In a recent study published in The Journal of the American College of Cardiology, researchers performed a secondary analysis of the semaglutide treatment effect in people with obesity and heart failure with a preserved left ventricular ejection fraction (STEP-HFpEF) program that included individuals with diabetes mellitus (STEP-HFpEF DM), stratified by biological sex.

Background

Obesity-associated cardiac failure with retained ejection fraction (HFpEF) is a significant worldwide health concern, particularly among women. Local and systemic changes cause HFpEF, resulting in severe symptoms, low functional status, and inferior clinical outcomes. Biological sex impacts heart failure risk factors, clinical presentation, treatment response, and prognosis.

Female patients with HFpEF had higher survival rates and required fewer hospitalizations. Gender variations in ventricular structure, function, body composition, and adiposity distribution might promote aberrant inflammation, resulting in severe clinical symptoms in women. As women gain weight, their blood and plasma volumes rise. However, there is insufficient information on sex differences in baseline characteristics, outcomes, and pharmacotherapeutic responses.

About the study

In the present study, researchers analyzed STEP-HFpEF program (including STEP-HFpEF DM) data to explore the impact of biological sex on anthropometric, cardiovascular health-related, and inflammatory parameters and semaglutide therapy.

The researchers recruited participants from 129 locations across 18 nations in Europe, Asia, and the northern and southern parts of America. They 1:1 randomized the participants with cardiac failure, left ventricular ejection fraction (LVEF) ≥45%, Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) below 90 points, and body mass index (BMI) ≥30 kg m^-2 to receive 2.40 mg of semaglutide once weekly or placebo over 52 weeks.

Eligible participants had the New York Heart Association (NYHA) functional classes II to IV, a six-minute walking distance (6MWD) of ≥100 m, and a minimum of increased filling pressure, increased N-terminal pro-brain natriuretic peptide (NT-proBNP) levels with structural echocardiographic irregularities, or a previous history of heart failure-related hospital admission in the prior year with current diuretic therapy.

The researchers excluded individuals with previous or scheduled bariatric surgery, considerable weight change in recent times, or elevated systolic blood pressures, as well as those with severe diabetic maculopathy or retinopathy (for STEPHFpEF DM).

The primary outcomes were weight and KCCQ-CSS changes. Secondary outcomes included alterations in 6MWD, the composite outcome comprising any-cause mortality, heart failure events, and C-reactive protein (CRP) expression in males and females. Exploratory outcomes included changes in waist circumference, systolic-type blood pressure, and NT-proBNP levels.

As exploratory endpoints, the researchers also assessed changes in scores for overall summary, total symptoms, symptom burden, symptom frequency, physical limitations, social limitations, and life quality. Participants reported adverse events (AEs) and serious-type AEs (SAEs) leading to drug discontinuation or death. The researchers used logistic regressions for analysis.

Results

Among 1,145 participants (529 from STEP-HFpEF and 616 from STEP-HFpEF DM), 570 (50%) were female. Females had higher LVEF, BMI, CRP, physical limitations, and worse heart failure symptoms and a lower likelihood of having prior histories of coronary heart disease or atrial fibrillation and consuming sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARB) compared to men. Baseline 6MWD and KCCQ-CSS values were lower among females.

Semaglutide treatment increased KCCQ-CSS scores irrespective of gender (average difference in females +7.6 points; males +7.5 points) but lowered body weight to a greater extent in females (average difference in females 9.6%; males 7.2%). Semaglutide also improved the composite outcome, 6MWD, and exploratory outcomes in both genders. Similar semaglutide effects on HF outcomes in both genders indicate that mechanisms underlying weight loss may mediate the drug effects in obesity-associated HFpEF.

Semaglutide recipients reported fewer serious AEs than placebo recipients. However, gastrointestinal adverse events and SAEs resulting in drug discontinuation were similar in both groups. Responder analyses showed equivalent percentages of individuals experiencing a minimum of five-point, 10-point, 15-point, and 20-point improvements in KCCQ-CSS scores by semaglutide treatment vs. placebo in both sexes.

Conclusions

Overall, the study found that among those with obesity-associated HFpEF, 2.40 mg of semaglutide lowered body weight more in females. Regardless of gender, semaglitude therapy improved heart failure-related symptoms, exercise function, physical constraints, inflammation, and natriuretic peptides. Semaglutide was well tolerated, with fewer major side events than placebo in both sexes.

Women have higher total adiposity, inflammation, symptom intensity, and activity restriction, implying significant pathophysiologic sex differences, emphasizing the significance of aggressive therapy in women with obesity-related HFpEF. Although semaglutide improves patient-reported outcomes and exercise performance, more studies assessing incretin-based treatments to minimize clinical events in obesity-related HFpEF are required.