Key Points:
- Semaglutide improves symptoms and functional capacity in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the mechanisms underlying these benefits remain uncertain.
- CAMEO-SEMA was a single-center, double-blind, placebo-controlled randomized trial of 81 patients with obesity-related HFpEF assigned to semaglutide or placebo for 52 weeks. The primary endpoint was the change in invasively measured pulmonary artery wedge pressure (PAWP) during low-intensity exercise.
- At 52 weeks, semaglutide significantly reduced exercise PAWP compared with placebo (between-group difference -10.6 mmHg [-13.3, -8.0]). Hemodynamic remission, defined as normalization of resting and exercise PAWP, occurred in 53.7% versus 7.4% of patients, respectively.
- Semaglutide also improved left atrial function, LV diastolic filling, and cardiac remodeling in a prespecified cardiac MRI substudy, providing mechanistic insight into its benefits in obesity-related HFpEF.
Obesity is an important contributor to heart failure with preserved ejection fraction (HFpEF), characterized by elevated cardiac filling pressures, particularly during exercise. Previous trials, including STEP-HFpEF, demonstrated that semaglutide improves symptoms and functional capacity in patients with obesity-related HFpEF. However, whether these benefits reflect improvements in cardiac hemodynamics and function remains uncertain.
On November 8th, 2026, results from “Semaglutide Ameliorates the Seminal Hemodynamic Features of Obesity-Related HFpEF” (CAMEO-SEMA) were presented at the American Heart Association Scientific Sessions 2026 in Chicago, IL, with simultaneous publication of the primary trial and cardiac MRI substudy in Nature Medicine.
CAMEO-SEMA was a single-center, double-blind, placebo-controlled randomized trial enrolling 81 patients with symptomatic HFpEF, LVEF ≥50%, BMI ≥30 kg/m², and invasively confirmed elevated exercise PAWP (≥25 mmHg). Patients were randomized 2:1 to semaglutide (n=54), titrated to 2.4 mg subcutaneously weekly, or placebo (n=27) for 52 weeks. The primary endpoint was the change in PAWP during low-intensity exercise at 20 watts. Additional outcomes included resting and peak exercise hemodynamics, health status, and hemodynamic remission, defined as PAWP <15 mmHg at rest and <25 mmHg during 20W exercise.
The median age was 68 years, 58% were women, and median BMI was 36.8 kg/m². At baseline, mean PAWP increased from 17.5 mmHg at rest to 31.7 mmHg during 20W exercise. Of 81 randomized participants, 70 completed the primary endpoint assessment, with all randomized participants included in the intention-to-treat analysis using available data.
At 52 weeks, PAWP during low-intensity exercise decreased by 9.8 mmHg with semaglutide compared with an increase of 0.9 mmHg with placebo (between-group difference -10.6 mmHg [-13.3 to -8.0]). Semaglutide also significantly reduced resting PAWP (-7.1 mmHg [-9.8 to -4.4]) and peak exercise PAWP (-10.0 mmHg [-12.8 to -7.2]), with additional reductions in pulmonary artery, right atrial, and systemic blood pressures.
Hemodynamic remission occurred in 53.7% of semaglutide-treated patients compared with 7.4% receiving placebo (OR 14.1 [3.0 to 134.6]). Compared with placebo, semaglutide also reduced body weight by 13.2% and improved the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) by 15.0 points. Patients achieving hemodynamic remission experienced greater improvements in KCCQ-OSS than those who did not (between-group difference 14.3 points [4.7, 23.9]).
In a prespecified cardiac MRI substudy involving 49 participants, semaglutide significantly improved left atrial reservoir strain (5.7 percentage points [0.3 to 9.7]) and LV diastolic filling dynamics, measured by early filling rate indexed to end-diastolic volume (+0.64 s⁻¹ [0.42 to 1.00]). Semaglutide also reduced LV mass (-16.0 g) and left atrial volume (-9.0 mL), while improving right ventricular ejection fraction (4.0 percentage points). Improvements in atrial function and ventricular filling correlated with reductions in exercise PAWP.
CAMEO-SEMA provides important mechanistic evidence that semaglutide improves cardiac hemodynamics, function, and remodeling in obesity-related HFpEF. However, the study was small, conducted at a single center, and was not designed to assess clinical outcomes such as heart failure worsening or hospitalizations. Furthermore, greater weight loss was associated with improved cardiac function and hemodynamics, but whether these benefits are mediated by weight loss or other semaglutide effects remains uncertain.
Dr. Borlaug of the Mayo Clinic concluded: “These findings demonstrate a powerful effect of semaglutide on the fundamental hemodynamic and cardiac determinants of HFpEF.”