SELECT

Published

Lincoff AM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes". The New England Journal of Medicine. 2023. Epub 2023-11-11:1-12.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among adults with ASCVD and BMI ≥27 kg/m² but no diabetes, does use of the GLP-1 agonist semaglutide lower risk of CV mortality, nonfatal MI, or nonfatal stroke when compared with placebo?

Bottom Line

Among adults with ASCVD and BMI ≥27 kg/m² but no diabetes, semaglutide (a GLP-1 agonist) lowers risk of CV mortality, nonfatal MI, or nonfatal stroke when compared with placebo.

Major Points

GLP-1 agonists were originally developed for management of diabetes but were later shown to drive weight loss among individuals with obesity (see STEP 1, 2021). Persons with diabetes are at greater risk for CVD events, and the 2016 SUSTAIN-6 trial found the GLP-1 agonist semaglutide to be associated with lower risk of CVD events among adults with T2DM with high CVD risk when compared with placebo. Whether semaglutide similarly lowers risk of CVD events is unknown.

The 2023 Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) trial randomized 17,604 adults with overweight or obesity and prior CVD events (MI, stroke, PAD) but no diabetes to semaglutide or placebo. At 34 months, semaglutide was associated with a lower risk of CV mortality, nonfatal MI, or nonfatal stroke when compared to placebo (6.5% vs. 8.0%; HR 0.80; 95% CI 0.72-0.90; P<0.001; NNT=67). In comparison with placebo, participants randomized to semaglutide had greater weight loss, greater reductions in Hgb A1c, BP, CRP, and atherogenic lipid particles. Semaglutide had lower risk of severe adverse events than placebo (33% vs 36%), but had a higher rate of discontinuation for adverse vents than placebo (17% vs 8%), which was most commonly from GI disorders

SELECT provides additional evidence for the use of GLP-1 agonists among individuals with higher weight (in this trial, BMI ≥27 kg/m²) and prior CVD risk. Whether GLP-1 agonists lower CVD risk among individuals with prior CVD and lower weight or CVD risk among individuals with higher weight but no prior CVD event is unknown.

Guidelines

As of November 2023, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, randomized placebo-controlled trial
• N=17,604
  • Semaglutide (n=8803)
  • Placebo (n=8801)
• Setting: 804 sites in 41 countries
• Enrollment: 2018-2021
• Mean follow-up: 34 months
• Analysis: Intention-to-treat
• Primary outcome: CV mortality, nonfatal MI, or nonfatal stroke

Population

Inclusion Criteria

Detailed in the supplementary appendix.

• Aged ≥45y
• BMI ≥27 kg/m²
• CVD, defined by ≥1 of these:
  • Prior MI
  • Prior ischemic or hemorrhagic stroke
  • PAD wit intermittent claudication with ABI <0.85, prior peripheral artery revascularization, or prior PAD-related amputation

Exclusion Criteria

• In the prior 60 days: MI, stroke, UA hospitalization, TIA
• Planned coronary, carotid, or peripheral artery revascularization
• Ever had HF NYHA class IV
• Hgb A1c ≥6.5%
• Known T1DM or T2DM except for gestational DM
• Chronic pancreatitis or acute pancreatitis in prior 180 days
• ESRD
• Cancer in prior 5 years except for BCC or SCC of skin
• Severe psychiatric condition
• Hypersensitivity to study agent
• Pregnant or able to become pregnant without effective birth control

Baseline Characteristics

From the semaglutide group.

• Demographics: Age 62 years; 72% men; 84% White, 8% Asian, 4% Black, 3% other race; 10% Hispanic/Latino
• Anthropometrics: Weight 96 kg, BMI 33 kg/m², waist circumference 111 cm
• Labs: Hgb A1c 5.8% (A1c <5.7% 33%; ≥5.7% 67%), CRP 1.87 mg/L, eGFR 84 mL/min/1.73 m², TC 153, HDL 44, LDL 78, TG 134
• BP 131/79
• HR 69 BPM
• EQ-5D-5L score: 0.88 (out of 1, higher is better health status as reported by participants)
• EQ-5D-VAS: 77 (out of 100, higher indicates better health status as reported by participants)
• CV eligibility: MI only 68%, stroke only 18%, PAD only 4%, ≥2 eligibility criteria 8%, other 2%

Interventions

• Participants were randomized to a group:
  • Semaglutide - 2.4 mg subcutaneously weekly, uptitrated from 0.24 mg weekly over 16 weeks. Lower doses used as needed for tolerability.
  • Placebo

Outcomes

Presented as semaglutide vs. placebo.

Primary Outcome

CV mortality, nonfatal MI, or nonfatal stroke

6.5% vs. 8.0% (HR 0.80; 95% CI 0.72-0.90; P<0.001; NNT=67)

Secondary Outcomes

P values were not given for most outcomes.

