By Michael H. Crawford, MD
SYNOPSIS: The second trial of semaglutide in obese patients with heart failure and preserved left ventricular ejection fraction, this one in people with type 2 diabetes, also has shown significant improvements in symptoms and exercise function with significantly fewer adverse effects than placebo-treated patients.
SOURCE: Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med 2024;390:1394-1407.
Semaglutide, a glucacgon-like peptide-1 (GLP-1) receptor agonist, has been shown to decrease weight, increase exercise tolerance, and improve symptoms in non-diabetic patients with heart failure with preserved ejection fraction (HFpEF) compared to placebo (STEP-HFpEF).1 Type 2 diabetes patients with obesity and HFpEF are a more challenging group because they represent a more advanced phenotype, and many are taking sodium glucose cotransporter-2 (SGLT-2) inhibitors, which have been shown to reduce HF events. Thus, the Semaglutide Treatment Effect in People with Obesity and HFpEF and Diabetes Mellitus (STEP-HFpEF DM) is of interest. This study was conducted at 108 centers in 16 countries in Europe, Asia, and the Americas.
The investigators enrolled adults with type 2 diabetes and without retinopathy; with HF and EF ≥ 45%; with a body mass index (BMI) ≥ 30, stratified as < 35 or ≥ 35; and either elevated left ventricular filling pressures and increased natriuretic peptides or an HF hospitalization within the last 12 months and continued diuretic use. Semaglutide was titrated over four weeks to the final dose of 2.4 mg injected weekly for 52 weeks followed by five weeks of follow-up.
The primary dual endpoint was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in weight. Secondary endpoints included the six-minute walk test, C-reactive protein (CRP), all-cause death, and HF hospitalization.
Safety endpoints were adverse events, especially hypoglycemia and retinopathy. Also, the win ratio was assessed (benefit vs. no benefit in pairs of patients on treatment or placebo).
In 2021 and 2022, 616 patients were randomized. Fifty patients in the semaglutide group and 46 patients in the placebo group prematurely stopped participation in the trial, leaving 583 patients who completed it. The median age was 69 years, 44% were women, the median body weight was 103 kg, and the median BMI was 40, with 64% of patients ≥ 35.
Comparing the semaglutide group to the placebo group, the change in KCCQ-CSS was 14 vs. 6 (P < 0.001); change in weight, -10 kg vs. -3 kg (P < 0.001); change in six-minute walk test, 13 minutes vs. -2 minutes (P = 0.008); win% 59 vs. 37 (P < 0.001); percent-change in CRP, -42 vs. -13 (P < 0.001); serious adverse events, 18 patients vs. 29 patients (P = 0.002); HF hospitalizations, 7 patients vs. 18 patients; and death, 6 patients vs. 10 patients.
The authors concluded that at one year, semaglutide improved HF symptoms and physical limitations, and produced greater weight loss, than placebo in diabetes mellitus patients with obesity-related HFpEF.
Commentary
The STEP-HFpEF trials were conducted by the sponsor, Novo Nordisk, who was responsible for the data collection and statistical analysis. The softer endpoints, such as HF hospitalization, were adjudicated by an independent committee. The authors interpreted the data and produced the manuscript independently. This is about as good as you can get with a study not funded by governments or societies.
These two trials were designed to evaluate symptoms, physical limitations, and exercise function. Also, they allowed all the usual baseline medications that HF and diabetes mellitus patients are taking. About one-third of the patients in STEP-HF DM were taking an SGLT2 inhibitor, and most were taking a renin-angiotensin system antagonist, a beta-blocker, and a diuretic. Also, most were taking metformin, and 20% were receiving insulin.
Notwithstanding this polypharmacy, there was no increase in adverse events with semaglutide. Importantly, despite significant decreases in glycated hemoglobin with semaglutide, there was no increase in hypoglycemic events or retinopathy.
STEP-HFpEF DM showed significant reductions in symptoms and improvements in physical function even though there was less weight loss than was seen in STEP-HFpEF. This probably is because diabetes mellitus patients with HFpEF are a less healthy phenotype with more myocardial, microvascular, mitochondrial, and skeletal muscle dysfunction; more inflammation; and worse exercise function. Thus, the consistent results in diabetes mellitus and non-diabetes mellitus HFpEF patients are reassuring.
There are limitations to STEP-HF DM. Although the participation of Black patients in the United States was 26%, it was low overall. Also, the study was not designed to assess hospitalizations. In addition, there were missing data, as might be expected in an international trial.
At this point, with two trials showing benefits at least in symptoms in HFpEF patients with and without diabetes mellitus, GLP-1 receptor agonists are becoming first-line therapy for such patients and seem to have indications beyond being weight-loss drugs. One recent trial showed that GLP-1 agents helped control blood pressure in hypertensive obese patients.
A remaining issue is whether the cardiology community will fully embrace these agents or rely on primary care/diabetologists/bariatricians to help manage obese patients with HFpEF.
Reference
- Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 2023;389:1069-1084.
The second trial of semaglutide in obese patients with heart failure and preserved left ventricular ejection fraction, this one in people with type 2 diabetes, also has shown significant improvements in symptoms and exercise function with significantly fewer adverse effects than placebo-treated patients.
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