Obesity

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

Antidiabetic drug tirzepatide (Mounjaro) shows superiority over semaglutide (Ozempic, Wegovy, and Rybelsus) in controlling blood glucose as well as in the amount of weight lost, results from a meta-analysis of 22 randomized controlled trials show.

“The results indicate tirzepatide’s superior performance over subcutaneous semaglutide in managing blood sugar and achieving weight loss, making it a promising option in the pharmaceutical management of type 2 diabetes,” first author Thomas Karagiannis, MD, PhD, Aristotle University of Thessaloniki, Greece, said in an interview.

“In clinical context, the most potent doses of each drug revealed a clear difference regarding weight loss, with tirzepatide resulting in an average weight reduction that exceeded that of semaglutide by 5.7 kg (12.6 pounds),” he said.

The study is scheduled to be presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in early October.

While a multitude of studies have been conducted for tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 agonist, studies comparing the two drugs directly are lacking.

For a more comprehensive understanding of how the drugs compare, Dr. Karagiannis and colleagues conducted the meta-analysis of 22 trials, including two direct comparisons, the SURPASS-2 trial and a smaller trial, and 20 other studies comparing either semaglutide or tirzepatide with a common comparator, such as placebo, basal insulin, or other GLP-RA-1 drugs.

Overall, 18,472 participants were included in the studies.

All included studies had assessed a maintenance dose of tirzepatide of either 5, 10, or 15 mg once weekly or semaglutide at doses of 0.5, 1.0, or 2.0 mg once weekly for at least 12 weeks. All comparisons were for subcutaneous injection formulations (semaglutide can also be taken orally).
 

Blood glucose reduction

Tirzepatide at 15 mg was found to have the highest efficacy in the reduction of A1c compared with placebo, with a mean difference of –2.00%, followed by tirzepatide 10 mg (–1.86%) and semaglutide 2.0 mg (–1.62%).

All three of the tirzepatide doses had greater reductions in A1c compared with the respective low, medium, and high doses of semaglutide.

Dr. Karagiannis noted that the differences are significant: “An A1c reduction even by 0.5% is often deemed clinically important,” he said.
 

Body weight reduction comparisons

The reductions in body weight across the three drug doses were greater with tirzepatide (–10.96 kg [24.2 pounds], –8.75 kg [19.3 pounds], and –6.16 kg [13.6 pounds] for 15, 10, and 5 mg, respectively) compared with semaglutide (–5.24 kg [11.6 pounds], –4.44 kg [9.8 pounds], and –2.72 kg [6 pounds] for semaglutide 2.0, 1.0, and 0.5 mg, respectively).

In terms of drug-to-drug comparisons, tirzepatide 15 mg had a mean of 5.72 kg (12.6 pounds) greater reduction in body weight vs. semaglutide 2.0 mg; tirzepatide 10 mg had a mean of 3.52 kg (7.8 pounds) reduction vs. semaglutide 2.0 mg; and tirzepatide 5 mg had a mean of a 1.72 kg (3.8 pounds) greater reduction vs. semaglutide 1.0 mg.
 

Adverse events: Increased GI events with highest tirzepatide dose

Regarding the gastrointestinal adverse events associated with the drugs, tirzepatide 15 mg had the highest rate of the two drugs at their various doses, with a risk ratio (RR) of 3.57 compared with placebo for nausea, an RR of 4.35 for vomiting, and 2.04 for diarrhea.

There were no significant differences between the two drugs for the gastrointestinal events, with the exception of the highest dose of tirzepatide, 15 mg, which had a higher risk of vomiting vs. semaglutide 1.0 (RR 1.39) and semaglutide 0.5 mg (RR 1.85).

In addition, tirzepatide 15 mg had a higher risk vs. semaglutide 0.5 mg for nausea (RR 1.45).

There were no significant differences between the two drugs and placebo in the risk of serious adverse events.
 

Real-world applications, comparisons

Dr. Karagiannis noted that the results indicate that benefits of the efficacy of the higher tirzepatide dose need to be balanced with those potential side effects.

“Although the efficacy of the high tirzepatide dose might make it a favorable choice, its real-world application can be affected on an individual’s ability to tolerate these side effects in case they occur,” he explained.

Ultimately, “some patients may prioritize tolerability over enhanced efficacy,” he added.

Furthermore, while all three maintenance doses of tirzepatide analyzed have received marketing authorization, “to get a clearer picture of the real-world tolerance to these doses outside the context of randomized controlled trials, well-designed observational studies would be necessary,” Dr. Karagiannis said.

Among other issues of comparison with the two drugs is cost.

In a recent analysis, the cost per 1% of body weight reduction was reported to be $1,197 for high-dose tirzepatide (15 mg) vs. $1,511 for semaglutide 2.4 mg, with an overall cost of 72 weeks of therapy with tirzepatide at $17,527 compared with $22,878 for semaglutide.

