, results of a new study suggest. 

METHODOLOGY:

• The analysis included 5951 women aged 63-99 years (mean age, 78.6 years), including 33.7% Black, 17.2% Hispanic, and 49.2% White individuals without HF from the Objective Physical Activity and Cardiovascular Health (OPACH) study, an ancillary to the Women’s Health Initiative Long-Life Study.
• Participants wore an accelerometer on their hip 24 hours a day for up to 7 consecutive days except when in water, kept nightly sleep logs, completed questionnaires to provide information on medical history and sociodemographic and lifestyle factors, and self-rated their general health status.
• Researchers recorded their use of assistive walking devices; determined body mass index as well as blood pressure; obtained fasting serum glucose, total and high-density lipoprotein cholesterol, triglyceride, and high-sensitivity C-reactive protein concentrations; and scored participants’ multimorbidity.
• They determined intensity-specific PA using vector magnitude acceleration cut points (light PA, 19-518 counts/15 s; moderate to vigorous PA [MVPA], > 518) and steps per day using dedicated software, and they quantified sedentary time (total and mean bout duration).
• The primary outcome was overall self-reported HF later adjudicated by physicians using medical record reviews; secondary endpoints were heart failure with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), classified by an EF of < 45% or 45% or > 45%, respectively, after cardiac imaging.

TAKEAWAY:

• A total of 407 HF cases (including 257 HFpEF and 110 HFrEF) were identified during a mean of 7.5 years of follow-up.
• HFrEF was not associated with PA measures in the fully adjusted model (which controlled extensively for health and physical functioning status), but overall HF and HFpEF were inversely associated with total PA (per 1-standard deviation [SD] increment: hazard ratio [HR] 0.85; 95% CI, 0.75-0.95 and HR, 0.78; 95% CI, 0.67-0.91, respectively), light PA (HR, 0.88; 95% CI, 0.78-0.98 and HR, 0.80; 95% CI, 0.70-0.93, respectively) and MVPA (HR, 0.84; 95% CI, 0.73-0.97 and HR, 0.85; 95% CI, 0.72-1.01, respectively).
• With regard to daily steps, each 1-SD increment was associated with a significant 26% lower risk for overall HF (HR 0.74; 95% CI, 0.63-0.88) and 29% lower risk for HFpEF (HR, 0.71; 95% CI, 0.57-0.88), with these inverse risks becoming significant at about 2000 steps/d, “far less than the often touted 10,000 steps/d for promoting health benefits,” noted the authors.
• Total sedentary time was positively associated (per 1 SD in the fully adjusted model) with risks of overall HF (HR, 1.17; 95% CI, 1.04-1.33) and HFpEF (HR, 1.29; 95% CI, 1.10-1.51) but not HFrEF; mean sedentary bout duration was significantly inversely associated with HFrEF (per 1 SD: HR, 0.76; 95% CI, 0.61-0.97), although the relatively small number of cases at the extremes of bout duration may contribute to this unexpected inverse association, said the authors.

IN PRACTICE:

The implications of promoting PA, regardless of intensity, for primary HFpEF prevention in later life, “has profound public health and clinical relevance,” the authors concluded. They noted that HFpEF is a “burgeoning epidemic” that disproportionately affects women and minorities with limited available therapies.

STUDY DETAILS:

The study, led by Michael J. LaMonte, PhD, MPH, University at Buffalo-SUNY, Buffalo, New York, was published online on February 21, 2024, in JAMA Cardiology.

LIMITATIONS:

There was only a single accelerometer assessment of PA and sedentary exposures and relatively small numbers of HFrEF cases, which restricted analytic precision. Although researchers controlled for several established vascular biomarkers, they did not have HF-specific measures such as cardiac troponin or N-terminal pro–brain natriuretic peptide. It’s unknown if the findings can be generalized to men and populations dissimilar to women in OPACH.

DISCLOSURES:

The study was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services. LaMonte reported receiving grants from the National Institutes of Health during the conduct of the study; see paper for disclosures of the other authors.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Women may gain greater health benefits from regular physical activity at equivalent or lower doses of activity, compared with men, according to data from more than 400,000 US adults. 

Over two decades, with any regular physical activity, all-cause mortality risk was reduced by 24% in women vs 15% in men, and cardiovascular mortality risk was reduced by 36% and 14%, respectively, compared with inactivity, researchers found. 

Participating in strength training exercises (vs not) was associated with a reduced risk for all-cause death of 19% in women and 11% men and reductions in cardiovascular death of 30% and 11%, respectively.

“Women have historically and statistically lagged behind men in engaging in meaningful exercise,” co–lead author Martha Gulati, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement. “The beauty of this study is learning that women can get more out of each minute of moderate to vigorous activity than men do. It’s an incentivizing notion that we hope women will take to heart.”

The study was published online February 19 in the Journal of the American College of Cardiology. 
 

Sex-Specific Exercise Advice? 

The findings are based on leisure-time physical activity data collected over roughly 20 years via the National Health Interview Survey for 412,413 US adults aged 27-61 years. During roughly 4.9 million person-years of follow-up, there were 39,935 all-cause deaths and 11,670 cardiovascular deaths.

