Semaglutide Treatment Effect in People With Obesity and Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus - STEP-HFpEF DM

Aug 26, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Novo Nordisk
Date Presented:
04/06/2024
Date Published:
08/19/2024
Date Updated:
08/26/2024
Original Posted Date:
04/06/2024
References

Contribution To Literature:

Highlighted text has been updated as of August 26, 2024.

The STEP-HFpEF DM trial showed that among obese patients with HFpEF and type 2 DM, once weekly subcutaneous semaglutide was superior to placebo in improving body weight and patient-oriented QoL outcomes at 52 weeks.

Description:

The goal of the trial was to compare the safety and efficacy of semaglutide among patients with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (DM).

Study Design

Patients were randomized in a 1:1 fashion to once weekly subcutaneous semaglutide (n = 310) or matching placebo (n = 306) for 52 weeks. Semaglutide treatment was initiated at a dose of 0.25 mg once weekly for the first 4 weeks, and the dose was escalated every 4 weeks with the aim of reaching the maintenance dose of 2.4 mg by week 16.

  • Total randomized participants: 616
  • Median duration of follow-up: 52 weeks
  • Median patient age: 69 years
  • Percentage female: 44%

Inclusion criteria:

  • Left ventricular ejection fraction (LVEF) ≥45%, New York Heart Association (NYHA) functional class II–IV, Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) <90 points, 6-minute walk distance (6MWD) ≥100 m, and ≥1 of the following:
    • Elevated LV filling pressures (invasively measured)
    • Elevated natriuretic peptide levels and structural echocardiographic abnormalities
    • HF hospitalization (previous 12 months) and ongoing requirement for diuretics and/or structural echocardiographic abnormalities
  • Type 2 DM diagnosed ≥90 days prior to screening with glycated hemoglobin (HbA1c) ≤10%

Exclusion criteria:

  • Prior/planned bariatric surgery
  • Recent self-reported weight change >5 kg (>11 lbs)
  • Recent adverse cardiovascular event or HF hospitalization
  • Systolic blood pressure >160 mm Hg at screening
  • History of type 1 DM
  • Recent glucagon-like peptide-1 (GLP-1) receptor agonist use
  • Uncontrolled diabetic retinopathy

Other salient features/characteristics:

  • White race: 84%
  • Median body weight: 103 kg
  • Median body mass index (BMI): 37 kg/m2
  • Atrial fibrillation at baseline: 39%
  • Median baseline NT-pro–B-type natriuretic peptide (NT-proBNP): 493 pg/mL
  • Baseline medications: diuretic: 81%, mineralocorticoid receptor antagonist: 33%, sodium–glucose cotransporter 2 (SGLT2) inhibitor: 33%

Principal Findings:

The co-primary endpoints for semaglutide vs. placebo from baseline to week 52:

  • Change in KCCQ-CSS: 13.7 vs. 6.4 (p < 0.001)
  • % change in body weight: -9.8% vs. -3.4% (p < 0.001)

Change in body weight was higher among patients not on SGLT2 inhibitors vs. those on it at baseline (-7.2% vs. -4.7%, p for interaction = 0.04).

Key secondary outcomes for semaglutide vs. placebo:

  • Change in 6MWD from baseline to week 52: 12.7 vs. -1.6 m (p = 0.008)
  • Hierarchical composite endpoint (proportion of wins): 58.7% vs. 36.8% (p < 0.001)
  • Change in HbA1c from baseline to week 52: -0.7 vs. 0.1 (p < 0.05)
  • Percentage reduction from baseline to week 52 in NT-proBNP: -23.2 vs. -4.6 (p < 0.05)
  • Time to first HF event: 7 vs. 18 (hazard ratio 0.40, 95% confidence interval 0.15-0.92)
  • All-cause mortality: 1.9% vs. 3.3% (p > 0.05)

Effect by sex (STEP-HFpEF and STEP-HFpEF DM pooled analysis): 49.7% were women. Women had higher LVEF and presented with worse symptoms and physical limitations: a higher proportion of women than men were classified as NYHA functional class III-IV, and baseline KCCQ-CSS and 6MWD were lower in women. Women were also less likely to have a history of coronary artery disease or atrial fibrillation. Compared with placebo, semaglutide improved KCCQ-CSS regardless of sex (mean difference in women: +7.6 points [95% CI 4.5-10.7]; men: +7.5 points [95% CI 4.3-10.6]; p for interaction = 0.94) but reduced body weight more in women (mean difference in women: -9.6% [95% CI 10.9%-8.4%]; men: -7.2% [95% CI 8.4%-6.0%]; p for interaction = 0.006).

Interpretation:

The results of this trial show that among obese patients with HFpEF and type 2 DM, once weekly subcutaneous semaglutide was superior to placebo in improving body weight (~6.4% greater weight loss) and patient-oriented quality of life (QoL) outcomes including KCCQ-CSS and 6MWD at 52 weeks. The trial was underpowered for clinical events, although reductions in HF events were noted. These are landmark findings and mirror similar findings in the STEP-HFpEF trial, which included patients with and without DM. Taken together, they support a larger outcomes trial to study the effect of GLP-1 receptor agonist among patients with HFpEF and obesity.

Interestingly, weight loss in this trial was lower compared with STEP-HFpEF (10.7% vs. 6.4%). Although it is hard to directly compare across trials, it is possible that this difference was driven by a difference in SGLT2 inhibitor use between the trials (3.6% in STEP-HFpEF vs. 33% in the current trial); there was also evidence of effect modification by baseline SGLT2 inhibitor use in the current trial, such that a larger benefit was noted among those who were not on it at baseline. That said, even among patients who were on SGLT2 inhibitors at baseline (Class 2a recommendation), a benefit with GLP-1 receptor agonists was observed. It is still somewhat unclear if the improvements in HF-related QoL measures were driven by weight loss (suggesting that other weight loss measures could be considered and potentially beneficial) or independent of this, but increasingly likely that both mechanisms are involved.

References:

Verma S, Butler J, Borlaug BA, et al., on behalf of the STEP-HFpEF Trial Committees and Investigators. Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials. J Am Coll Cardiol 2024;84:773-85.

Editorial Comment: Ostrominski JW, Lala A. Incretin-Based Therapies in Women With Obesity-Related HFpEF: Time to STEP Into a Paradigm of Integrated Care. J Am Coll Cardiol 2024;84:786-9.

Kosiborod MN, Petrie MC, Borlaug BA, et al., on behalf of the STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in Patients With Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med 2024;390:1394-1407.

Presented by Dr. Mikhail Kosiborod at the American College of Cardiology Annual Scientific Session (ACC.24), Atlanta, GA, April 6, 2024.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies

Keywords: ACC24, ACC Annual Scientific Session, Diabetes Mellitus, Type 2, Glucagon-Like Peptide-1 Receptor, Heart Failure, Preserved Ejection Fraction, Novel Agents, Obesity


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