Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity - SELECT

Sep 12, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD,MPH,FACC
Trial Sponsor:
Novo Nordisk
Date Presented:
11/11/2023
Date Published:
08/24/2024
Date Updated:
09/12/2024
Original Posted Date:
11/10/2023
References

Contribution To Literature:

Highlighted text has been updated as of September 12, 2024.

The SELECT trial showed that in patients with overweight or obesity and established CVD but without diabetes, once-weekly subcutaneous semaglutide was associated with a decreased risk of MACE comprised of CV death, nonfatal MI, and stroke compared with placebo.

Description:

The goal of the trial was to determine the association of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), with cardiovascular (CV) events in a secondary prevention cohort of patients with overweight or obesity and prior CV disease (CVD) without diabetes mellitus (DM).

Study Design

  • Randomized
  • International multicenter
  • Double-blind
  • Placebo-controlled

Patients with overweight or obesity (body mass index [BMI] ≥27 kg/m2) and established CVD were randomized to receive once-weekly subcutaneous semaglutide (n = 8,803) vs. placebo (n = 8,801). Semaglutide was initiated at 0.24 mg once weekly and increased every 4 weeks as tolerated until the target (2.4 mg weekly) or maximally tolerated dose was reached. Management of incident DM during the trial was deferred to the treating provider, although open-label use of a GLP-1 RA was prohibited.

  • Total number of enrollees: 17,604
  • Mean duration of follow-up: 40 months
  • Mean patient age: 62 years
  • Percentage female: 28%

Inclusion criteria:

  • Age ≥45 years
  • BMI ≥27 kg/m2
  • Prior myocardial infarction (MI), stroke, or peripheral arterial disease with claudication and ankle-brachial index <0.85, prior revascularization, or amputation

Exclusion criteria:

  • MI, unstable angina, stroke, or transient ischemic attack ≤60 days prior
  • Upcoming planned revascularization
  • New York Heart Association (NYHA) class IV heart failure (HF) symptoms
  • History of DM or hemoglobin A1c (HbA1c) ≥6.5%
  • GLP-1 RA use ≤90 days prior
  • Acute pancreatitis ≤180 days prior
  • Chronic pancreatitis
  • Personal or first-degree relative history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
  • End-stage renal disease or dialysis requirement

Other salient features/characteristics:

  • Mean BMI: 33.3 kg/m2
  • BMI ≥30 kg/m2: 71.5%
  • Prior MI: 76%
  • Prior stroke: 23%
  • Symptomatic peripheral arterial disease: 9%
  • Prediabetes (HbA1c 5.7-6.4%): 66%
  • Percentage on statin therapy: 88%
  • Percentage of semaglutide arm achieving target dose: 77%
  • Mean exposure to target semaglutide dose: 33 months
  • HF with preserved ejection fraction (HFpEF): 13%
  • HF with reduced EF (HFrEF): 8%
  • NYHA class I-II: 91.3% of HF cohort

Principal Findings:

The primary outcome, major adverse CV events (MACE: composite of CV death, nonfatal MI, and nonfatal stroke), for semaglutide vs. placebo, was: 6.5% vs. 8.0% (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.72-0.90, p < 0.001).

Prespecified subgroup analyses of the primary outcome for semaglutide vs. placebo:

  • Female vs. male: HR 0.84 (95% CI 0.66-1.07) vs. HR 0.79 (95% CI 0.70-0.90)
  • HbA1c <5.7% vs. ≥5.7%: HR 0.82 (95% CI 0.68-1.00) vs. HR 0.79 (95% CI 0.69-0.90)
  • HF vs. no HF: HR 0.72 (95% CI 0.60-0.87) vs. HR 0.84 (95% CI 0.74-0.97), p for interaction = 0.19
  • HFrEF vs. HFpEF: HR 0.65 (95% CI 0.49-0.87) vs. HR 0.69 (95% CI 0.51-0.91), p for interaction = 0.82

Secondary outcomes for semaglutide vs. placebo:

  • CV death: 2.5% vs. 3.0% (HR 0.85, 95% CI 0.71-1.01, p = 0.07)
  • All-cause death: 4.3% vs. 5.2% (HR 0.81, 95% CI 0.71-0.93)
  • Nonfatal MI: 2.7% vs. 3.7% (HR 0.72, 95% CI 0.61-0.85)

HF composite outcome, CV death or HF hospitalization, for semaglutide vs. placebo: 3.4% vs. 4.1% (HR 0.82, 95% CI 0.71-0.96)

  • HF vs. no HF: HR 0.79 (95% CI 0.64-0.98) vs. HR 0.85 (95% CI 0.68-1.06), p for interaction = 0.64
  • HFrEF vs. HFpEF: HR 0.79 (95% CI 0.58-1.08) vs. HR 0.75 (95% CI 0.52-1.07), p for interaction = 0.79

Additional outcomes for semaglutide vs. placebo:

  • HbA1c ≥6.5%: 3.5% vs. 12.0% (HR 0.27, 95% CI 0.24-0.31)
  • Change in systolic blood pressure: –3.8 vs. –0.5 mm Hg
  • Mean change in body weight at 104 weeks: –9.4% vs. –0.9%

Adverse events for semaglutide vs. placebo:

  • All serious adverse events: 33.4% vs. 36.4% (p < 0.001)
  • Adverse events leading to trial drug discontinuation: 16.6% vs. 8.2% (p < 0.001)
  • Gastrointestinal (GI) complications: 10.0% vs. 2.0% (p < 0.001)
  • Acute pancreatitis: 0.2% vs. 0.3% (p = 0.28)
  • Acute kidney failure: 1.9% vs. 2.3% (p = 0.13)
  • Malignant neoplasms: 4.8% vs. 4.7% (p = 0.92)

Interpretation:

In patients with overweight or obesity and established CVD without DM, once-weekly subcutaneous semaglutide was associated with a 20% reduction in major adverse cardiac events during a mean exposure period of 33 months. This benefit was observed even in the setting of widespread concurrent statin use. Study drug discontinuation was twice as common in the semaglutide arm and was primarily due to gastrointestinal intolerance, a known side effect of GLP-1 RAs. Other serious adverse effects were largely similar or less frequent with semaglutide.

Prior studies of lifestyle and pharmacologic interventions have not demonstrated a strong effect in reducing the CV risk associated with overweight and obesity. The SELECT trial extends the findings of SUSTAIN-6 and other GLP-1 RA trials, which have demonstrated CV benefit in DM, to this increased-risk population. The cardioprotective effects of GLP-1 RA are not fully understood and likely multifactorial, as observed from the greater reduction in both systolic blood pressure and incident DM in the treatment arm. The latter is of significance given the prevalence of prediabetes in the study cohort as well the associated interaction on exploratory subgroup analysis. Based on these data, subcutaneous semaglutide may have an expanded role in secondary CVD prevention in patients without DM and with overweight or obesity.

In patients with HF, semaglutide was associated with decreased MACE, HF hospitalization, and CV death compared with placebo. There was no interaction with HF subtype, and adverse event profiles were similar to the overall cohort. These findings support the safety and clinical use of semaglutide in patients with obesity, atherosclerotic CVD, and HFrEF or HFpEF with NYHA class I-II symptoms. The role of GLP-1 RA in more symptomatic HF and in combination with sodium-glucose cotransporter 2 inhibitors remains a valuable question for future inquiry.

References:

Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet 2024;404:773-86.

Lincoff AM, Brown-Frandsen K, Colhoun HM, et al., on behalf of the SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity Without Diabetes. N Engl J Med 2023;389:2221-32.

Editorial: Khera A, Powell-Wiley. SELECTing Treatments for Cardiovascular Disease — Obesity in the Spotlight. N Engl J Med 2023;389:2287-8.

Presented by Dr. Abraham Lincoff at the American Heart Association Scientific Sessions, Philadelphia, PA, November 11, 2023.

Clinical Topics: Acute Coronary Syndromes

Keywords: AHA23, AHA Annual Scientific Sessions, Glucagon-Like Peptide-1 Receptor, Obesity


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