Both men and women achieved a peak survival benefit at 300 minutes of weekly moderate to vigorous aerobic physical activity. But the mortality reduction was substantially greater in women than in men for the same amount of regular exercise (24% vs 18%). 

Similarly, for any given dose of physical activity leading up to 300 minutes per week, women derived proportionately greater survival benefits than did men, the authors reported. 

“Importantly, the greater magnitude of physical activity-related survival benefit in women than men was consistently found across varied measures and types of physical activity including frequency, duration per session, and intensity of aerobic physical activity, as well as frequency of muscle strengthening activities,” they wrote. 

They say multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between men and women. For example, compared with men, women may use more respiratory, metabolic, and strength demands to conduct the same movement and in turn, reap greater health benefits.

The study also showed only 33% of women and 43% of men regularly engaged in aerobic physical activity, whereas only 20% of women and 28% of men completed a weekly strength training session.

“We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise,” senior author Susan Cheng, MD, with the Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a statement.

In an accompanying editorial, Wael A. Jaber, MD, and Erika Hutt, MD, from Cleveland Clinic Ohio, wrote that this analysis “brings us one step farther in gaining insights into the role and influence of physiological responses to exercise with a sex-specific lens.” 

The study is “well designed and adds important information to the body of literature that can potentially close the gender gap and optimize sex-specific physical activity recommendations by policy makers and societal guidelines,” they wrote. 

“This study emphasizes that there is no singular approach for exercise. A person’s physical activity needs and goals may change based on their age, health status, and schedule — but the value of any type of exercise is irrefutable,” Eric J. Shiroma, ScD, with the National Heart, Lung, and Blood Institute, said in a statement. 

The study was supported in part by grants from the National Institutes of Health. The authors and editorial writers have declared no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.

TOPLINE:

Two breakdown products from excess niacin, called 2PY and 4PY, were strongly associated with myocardial infarction, stroke, and other adverse cardiac events, suggesting that niacin supplementation may require a more “nuanced, titrated approach,” researchers said.

METHODOLOGY:

• Investigators performed an untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort of 1162 individuals (36% women).
• Additional analyses were performed in a US validation cohort, including measurement of soluble vascular adhesion molecule-1 (sVCAM-1), and on archival fasting samples from patients in a European validation cohort undergoing diagnostic coronary angiography.
• Genetic analyses of samples from the UK Biobank were used to test the association with sVCAM-1 levels of a genetic variant, rs10496731, which was significantly associated with both N1-methyl-2-pyridone-5-carboxamide (2 PY) and N1-methyl-4-pyridone-3-carboxamide (4PY) levels.

TAKEAWAY:

• Niacin metabolism was associated with incident major adverse cardiovascular events (MACE).
• Plasma levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year MACE risk in two validation cohorts (US: 2331 total, 33% women; European: 832 total, 30% women), with adjusted hazard ratios for 2PY of 1.64 and 2.02, respectively, and for 4PY, 1.89 and 1.99.
• The genetic variant rs10496731 was significantly associated with levels of sVCAM-1.
• Treatment with physiological levels of 4PY, but not 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice, suggesting an inflammation-dependent mechanism underlying the clinical association of 4PY, in particular, with MACE.
• In functional testing, a physiological level of 4PY, but not 2PY, provoked messenger RNA and protein expression of VCAM-1 on human endothelial cells.

IN PRACTICE:

“Total niacin consumption in the US averaged 48 mg/d from 2017 to 2020 — more than triple the Recommended Daily Allowance — and 2PY and 4PY were also increased by nicotinamideriboside and nicotinamide mononucleotide, both of which are commonly sold supplements with claimed antiaging benefits,” the authors noted.

“The present studies suggest that niacin pool supplementation may optimally require a more nuanced, titrated approach to achieve intended health benefits,” while not fostering excess 4PY generation.

SOURCE:

Stanley Hazen, MD, PhD, of Cleveland Clinic, Cleveland, Ohio, was the principal author of the study, published online in Nature Medicine.

LIMITATIONS:

Measurement of 2PY and 4PY in the validation cohorts was performed only once, whereas serial measures might have provided enhanced prognostic value for incident cardiovascular disease (CVD) risks. Cohorts were recruited at quaternary referral centers and showed a high prevalence of CVD and cardiometabolic disease risk factors. Although the meta-analysis of the community-based genomic (Biobank) studies showed a link between 4PY and VCAM-1 expression in multiple ethnic groups, the clinical studies linking 4PY to CVD events were based on high-risk European ancestry populations in the US and European cohorts.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health (NIH; both the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements: A), Pilot Project Programs of the USC Center for Genetic Epidemiology and Southern California Environmental Health Sciences Center, and the Deutsche Forschungsgemeinschaft. One co-author was supported, in part, by NIH training grants; another was a participant in the BIH-Charité Advanced Clinician Scientist Program funded by Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio study [validation cohort] was partially supported by Sanofi-Aventis Deutschland GmbH. The UK Biobank Resource provided access to their data. Dr. Hazen and a co-author reported being coinventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and Dr. Hazen and two co-authors received funds from industry.

A version of the article appeared on Medscape.com.