Overall, patients and clinicians should consider the full range of differences and similarities between the medications, “from [their] efficacy and side effects to cost-effectiveness, long-term safety, and cardiovascular profile,” Dr. Karagiannis said.

Semaglutide is currently approved by the Food and Drug Administration for treatment of type 2 diabetes and obesity/weight loss management.

Tirzepatide has also received approval for the treatment of type 2 diabetes and its manufacturers have submitted applications for its approval for obesity/weight loss management.

Dr. Karagiannis reports no relevant financial relationships.

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

TOPLINE:

Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.

METHODOLOGY:

• Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
• A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
• The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
• Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.

TAKEAWAY:

• In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
• There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
• Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
• The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).

IN PRACTICE:

“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”

SOURCE:

Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online  in JAMA Network Open.

LIMITATIONS:

Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.

DISCLOSURES:

Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.

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

TOPLINE:

Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.

METHODOLOGY:

• Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
• A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
• The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
• Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.

TAKEAWAY:

• In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
• There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
• Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
• The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).

IN PRACTICE:

“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”

SOURCE:

Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online  in JAMA Network Open.

LIMITATIONS:

Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.

DISCLOSURES:

Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.

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

TOPLINE:

Compared with body mass index, waist-hip ratio (WHR) had the strongest and most consistent association with all-cause mortality and was the only measurement unaffected by BMI.

METHODOLOGY:

• Cohort study of incident deaths from the U.K. Biobank (2006-2022), including data from 22 centers across the United Kingdom.
• A total of 387,672 participants were divided into a discovery cohort (n = 337,078) and validation cohort (n = 50,594), with the latter consisting of 25,297 deaths and 2,297 controls.
• The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses.
• Exposure-outcome associations were analyzed through observational and mendelian randomization analyses.

TAKEAWAY:

• In adjusted analysis, a J-shaped association was found for both measured BMI and fat mass index (FMI), whereas the association with WHR was linear (hazard ratio 1.41 per standard deviation increase).
• There was a significant association between all three adiposity measures and all-cause mortality, with odds ratio 1.29 per SD change in genetically determined BMI (P = 1.44×10-13), 1.45 per SD change in genetically determined FMI, 1.45 (P = 6.27×10-30), and 1.51 per SD change in genetically determined WHR (P = 2.11×10-9).
• Compared with BMI, WHR had the stronger association with all-cause mortality, although it was not significantly stronger than FMI.
• The association of genetically determined BMI and FMI with all-cause mortality varied across quantiles of observed BMI, but WHR did not (P = .04, P = .02, and P = .58, for BMI, FMI, and WHR, respectively).

IN PRACTICE:

“Current World Health Organization recommendations for optimal BMI range are inaccurate across individuals with various body compositions and therefore suboptimal for clinical guidelines.”

SOURCE:

Study by Irfan Khan, MSc, of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton, Ont., and colleagues. Published online  in JAMA Network Open.

LIMITATIONS:

Study population was genetically homogeneous, White, and British, so results may not be representative of other racial or ethnic groups.

DISCLOSURES:

Study was funded by, and Irfan Khan received support from, the Ontario Graduate Scholarship–Masters Scholarship, awarded by the government of Ontario.

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

The AGA Government Affairs Committee is pleased to announce that the Senate and House have reintroduced the bipartisan Treat and Reduce Obesity Act (TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.

The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.

You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.

Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
 

The AGA Government Affairs Committee is pleased to announce that the Senate and House have reintroduced the bipartisan Treat and Reduce Obesity Act (TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.

The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.

You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.

Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
 

The AGA Government Affairs Committee is pleased to announce that the Senate and House have reintroduced the bipartisan Treat and Reduce Obesity Act (TROA) (H.R. 4818/S. 2407). This legislation is a vital first step in expanding access to obesity treatment as it would expand Medicare coverage to include screening and treatment of obesity by a diverse range of health care providers who provide obesity care. The bill also includes coverage of behavioral counseling, prescription drugs for long-term weight management, and other prevention and treatment options.

The passage of TROA could lead to improved obesity care options because many private insurance companies model their covered health benefits to reflect Medicare.

You can help lawmakers understand the urgent need for expanded access to affordable, effective obesity treatments and how greater access to these tools will equip you to better care for your patients.

Use the new obesity advocacy toolkit to find the tools and resources you need, including an email template, sample phone script, op-ed template, and more, to assist you in reaching out to your elected officials and urging them to support the passage of TROA.
 

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.

As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.

The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise. As effective obesity drugs become more available and remain safe, it is likely that willpower will no longer dominate the populous psyche.

But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.

Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.

For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?

Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.

As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.

As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.

The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise. As effective obesity drugs become more available and remain safe, it is likely that willpower will no longer dominate the populous psyche.

