Promising Results for GLP-1 Receptor Agonists in Obesity-Related HFpEF

Glucagon-like peptide 1 (GLP-1) receptor agonists are gaining attention for the management of type 2 diabetes and obesity. These drugs have multifactorial effects that include stimulating glucose-dependent insulin secretion, delaying gastric emptying, and inhibiting postprandial glucagon secretion. Consequently, GLP-1 receptor agonists have been found to be efficacious in glycemic control in patients with type 2 diabetes and in reducing serious cardiovascular events in patients with type 2 diabetes and cardiovascular or renal disease. GLP-1 receptor agonists have also been shown to induce weight loss in individuals with obesity without diabetes. With such promising results, GLP-1 agonists are being considered for other conditions associated with obesity.

Among patients with heart failure with preserved ejection fraction (HFpEF), those with concomitant obesity appear to have worse clinical and hemodynamic features than patients without obesity. Patients with obesity-related HFpEF have greater degrees of volume overload, right heart dysfunction and remodeling, and increased levels of systemic inflammation. Further, some studies suggest that adipose tissue contributes to the development and progression of HFpEF. As such, weight loss through lifestyle modification and pharmacological means could greatly benefit this patient population.

To evaluate the effect of GLP-1 agonists on symptomatology and weight loss in patients with HFpEF and obesity, researchers conducted the multicentered, randomized, double-blind, placebo-controlled STEP-HFpEF trial. Patients with HFpEF and a body mass index (BMI) ≥30 kg/m2 were randomized to receive once weekly semaglutide injections or placebo for 52 weeks.

The mean change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 16.6 points in the semaglutide group versus 8.7 points in the placebo group (estimated difference, 7.8 points; 95% CI, 4.8 to 10.9; P<0.001). The mean percentage change in body weight was -13.3% versus -2.6%, respectively (estimated difference, -10.7 percentage points; 95% CI, -11.9% to -9.4%; P<0.001). The secondary endpoint of the mean change in 6-minute walk distance was 21.5 meters in the semaglutide group versus 1.2 meters in the placebo group.

These promising results support the use of GLP-1 agonists for the treatment in patients with HFpEF and obesity. In particular, the secondary endpoint of the mean change in 6-minute walk distance suggests significant positive changes in quality of life for the patients who received semaglutide. Whether this outcome could be attributed to improvement in functional capacity or cardiovascular function from weight loss is difficult to determine as the trial was not designed to evaluate cardiovascular events. Nonetheless, the change in physical function cannot be understated given the physical limitations HFpEF can have on patients. Semaglutide should now be considered as an adjunctive therapy in patients with obesity-related HFpEF, with the understanding that cost may be a substantial barrier.

Read the following NEJM Journal Watch summary for more details of this study.

Harlan M. Krumholz, MD, SM, reviewing Kosiborod MN et al. N Engl J Med 2023 Aug 25

Interest in glucagon-like peptide-1 (GLP-1) agonists for the treatment of obesity is growing rapidly, and trials are showing cardiovascular benefit. Now, researchers report findings of an industry-sponsored, international, randomized, double-blind, placebo-controlled trial (STEP-HFpEF; NCT04788511. opens in new tab) that tested whether 2.4 mg of once-weekly subcutaneous semaglutide can improve symptoms and physical function among people with heart failure with preserved systolic function (HFpEF) and obesity. The primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and percentage change in body weight, from baseline to week 52.

Among the 529 participants, the median age was 69 years, 56% were women, and 96% were white people. The mean improvement in the KCCQ-CSS (5 points is considered a meaningful change) was 17 points in the semaglutide group and 9 points in the placebo group, a significant difference. At week 52, the mean percentage change in body weight was also significantly greater in the semaglutide group than in the placebo group (–13% vs. –3%). Semaglutide was associated with better improvement in the 6-minute walk test, greater reduction in C-reactive protein level, and a lower likelihood of hospitalization for heart failure or an urgent visit. Serious adverse events were less frequent in the semaglutide group, who had significantly reduced incidence of cardiac disorder events.

Comment: STEP-HFpEF is another big win for semaglutide, coming on the heels of a recent announcement on August 8 that the yet-to-be-published SELECT trial, a secondary prevention trial, has shown that semaglutide can reduce the risk for major cardiovascular events in people with obesity. With STEP-HFpEF findings, we now have an evidence-based therapy for people with obesity who are suffering from HFpEF, and its side effect profile is quite reassuring. Future studies need to assess treatment in more-diverse populations, and for longer time periods. For now, this study is a major contribution and should provide hope to the many people suffering from HFpEF and obesity.

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Ann Cheung, MD, MBA, MS is a 2023–2024 NEJM Editorial Fellow. She is currently a pediatric hospitalist at Tufts Medical Center and Lowell General Hospital, where she also completed her pediatric hospital medicine fellowship training.