CV mortality

2.5% vs. 3.0% (HR 0.85; 95% CI 0.71-1.01; P=0.07; NNT=200)

All-cause mortality

4.3% vs. 5.2% (HR 0.81; 95% CI 0.71-0.93)

HF events

First CV mortality of HF hospitalization or urgent visit

3.4% vs. 4.1% (HR 0.82; 95% CI 0.71-0.96)

CV composite outcome

CV mortality, nonfatal MI, nonfatal stroke, coronary revascularization, UA hospitalization

All-cause mortality, nonfatal MI, nonfatal stroke

9.9% vs. 12.2% (HR 0.80; 95% CI 0.73-0.87)

CV composite or CV mortality

8.1% vs. 10.0% (HR 0.80; 95% CI 0.72-0.88)

Nonfatal MI

2.7% vs. 3.7% (HR 0.72; 95% CI 0.61-0.85)

Nonfatal stroke

1.7% vs. 1.9% (HR 0.93; 95% CI 0.74-1.15)

HF hospitalization or urgent visit

1.1% vs. 1.4% (HR 0.79; 95% CI 0.60-1.03)

Coronary revascularization

5.4% vs. 6.9% (HR 0.77; 95% CI 0.68-1.13)

UA hospitalization

1.2% vs. 1.4% (HR 0.87; 95% CI 0.67-1.13)

Hemoglobin A1c ≥6.5%

3.5% vs. 12.0% (HR 0.27; 95% CI 0.24-0.31)

Nephropathy events

Renal mortality, ESRD, eGFR <15 mL/min/1.73 m², persistent 50% reduction in eGFR, onset of albumin:creatinine >30 mg/g

1.8% vs. 2.2% (HR 0.78; 95% CI 0.63-0.96)

Hemoglobin A1c ≥5.7% among those with baseline Hgb A1c <5.7%

21.3% vs. 50.5% (HR 0.33; 95% CI 0.30-0.36)

Week 52: 66% vs. 20% (difference 10; 95% CI 9 to 11)

Week 104: 66% vs. 21% (difference 9; 95% CI 8 to 10)

Change from baseline to week 104

Weight: -9.3% vs. -0.8% (-8.51; 95% CI-8.75 to -8.27)

Waist circumference: -7.47 cm vs. -0.94 cm (-6.53; 95% CI -6.79 to -6.27)

Hgb A1c: -0.31% vs. 0.01% (-0.32; 95% CI -0.33 to -0.31)

SBP: -3.66 vs. -0.35 mm Hg (-3.31; 95% CI -3.75 to -2.88)

DBP: -0.92 vs. -0.47 mm Hg (-0.55; 95% CI -0.83 to -0.27)

HR: 3.79 vs. 0.69 BPM (3.10; 95% CI 2.80 to 3.39)

EQ-5D-5L index score: 0.01 vs. -0.01 (0.01; 95% CI 0.01 to 0.02)

EQ-5D-VAS score: 2.5 vs. 0.9 (1.60; 95% CI 1.16 to 2.04)

CRP: -39.1% vs. -2.1% (-37.82; 95% CI -39.70 to -35.90)

TC: -4.6% vs. -1.9% (-2.77; 95% CI -3.37 to -2.16)

HDL: 4.9% vs. 0.6% (4.24; 95% CI 3.70 to 4.79)

LDL: -5.2% vs. -3.1% (-2.18; 95% CI -3.22 to -1.12)

TG: -18.3% vs. -3.2% (-15.64; 95% CI -16.68 to -14.58)

Subgroup Analysis

There was a similar proportion with the primary outcome when stratified by sex, age, BMI, CV disease type, presence of HF, eGFR, Hgb A1c, region, race, and ethnicity. For details, see Figure S5 in the Supplementary Appendix.

Adverse Events

Serious

33% vs. 36% (P<0.001)

Cardiac: 12% vs. 14% (P<0.001)

Infectious: 7% vs. 8% (P=0.001)

Neurological: 5% vs 6% (P=0.08)

Surgical/medical procedures: 5% vs. 6% (P<0.001)

Neoplasia: 5% vs. 5% (P=0.94)

GI: 4% vs. 4% (P=0.48)

Any severity, leading to permanent discontinuation of study medication

17% vs. 8% (P<0.001)

GI: 10% vs. 2% (P<0.001)

Neurological: 1% vs. 1% (P=0.03)

Metabolic/nutritional: 1% vs. <1% (P<0.001)

Injection site related: 1% vs. 0.5% (P<0.001)

Neoplasia: 0.9% vs. 1.2% (P=0.07)

Infectious: 1% vs. 1% (P=0.47)

Any severity, special interest

Covid-19 events: 24% vs. 24% (P=0.46)

Malignancy: 5% vs. 5% (P=0.92)

Gallbladder 2.8% vs. 2.3% (P=0.04)

Acute kidney failure: 2% vs. 2% (P=0.13)

Acute pancreatitis: 0.2% vs. 0.3% (P=0.28)

Criticisms

• Unclear efficacy among participants without CVD.
• The BMI threshold used (27 kg/m²) is in between overweight and obesity BMI categories.

Funding

Novo Nordisk, the manufacturers of Ozempic and Wegovy (the brand names for semaglutide).