But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.

Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.

For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?

Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.

As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

A few months ago I wrote a column in which I reluctantly supported designating obesity as a disease. My rationale was that in the more than 50 years that I have been watching the ebb and flow of medicine in this country I have seen very little, if any, evidence of success in our attempts to prevent obesity. Given this abysmal track record, the pragmatic side of my brain says why not label it a disease and begin to focus on treatment. However, I closed the column urging that we not lose sight of our core values and completely abandon any attempts at prevention.

As the months have rolled by, I have become increasingly concerned that preventing obesity is slipping further down the slippery slope to oblivion, greased by the success of semaglutide and the prospect of similar drugs in the pipeline. Before turning in our credentials as card-carrying preventionists, we need to step back and take another look at how we approach obesity from the pediatric side.

The majority of Americans believe that obesity occurs when an individual consumes more calories than he or she burns by being active. Some nutritionists criticize this “energy balance” model view as too simplistic and prefer a carbohydrate insulin model, which considers obesity as a metabolic disorder that is better managed by adjusting what the individual eats with less focus on amounts and the role of exercise. However, while the public may acknowledge that there are some individuals to whom genetics has dealt a more difficult hand, it continues to put a high priority on the dual roles of willpower and exercise. As effective obesity drugs become more available and remain safe, it is likely that willpower will no longer dominate the populous psyche.

But, what about children? At what point, if ever, does willpower enter the obesity discussion? A child may be able to exert some control over his or her diet by eating selectively. But, until the child acquires a certain level of resources and maturity it is parents who should be dictating the volume and variety of available food from which the child can choose. And, on the other side of the energy equation, parents should be playing a significant role in how much or how little physical activity their children engage in.

Of course there are many children whose genes predispose them to obesity when food is cheap and abundant. And, there are numerous families for whom socioeconomic factors limit their ability to control their children’s diet and activity options. However, we mustn’t lose sight of the fact that the majority of families may be making choices for their children that are contributing to the obesity problem in this country.

For example, a recent study published in Pediatrics has found that mean television viewing time during childhood and adolescence was associated with metabolic syndrome at age 45. Is this a failure on our part to anticipate this finding when for decades we as physicians have already seen anecdotal evidence to support it? Or is this another example of a willpower deficit by parents who likewise must have had an inkling that sitting on the couch watching television wasn’t healthy for their children?

Or is this just more evidence that as a nation we lack the political will to enact laws and develop programs aimed at heading off obesity in early childhood before it reaches the point that we have learned, from sad experience, is beyond the reach of dietary change, increased physical activity, and the fragility of normal human willpower. Here I’m talking about the disappearance of meaningful physical education in the schools, the failure to effectively prevent the marketing of poor nutritional foods and beverages to children, and the failure to aggressively promote universal breastfeeding-friendly workplaces and schedules, to name just a few.

As individuals we know all too well the limits of our own willpower. But, collectively as a nation we should be able to pool those fragmentary resources into a force for positive change. We may have thrown in the towel when we have opted to treat obesity as a disease in adults. Let’s find the will to work on prevention in early childhood when the window for change is still open.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

In medical school, we were repeatedly advised that there is both a science and an art to the practice of medicine. In these days of doc-in-a-box online consultations for obesity, it’s tempting to think that there’s a one-size-fits-all purely scientific approach for these new weight loss medications. Yet, for every nine patients who lose weight seemingly effortlessly on this class of medication, there is always one whose body stubbornly refuses to submit.

Adam is a 58-year-old man who came to me recently because he was having difficulty losing weight. Over the past 20 years, he’d been steadily gaining weight and now, technically has morbid obesity (a term which should arguably be obsolete). His weight gain is complicated by high blood pressure, high cholesterol, and obstructive sleep apnea. His sleep apnea has caused such profound exhaustion that he no longer has the energy to work out. He also has significant ADHD, which has been left untreated because of his ability to white-knuckle it through his many daily meetings and calls. A married father of three, he is a successful portfolio manager at a high-yield bond fund.

Adam tends to eat minimally during the day, thereby baffling his colleagues with the stark contrast between his minimal caloric intake and his large belly. However, when he returns from work late at night (kids safely tucked into bed), the floodgates open. He reports polishing off pints of ice cream, scarfing down bags of cookies, inhaling trays of brownies. No carbohydrate is off limits to him once he steps off the Metro North train and crosses the threshold from work to home. 

Does Adam simply lack the desire or common-sense willpower to make the necessary changes in his lifestyle or is there something more complicated at play?

I would argue that Adam’s ADHD triggered a binge-eating disorder (BED) that festered unchecked over the past 20 years. Patients with BED typically eat massive quantities of food over short periods of time – often when they’re not even hungry. Adam admitted that he would generally continue to eat well after feeling stuffed to the brim. It is well known that ADHD is a leading cause of binge-eating tendencies. So, what is the link between these two seemingly unrelated disorders?

