Semaglutide Helps Women Lose More Weight than Men, Study Finds

Researchers conducted a secondary analysis of the semaglutide treatment effect in individuals with obesity and heart failure who were part of the preserved left ventricular ejection fraction (STEP-HFpEF) program. This program included people with diabetes mellitus (STEP-HFpEF DM), who were categorized based on biological sex. The study was published in The Journal of the American College of Cardiology.

Context

A major global health concern is obesity-associated heart failure with maintained ejection fraction (HFpEF), which is more common in women. HFpEF is brought on by both systemic and local alterations, and it is characterized by severe symptoms, poor functional status, and subpar clinical outcomes. Heart failure risk factors, clinical presentation, response to treatment, and prognosis are all impacted by biological sex.

Female patients with HFpEF required shorter hospital stays and had better survival rates. Gender differences in the distribution of fat, body composition, and ventricular structure and function may encourage abnormal inflammation, which in women may lead to severe clinical symptoms. Women’s blood and plasma volumes rise as they acquire weight. On the other hand, there is not enough data regarding sex differences in outcomes, baseline characteristics, and pharmacotherapeutic responses.

Concerning the study

The current study examined the effects of biological sex on anthropometric, cardiovascular health-related, inflammatory, and semaglutide therapeutic parameters by analyzing data from the STEP-HFpEF program (including STEP-HFpEF DM).

Participants were gathered by the researchers from 129 sites spread over 18 countries in Europe, Asia, and the northern and southern regions of America. Participants with cardiac failure, left ventricular ejection fraction (LVEF) ≥45%, clinical summary scores (KCCQ-CSS) on the Kansas City Cardiomyopathy Questionnaire (below 90 points), and body mass index (BMI) ≥30 kg m-2 were randomized 1:1 to receive 2.40 mg of semaglutide once weekly for 52 weeks, or a placebo.

A minimum of increased filling pressure, elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels with structural echocardiographic irregularities, or a history of heart failure-related hospital admission in the previous year with current diuretic therapy were required for eligibility. Participants also needed to have the New York Heart Association (NYHA) functional classes II to IV.

Those having scheduled or prior bariatric surgery, significant recent weight loss, increased systolic blood pressure, or severe diabetic maculopathy or retinopathy (for STEPHFpEF DM) were not included in the study.

Changes in weight and KCCQ-CSS were the main results. Changes in 6MWD, the composite outcome including heart failure episodes, any-cause mortality, and male and female C-reactive protein (CRP) expression, were among the secondary outcomes. Waist circumference, systolic-type blood pressure, and NT-proBNP levels were among the exploratory outcomes measured.

The researchers also evaluated improvements in scores for total symptoms, symptom load, symptom frequency, physical limits, social constraints, and life quality as exploratory goals. Participants reported significant adverse events (SAEs) and adverse events (AEs) that required stopping medication or resulted in death. Logistic regressions were employed by the researchers for analysis.

Outcomes
Of the 1,145 participants, 570 (or 50%) were female (529 from STEP-HFpEF and 616 from STEP-HFpEF DM). Compared to men, women had higher LVEF, BMI, CRP, physical limitations, and worse heart failure symptoms. They also had a lower chance of consuming ACE, ARB, or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as well as having a history of coronary heart disease or atrial fibrillation or taking them previously. Females had lower baseline 6MWD and KCCQ-CSS values.

Semaglutide therapy reduced body weight more significantly in females (average difference in females 9.6%; average difference in males 7.2%) but enhanced KCCQ-CSS scores regardless of gender (average difference in ladies +7.6 points; males +7.5 points). Additionally, semaglutide enhanced the exploratory results, 6MWD, and composite outcome for both genders. Drug effects in obesity-associated HFpEF may be mediated by systems underpinning weight loss, as suggested by similar semaglutide effects on HF outcomes in both genders.

Compared to placebo receivers, semaglutide users reported fewer major adverse events. On the other hand, both groups experienced comparable gastrointestinal side events and SAEs that led to medication discontinuation. Respondent analyses revealed comparable percentages of people who, in comparison to placebo, experienced at least five-point, ten-point, fifteen-point, and twenty-point improvements in KCCQ-CSS scores after receiving semaglutide medication.

In conclusion

Overall, the study discovered that 2.40 mg of semaglutide decreased body weight more in females with obesity-associated HFpEF. Semaglitude therapy reduced inflammation, natriuretic peptides, physical limitations, exercise function, and heart failure-related symptoms in both sexes. In both genders, semaglutide was well tolerated and had fewer significant adverse effects than a placebo.

The importance of aggressive therapy in women with obesity-related HFpEF is highlighted by the greater levels of overall adiposity, inflammation, symptom intensity, and activity restriction observed in women. These findings suggest significant pathophysiologic sex differences. While semaglutide enhances exercise performance and patient-reported outcomes, further research is needed to evaluate incretin-based therapies for reducing clinical events in obesity-related HFpEF.

For more information: Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure with Preserved Ejection Fraction,  The Journal of the American College of Cardiology, https://doi.org/10.1016/j.jacc.2024.06.001