GLP-1RA improves HF symptoms and physical function in patients with HFpEF and obesity

ESC Congress 2023 STEP HFpEF showed that once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations and exercise function, and led to greater weight loss in patients with HFpEF and obesity, compared with placebo.

Presented at the ESC Congress 2023 by: Mikhail Kosiborod, MD - Kansas City, MO, USA

Introduction and methods

A large proportion of patients with HFpEF are overweight or have obesity. It has become increasingly clear that obesity is not just a comorbidity, but plays a key role in the development and progression of HFpEF. The GLP-1RA semaglutide has previously shown to promote weight loss in patients with obesity or overweight. The current STEP HFpEF trial investigated the effects of semaglutide on symptoms, physical limitations, exercise function, and weight loss, in patients with HFpEF and obesity.

The trial randomized 529 patients (mean age 69 years, 56.1% women) with HFpEF (LVEF ≥45%), BMI ≥30 kg/m2, NYHA class II–IV and KCCQ-CSS <90 points in a 1:1 ratio to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo for 52 weeks.

The first primary endpoint was change in KCCQ-CSS from baseline to week 52 and the second primary endpoint was change in body weight during the same time period. Confirmatory secondary endpoints were change in 6-minute walk distance (6MWD) , a hierarchical composite endpoint (consisting of death, HF events, change in KCCQ-CSS, and change in 6MWD), and change in CRP.

Main results

Dual primary outcomes

• Treatment with semaglutide led to a larger improvement in KCCQ-CSS from baseline to week 52, compared with placebo (mean change +16.6 points vs +8.7 points, ETD 7.8 points, 95%CI: 4.8 to 10.9, P=0.0000006).
• The mean change in body weight from baseline to week 52 was -13.3% in the semaglutide group compared with -2.6% in the placebo group (ETD: -10.7%, 95%CI -11.9% to -9.4%, P<0.001).

Confirmatory secondary endpoints

• A larger improvement in 6MWD was seen with semaglutide (+21.5 meters), compared with placebo (+1,2 meters; ETD: 20.3 meters, 95%CI 8.6 to 32.1, p<0.001).
• Treatment with semaglutide led to more wins than placebo for the hierarchical composite endpoint (win ratio 1.72, 95% CI 1.37 to 2.15; p<0.001). This effect was mainly driven by change in KCCQ-CSS.
• The mean change in CRP was greater with semaglutide (-43.5%) than with placebo (-7.3%; ETR 0.61, 95%CI 0.51 to 0.72, P<0.001).

Exploratory outcomes

• STEP HFpEF was not an outcome trial and therefore not powered for outcomes. However HF events were investigated as an exploratory outcome. The number of patients experiencing an HF hospitalization or urgent visit was 1 in the semaglutide group and 12 in the placebo group.

Safety results

• A smaller proportion of patients experienced a SAE in semaglutide group compared with the placebo group (13,3% vs. 26.7%, P=0.001). There were also less cardiac disorders with semaglutide than with placebo (11.3% vs. 2.7%, P=0.001). A larger proportion of patients in the semaglutide group experienced an AE that led to discontinuation of study drug compared with placebo (13.3% vs. 5.3%). AEs that led to discontinuation were mostly gastrointestinal events.

Conclusion

Once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations and exercise function, and led to greater weight loss in patients with HFpEF and obesity, compared with placebo. Mikhail Kosiborod said “Collectively, these results indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity”.

• Our reporting is based on the information provided at the ESC Congress 2023 -

The results of this study were simultaneously published in N. Engl. J. Med. Watch the video with Mikhail Kosiborod about this trial