The answer probably lies with dopamine, a neurotransmitter produced in the reward centers of the brain that regulates how people experience pleasure and control impulses. We believe that people with ADHD have low levels of dopamine (it’s actually a bit more complicated, but this is the general idea). These low levels of dopamine lead people to self-medicate with sugars, salt, and fats to increase dopamine levels.

Lisdexamfetamine (Vyvanse) is a Food and Drug Administration–approved treatment option for both ADHD and binge eating. It raises the levels of dopamine (as well as norepinephrine) in the brain’s reward center. Often, the strong urge to binge subsides rapidly once ADHD is properly treated.

Rather than starting Adam on a semaglutide or similar agent, I opted to start him on lisdexamfetamine. When I spoke to him 1 week later, he confided that the world suddenly shifted into focus, and he was able to plan his meals throughout the day and resist the urge to binge late at night.

I may eventually add a semaglutide-like medication if his weight loss plateaus, but for now, I will focus on raising his dopamine levels to tackle the underlying cause of his weight gain.

Dr. Messer is a clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. She disclosed no relevant conflicts of interest.

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

In medical school, we were repeatedly advised that there is both a science and an art to the practice of medicine. In these days of doc-in-a-box online consultations for obesity, it’s tempting to think that there’s a one-size-fits-all purely scientific approach for these new weight loss medications. Yet, for every nine patients who lose weight seemingly effortlessly on this class of medication, there is always one whose body stubbornly refuses to submit.

Adam is a 58-year-old man who came to me recently because he was having difficulty losing weight. Over the past 20 years, he’d been steadily gaining weight and now, technically has morbid obesity (a term which should arguably be obsolete). His weight gain is complicated by high blood pressure, high cholesterol, and obstructive sleep apnea. His sleep apnea has caused such profound exhaustion that he no longer has the energy to work out. He also has significant ADHD, which has been left untreated because of his ability to white-knuckle it through his many daily meetings and calls. A married father of three, he is a successful portfolio manager at a high-yield bond fund.

Adam tends to eat minimally during the day, thereby baffling his colleagues with the stark contrast between his minimal caloric intake and his large belly. However, when he returns from work late at night (kids safely tucked into bed), the floodgates open. He reports polishing off pints of ice cream, scarfing down bags of cookies, inhaling trays of brownies. No carbohydrate is off limits to him once he steps off the Metro North train and crosses the threshold from work to home. 

Does Adam simply lack the desire or common-sense willpower to make the necessary changes in his lifestyle or is there something more complicated at play?

I would argue that Adam’s ADHD triggered a binge-eating disorder (BED) that festered unchecked over the past 20 years. Patients with BED typically eat massive quantities of food over short periods of time – often when they’re not even hungry. Adam admitted that he would generally continue to eat well after feeling stuffed to the brim. It is well known that ADHD is a leading cause of binge-eating tendencies. So, what is the link between these two seemingly unrelated disorders?

The answer probably lies with dopamine, a neurotransmitter produced in the reward centers of the brain that regulates how people experience pleasure and control impulses. We believe that people with ADHD have low levels of dopamine (it’s actually a bit more complicated, but this is the general idea). These low levels of dopamine lead people to self-medicate with sugars, salt, and fats to increase dopamine levels.

Lisdexamfetamine (Vyvanse) is a Food and Drug Administration–approved treatment option for both ADHD and binge eating. It raises the levels of dopamine (as well as norepinephrine) in the brain’s reward center. Often, the strong urge to binge subsides rapidly once ADHD is properly treated.

Rather than starting Adam on a semaglutide or similar agent, I opted to start him on lisdexamfetamine. When I spoke to him 1 week later, he confided that the world suddenly shifted into focus, and he was able to plan his meals throughout the day and resist the urge to binge late at night.

I may eventually add a semaglutide-like medication if his weight loss plateaus, but for now, I will focus on raising his dopamine levels to tackle the underlying cause of his weight gain.

Dr. Messer is a clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. She disclosed no relevant conflicts of interest.

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

In medical school, we were repeatedly advised that there is both a science and an art to the practice of medicine. In these days of doc-in-a-box online consultations for obesity, it’s tempting to think that there’s a one-size-fits-all purely scientific approach for these new weight loss medications. Yet, for every nine patients who lose weight seemingly effortlessly on this class of medication, there is always one whose body stubbornly refuses to submit.

