As blogged previously, semaglutide 2.4mg (Wegovy) has been shown to markedly improve symptoms of heart failure in people with obesity (without diabetes) and heart failure with preserved ejection fraction (HFpEF for short), in a trial called the STEP HFpEF study. A new study was just published, showing similar results in people with obesity and diabetes and HFpEF. What do these new data teach us?

The STEP HFpEF DM study included 616 adults with type 2 diabetes, HFpEF (left ventricular ejection fraction (LVEF) ≥45%), and a body mass index of 30 or higher, to receive either semaglutide 2.4mg weekly or placebo for one year.  The primary endpoints were change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS – a questionnaire that measures symptoms, physical and social limitations, and quality of life in people with heart failure), and change in body weight. A third of participants were on SGLT2 inhibitors (medications which treat diabetes and heart failure), and 21% were on insulin at baseline.

At one year, the mean change in the KCCQ-CSS was 13.7 points with semaglutide vs 6.4 points with placebo (estimated difference 7.3 points).   They also found that people in the semaglutide group could walk 14m farther than the placebo group during a 6 minute test, had a greater reduction in inflammation (lower CRP) and NT-proBNP (a blood test marker of heart failure), and a greater number of ‘wins’ (win ratio 1.58 – read more on the win ratio in the paper). A treatment benefit was seen with semaglutide in people who were on SGLT2i, and in people not on SGLT2i (difference in change in KCCQ-CSS score between semaglutide and placebo group 5.3 and 8.3 points, respectively).   Weight loss was -9.8% with semaglutide vs -3.4% with placebo.

A prespecified pooled analysis of STEP HFpEF and STEP HFpEF DM put the data together from the two studies, allowing us to understand the benefits to HFpEF patients more precisely, and in greater detail. This analysis demonstrated consistency in results across most subgroups tested, including across body mass index (BMI <35, 35-40, ≥40kg/m2) and across the range of preserved ejection fraction (LVEF 45-50, 50-60, ≥60%). There was greater benefit in people with more severe heart failure (as evidenced by higher baseline NTproBNP) and in those with a history of atrial fibrillation. Although patients with type 2 diabetes lost approximately 40% less weight than those without diabetes, the improvements in KCCQ-CSS were similar.  These findings suggest that the mechanism by which semaglutide improves heart failure is at least partially independent of weight lost.  These trials were not powered to assess the effect of semaglutide on heart failure events nor mortality.

BOTTOM LINE: Semaglutide 2.4mg is the first GLP1 receptor agonist to show benefit to improve symptoms of heart failure with preserved ejection fraction (HFpEF), with the benefit now demostrated in people with or without type 2 diabetes. While providing clinically meaningful weight loss, the benefit of semaglutide to improve heart failure symptoms likely has mechanisms at play other than weight loss alone. The benefit of semaglutide 2.4mg to improve HFpEF symptoms is enjoyed irrespective of individual clinical and demographic characteristics.

Disclaimer: I am an investigator in clinical trials of semaglutide.  I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk).

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