Adam is a 58-year-old man who came to me recently because he was having difficulty losing weight. Over the past 20 years, he’d been steadily gaining weight and now, technically has morbid obesity (a term which should arguably be obsolete). His weight gain is complicated by high blood pressure, high cholesterol, and obstructive sleep apnea. His sleep apnea has caused such profound exhaustion that he no longer has the energy to work out. He also has significant ADHD, which has been left untreated because of his ability to white-knuckle it through his many daily meetings and calls. A married father of three, he is a successful portfolio manager at a high-yield bond fund.

Adam tends to eat minimally during the day, thereby baffling his colleagues with the stark contrast between his minimal caloric intake and his large belly. However, when he returns from work late at night (kids safely tucked into bed), the floodgates open. He reports polishing off pints of ice cream, scarfing down bags of cookies, inhaling trays of brownies. No carbohydrate is off limits to him once he steps off the Metro North train and crosses the threshold from work to home. 

Does Adam simply lack the desire or common-sense willpower to make the necessary changes in his lifestyle or is there something more complicated at play?

I would argue that Adam’s ADHD triggered a binge-eating disorder (BED) that festered unchecked over the past 20 years. Patients with BED typically eat massive quantities of food over short periods of time – often when they’re not even hungry. Adam admitted that he would generally continue to eat well after feeling stuffed to the brim. It is well known that ADHD is a leading cause of binge-eating tendencies. So, what is the link between these two seemingly unrelated disorders?

The answer probably lies with dopamine, a neurotransmitter produced in the reward centers of the brain that regulates how people experience pleasure and control impulses. We believe that people with ADHD have low levels of dopamine (it’s actually a bit more complicated, but this is the general idea). These low levels of dopamine lead people to self-medicate with sugars, salt, and fats to increase dopamine levels.

Lisdexamfetamine (Vyvanse) is a Food and Drug Administration–approved treatment option for both ADHD and binge eating. It raises the levels of dopamine (as well as norepinephrine) in the brain’s reward center. Often, the strong urge to binge subsides rapidly once ADHD is properly treated.

Rather than starting Adam on a semaglutide or similar agent, I opted to start him on lisdexamfetamine. When I spoke to him 1 week later, he confided that the world suddenly shifted into focus, and he was able to plan his meals throughout the day and resist the urge to binge late at night.

I may eventually add a semaglutide-like medication if his weight loss plateaus, but for now, I will focus on raising his dopamine levels to tackle the underlying cause of his weight gain.

Dr. Messer is a clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. She disclosed no relevant conflicts of interest.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Weight loss of at least 5% over a 3-year period was associated with significantly increased mortality in women at age 90, 95, and 100 years compared with those whose weight remained stable, based on data from more than 50,000 individuals.

Previous studies of later-life weight changes and mortality have yielded inconsistent results driven by considerations of weight loss intentionality, and data on older adults in particular are limited, wrote Aladdin H. Shadyab, PhD, of the University of California, San Diego, and colleagues.

In a study published in the Journals of Gerontology: Medical Sciences, the researchers reviewed data from the Women’s Health Initiative, a prospective study of factors affecting chronic disease development in postmenopausal women. The study population included 54,437 women who entered the WHI between 1993 and 1998 at ages 50-79 years. The mean baseline age was 69.8 years; 89.5% of the participants were White, 5.7% were Black, 2.7% were Asian, 2.5% were Hispanic/Latino, and the remaining 1.0% were multiracial, American Indian/Alaskan Native, Native Hawaiian/Other Pacific Islander, or unknown.

The primary outcomes were the associations of short-term (3-year) and long-term (10-year) weight changes with survival to ages 90, 95, and 100 years.

A total of 30,647 women survived to at least 90 years (56.3%).

Overall, women with a short-term weight loss of 5% or more of body weight were 33% less likely to survive to age 90 years, 35% less likely to survive to age 95 years, and 38% less likely to survive to age 100 years than were those whose weight remained stable (odds ratios, 0.67, 0.65, and 0.62, respectively).

The associations were stronger in cases of unintentional short-term weight loss. Intentional weight loss from baseline to year 3 was associated with 17% lower odds of survival to age 90 compared to stable weight (OR, 0.83), but unintentional weight loss was associated with 51% lower odds of survival to age 90 (OR, 0.49).

Similarly, women with 10-year weight loss of at least 5% were 40% less likely to survive to 90 years and 49% less likely to survive to 95 years (OR, 0.60 and OR, 0.51, respectively). The sample size was too small to assess the relation of 10-year weight loss with survival to 100 years, and intentionality was not assessed for 10-year weight changes.

By contrast, weight gain of at least 5% had no significant effect on survival to ages 90, 95, or 100 years, but stable weight over time increased the odds of living to ages 90 to 100 years by 1.2-fold to 2-fold compared to either intentional or unintentional weight loss of at least 5%.

The trends in results were similar across body weight categories (normal weight, overweight, and obese as defined by body mass index). Baseline age and smoking status had no significant effect on the results.

Some of the proportion of self-reported intentional weight loss in the study population may have been unintentional, the researchers wrote in their discussion.

“It is important to note that perceived intentionality of weight loss may be influenced by the many societal pressures to lose weight, especially among women, and therefore overestimate the behavioral changes underlying experienced weight loss in older adults,” they said.

The findings were limited by several factors including the potential for inaccurate self-reported weight loss intention, and the likelihood that the mean older age of the population at baseline (older than 60 years) meant that they were more likely to live longer regardless of weight changes, the researchers noted. Other limitations included the primarily White study population, and other residual confounding factors such as ill health that might drive weight loss, the researchers noted.

However, the results were strengthened by the large sample size and long follow-up period, and suggest that “blanket recommendations for weight loss in older women are unlikely to lead to better survival at advanced ages,” they concluded.
 

Data support weight monitoring

The investigators acknowledged that their data do not affect clinical recommendations for moderate weight loss in older women to improve health outcomes, especially in those with overweight or obesity, but instead “support close monitoring of the amount and speed of weight loss, particularly when unintentional, as an indicator of underlying poor health and predictor of decreased lifespan in older women.”

Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, agreed with this conclusion. The current study suggests that when older women lose a significant amount of weight unintentionally, it could be a sign of failing health, he said.

Weight gain or loss in old age is very different from weight issues in younger people, where clinicians may be encouraging weight loss to improve health outcomes, Dr. Skolnik said in an interview.

A key take-home message for clinicians, in addition to monitoring weight in older patients, is to emphasize nutrition for individuals in their 80s, 90s, and beyond, he said.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shadyab had no financial conflicts to disclose. Dr. Skolnik had no financial conflicts to disclose and serves on the editorial advisory board of Family Practice News.

Weight loss of at least 5% over a 3-year period was associated with significantly increased mortality in women at age 90, 95, and 100 years compared with those whose weight remained stable, based on data from more than 50,000 individuals.

Previous studies of later-life weight changes and mortality have yielded inconsistent results driven by considerations of weight loss intentionality, and data on older adults in particular are limited, wrote Aladdin H. Shadyab, PhD, of the University of California, San Diego, and colleagues.

In a study published in the Journals of Gerontology: Medical Sciences, the researchers reviewed data from the Women’s Health Initiative, a prospective study of factors affecting chronic disease development in postmenopausal women. The study population included 54,437 women who entered the WHI between 1993 and 1998 at ages 50-79 years. The mean baseline age was 69.8 years; 89.5% of the participants were White, 5.7% were Black, 2.7% were Asian, 2.5% were Hispanic/Latino, and the remaining 1.0% were multiracial, American Indian/Alaskan Native, Native Hawaiian/Other Pacific Islander, or unknown.

The primary outcomes were the associations of short-term (3-year) and long-term (10-year) weight changes with survival to ages 90, 95, and 100 years.

A total of 30,647 women survived to at least 90 years (56.3%).

Overall, women with a short-term weight loss of 5% or more of body weight were 33% less likely to survive to age 90 years, 35% less likely to survive to age 95 years, and 38% less likely to survive to age 100 years than were those whose weight remained stable (odds ratios, 0.67, 0.65, and 0.62, respectively).

The associations were stronger in cases of unintentional short-term weight loss. Intentional weight loss from baseline to year 3 was associated with 17% lower odds of survival to age 90 compared to stable weight (OR, 0.83), but unintentional weight loss was associated with 51% lower odds of survival to age 90 (OR, 0.49).

Similarly, women with 10-year weight loss of at least 5% were 40% less likely to survive to 90 years and 49% less likely to survive to 95 years (OR, 0.60 and OR, 0.51, respectively). The sample size was too small to assess the relation of 10-year weight loss with survival to 100 years, and intentionality was not assessed for 10-year weight changes.

By contrast, weight gain of at least 5% had no significant effect on survival to ages 90, 95, or 100 years, but stable weight over time increased the odds of living to ages 90 to 100 years by 1.2-fold to 2-fold compared to either intentional or unintentional weight loss of at least 5%.

The trends in results were similar across body weight categories (normal weight, overweight, and obese as defined by body mass index). Baseline age and smoking status had no significant effect on the results.

Some of the proportion of self-reported intentional weight loss in the study population may have been unintentional, the researchers wrote in their discussion.

“It is important to note that perceived intentionality of weight loss may be influenced by the many societal pressures to lose weight, especially among women, and therefore overestimate the behavioral changes underlying experienced weight loss in older adults,” they said.

The findings were limited by several factors including the potential for inaccurate self-reported weight loss intention, and the likelihood that the mean older age of the population at baseline (older than 60 years) meant that they were more likely to live longer regardless of weight changes, the researchers noted. Other limitations included the primarily White study population, and other residual confounding factors such as ill health that might drive weight loss, the researchers noted.

However, the results were strengthened by the large sample size and long follow-up period, and suggest that “blanket recommendations for weight loss in older women are unlikely to lead to better survival at advanced ages,” they concluded.
 

Data support weight monitoring

The investigators acknowledged that their data do not affect clinical recommendations for moderate weight loss in older women to improve health outcomes, especially in those with overweight or obesity, but instead “support close monitoring of the amount and speed of weight loss, particularly when unintentional, as an indicator of underlying poor health and predictor of decreased lifespan in older women.”

Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, agreed with this conclusion. The current study suggests that when older women lose a significant amount of weight unintentionally, it could be a sign of failing health, he said.

Weight gain or loss in old age is very different from weight issues in younger people, where clinicians may be encouraging weight loss to improve health outcomes, Dr. Skolnik said in an interview.

A key take-home message for clinicians, in addition to monitoring weight in older patients, is to emphasize nutrition for individuals in their 80s, 90s, and beyond, he said.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shadyab had no financial conflicts to disclose. Dr. Skolnik had no financial conflicts to disclose and serves on the editorial advisory board of Family Practice News.

Weight loss of at least 5% over a 3-year period was associated with significantly increased mortality in women at age 90, 95, and 100 years compared with those whose weight remained stable, based on data from more than 50,000 individuals.

Previous studies of later-life weight changes and mortality have yielded inconsistent results driven by considerations of weight loss intentionality, and data on older adults in particular are limited, wrote Aladdin H. Shadyab, PhD, of the University of California, San Diego, and colleagues.

In a study published in the Journals of Gerontology: Medical Sciences, the researchers reviewed data from the Women’s Health Initiative, a prospective study of factors affecting chronic disease development in postmenopausal women. The study population included 54,437 women who entered the WHI between 1993 and 1998 at ages 50-79 years. The mean baseline age was 69.8 years; 89.5% of the participants were White, 5.7% were Black, 2.7% were Asian, 2.5% were Hispanic/Latino, and the remaining 1.0% were multiracial, American Indian/Alaskan Native, Native Hawaiian/Other Pacific Islander, or unknown.

The primary outcomes were the associations of short-term (3-year) and long-term (10-year) weight changes with survival to ages 90, 95, and 100 years.

A total of 30,647 women survived to at least 90 years (56.3%).

Overall, women with a short-term weight loss of 5% or more of body weight were 33% less likely to survive to age 90 years, 35% less likely to survive to age 95 years, and 38% less likely to survive to age 100 years than were those whose weight remained stable (odds ratios, 0.67, 0.65, and 0.62, respectively).

The associations were stronger in cases of unintentional short-term weight loss. Intentional weight loss from baseline to year 3 was associated with 17% lower odds of survival to age 90 compared to stable weight (OR, 0.83), but unintentional weight loss was associated with 51% lower odds of survival to age 90 (OR, 0.49).

Similarly, women with 10-year weight loss of at least 5% were 40% less likely to survive to 90 years and 49% less likely to survive to 95 years (OR, 0.60 and OR, 0.51, respectively). The sample size was too small to assess the relation of 10-year weight loss with survival to 100 years, and intentionality was not assessed for 10-year weight changes.

By contrast, weight gain of at least 5% had no significant effect on survival to ages 90, 95, or 100 years, but stable weight over time increased the odds of living to ages 90 to 100 years by 1.2-fold to 2-fold compared to either intentional or unintentional weight loss of at least 5%.

The trends in results were similar across body weight categories (normal weight, overweight, and obese as defined by body mass index). Baseline age and smoking status had no significant effect on the results.

Some of the proportion of self-reported intentional weight loss in the study population may have been unintentional, the researchers wrote in their discussion.

“It is important to note that perceived intentionality of weight loss may be influenced by the many societal pressures to lose weight, especially among women, and therefore overestimate the behavioral changes underlying experienced weight loss in older adults,” they said.

The findings were limited by several factors including the potential for inaccurate self-reported weight loss intention, and the likelihood that the mean older age of the population at baseline (older than 60 years) meant that they were more likely to live longer regardless of weight changes, the researchers noted. Other limitations included the primarily White study population, and other residual confounding factors such as ill health that might drive weight loss, the researchers noted.

However, the results were strengthened by the large sample size and long follow-up period, and suggest that “blanket recommendations for weight loss in older women are unlikely to lead to better survival at advanced ages,” they concluded.
 

Data support weight monitoring

The investigators acknowledged that their data do not affect clinical recommendations for moderate weight loss in older women to improve health outcomes, especially in those with overweight or obesity, but instead “support close monitoring of the amount and speed of weight loss, particularly when unintentional, as an indicator of underlying poor health and predictor of decreased lifespan in older women.”

Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, agreed with this conclusion. The current study suggests that when older women lose a significant amount of weight unintentionally, it could be a sign of failing health, he said.

Weight gain or loss in old age is very different from weight issues in younger people, where clinicians may be encouraging weight loss to improve health outcomes, Dr. Skolnik said in an interview.

A key take-home message for clinicians, in addition to monitoring weight in older patients, is to emphasize nutrition for individuals in their 80s, 90s, and beyond, he said.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shadyab had no financial conflicts to disclose. Dr. Skolnik had no financial conflicts to disclose and serves on the editorial advisory board of Family Practice News.

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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

AMSTERDAM – The more weight patients lost while on weekly semaglutide treatment in the STEP-HFpEF trial, the better their outcomes, suggesting that weight loss by itself was a major reason why the treatment improved a broad range of prespecified study outcomes, including symptoms and physical limitations, exercise capacity, and inflammation, new analyses from the trial show.

At the annual congress of the European Society of Cardiology where he presented these new findings, Mikhail N. Kosiborod, MD, also posited that weight loss produced by weekly subcutaneous injections of 2.4 mg semaglutide (Wegovy) for 52 weeks in the study does not fully explain the multiple mechanisms that may be involved in producing this intervention’s effects in the STEP-HFpEF trial.

Mitchel L. Zoler/MDedge News

His report earlier at the congress and in a simultaneously published report of the trial’s primary outcomes established a role for medically induced weight loss in managing patients with obesity-phenotype HFpEF in a total of 529 randomized individuals with HFpEF and obesity but without diabetes.

The new analyses showed that for one of the two primary endpoints – the change from baseline in patients’ assessment on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ), the placebo-adjusted average change was a 16.1-point improvement in the 51 people with a 5%-10% weight loss during the 1-year study, and a 21.6-point improvement in the 58 who had at least a 20% weight loss, a between-group average 5.5 point difference that represents a clinically meaningful incremental improvement in this validated metric of symptoms and functional limitations.

Similar weight-related differences in benefit also occurred for the secondary outcomes of changes from baseline in 6-minute walk distance and in levels of C-reactive protein (CRP), a measure of systemic inflammation.

In an adjusted regression model, every 10% drop from baseline body weight was significantly linked with a 6.4-point improvement in KCCQ score, a 14.4 meter improvement in 6-minute walk distance, and a 28% relative reduction from baseline in CRP, reported Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.

These new, prespecified analyses also showed that people with obesity and HFpEF responded roughly the same to semaglutide treatment compared with placebo-treated controls regardless of their starting body mass index, including people with class 1 (30-34 kg/m²), class 2 (35-39 kg/m²), and class 3 (≥ 40 kg/m²) obesity.

Simultaneously with Dr. Kosiborod’s report at the congress, these findings appeared in a report posted online in Nature Medicine.
 

Not every benefit was fully mediated by weight loss

These analyses “do not tell us how much of the benefit was mediated by weight loss, but the data do say that the more weight a person lost, the more benefit they got,” Dr. Kosiborod explained in an interview. “That is not the same as saying that everything is mediated by weight. It doesn’t say that nothing beyond weight loss matters.”

He and his associates are planning a mediation analysis of data from STEP-HFpEF that will more directly address this issue.

“It’s likely that people who lost more weight with semaglutide also had greater benefits from other effects of semaglutide at the same time. Weight loss is a good surrogate marker” for the range of effects that a person receives from treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, Dr. Kosiborod said.

“GLP-1 receptor agonists may have direct effects on atherosclerosis, as well as other effects that are uncoupled from weight loss,” such as proven anti-inflammatory effects, he added.

Another exploratory effect from semaglutide treatment in the study and reported by Dr. Kosiborod was a significant reduction in serum levels of N-terminal pro brain natriuretic peptide, an association never previously seen with weight loss in people with heart failure.

“The outcomes we’ve already seen in STEP-HFpEF were largely symptomatic, which are extraordinarily important, but there may be a completely different relationship between weight and clinical events,” said John E. Deanfield, PhD, a professor of cardiology at University College Hospital, London, who was not involved in the study.

Dr. Deanfield noted that important prognostic markers such as cholesterol levels and blood pressure reductions are usually not temporally related to weight loss. “The idea that [the benefits seen in STEP-HFpEF] are purely from weight loss is something we need to be careful about,” he said.

“My gut feeling is that at least 75% of the effect [in STEP-HFpEF} was due to weight loss,” said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow, who was not associated with the research.

STEP-HFpEF was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to, and has received honoraria from, Novo Nordisk. He has been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Deanfield has been a consultant to Novo Nordisk as well as to Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Sanofi, and Takeda, and has received research funding from Aegerion, Colgate, MSD, Pfizer, and Roche. Dr. Sattar has been a consultant to Novo Nordisk as well as to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, and Roche Diagnostics.
 

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