GLP-1 cardiovascular outcomes: SELECT, STEP-HFpEF, FLOW, and what changed in 2024

Key takeaways

• SELECT (Lincoff 2023 NEJM) randomized 17,604 adults with obesity and established cardiovascular disease but no diabetes; semaglutide 2.4 mg reduced the primary three-point MACE composite from 8.0 percent to 6.5 percent over a mean 39.8 months (HR 0.80) .
• STEP-HFpEF (Kosiborod 2023 NEJM) randomized 529 adults with obesity-driven heart failure with preserved ejection fraction (BMI greater than or equal to 30, EF greater than or equal to 45 percent) and showed semaglutide 2.4 mg improved KCCQ-CSS by 7.8 points and 6-minute walk distance by 20.3 meters versus placebo over 52 weeks .
• STEP-HFpEF DM (Kosiborod 2024 NEJM) extended the same finding to patients with HFpEF, obesity, and type 2 diabetes .
• FLOW (Perkovic 2024 NEJM) was stopped early when an interim analysis showed semaglutide 1.0 mg cut a five-component kidney composite by 24 percent in T2D plus CKD over a median 3.4 years (HR 0.76) .
• Earlier glycemic-era trials in T2D set the foundation: LEADER (liraglutide), SUSTAIN-6 (injectable semaglutide), and REWIND (dulaglutide) each showed three-point MACE reductions in T2D populations .
• FDA expanded Wegovy's labeling in March 2024 to include reducing the risk of major adverse cardiovascular events in adults with established CVD and obesity or overweight, the first such label for an obesity drug .

What SELECT actually measured

SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a placebo-controlled superiority trial that enrolled adults aged 45 or older with established cardiovascular disease (prior MI, prior stroke, or symptomatic peripheral artery disease), a body mass index of 27 or higher, and no history of diabetes. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (three-point MACE).

Patients were randomized 1:1 to semaglutide 2.4 mg subcutaneously once weekly or matching placebo, in addition to standard of care. The primary endpoint event occurred in 569 of 8,803 patients (6.5 percent) on semaglutide and 701 of 8,801 (8.0 percent) on placebo over a mean 39.8 months of follow-up. The hazard ratio was 0.80 (95 percent CI 0.72 to 0.90; P less than 0.001) .

Important context: SELECT was a secondary-prevention trial. Patients had to have established CVD to enroll. The 20 percent relative risk reduction translates to an absolute risk reduction of 1.5 percentage points over roughly 3.3 years, or a number-needed-to-treat of about 67 to prevent one MACE event. Whether the same effect size applies to lower-risk primary-prevention populations is not established by SELECT.

STEP-HFpEF and the obesity-heart-failure axis

Heart failure with preserved ejection fraction (HFpEF) historically had few effective drug therapies. The STEP-HFpEF program tested whether semaglutide 2.4 mg, originally developed for weight loss, would also benefit patients with obesity-driven HFpEF (BMI 30 or higher, EF 45 percent or higher, NYHA class II to IV).

In the index 2023 trial of 529 non-diabetic patients, semaglutide produced a 7.8-point greater improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), a 13.3 percent greater reduction in body weight, a 20.3-meter greater improvement in 6-minute walk distance, and greater reductions in C-reactive protein over 52 weeks . The companion STEP-HFpEF DM trial extended these findings to patients with type 2 diabetes .

FLOW: kidney outcomes in T2D plus CKD

FLOW enrolled 3,533 adults with type 2 diabetes and chronic kidney disease (eGFR 50 to 75 with UACR over 300, or eGFR 25 to less than 50 with UACR over 100) and randomized to semaglutide 1.0 mg weekly or placebo. The primary outcome was a five-component kidney composite: kidney failure (sustained eGFR less than 15 or initiation of long-term kidney replacement), sustained eGFR decline of at least 50 percent, or death from kidney or cardiovascular causes .

The trial was stopped early for efficacy. The primary outcome occurred in 331 of 1,767 (18.7 percent) on semaglutide versus 410 of 1,766 (23.2 percent) on placebo over a median 3.4 years. The hazard ratio was 0.76 (95 percent CI 0.66 to 0.88; P 0.0003). Cardiovascular death alone was reduced (HR 0.71), and the eGFR slope was 1.16 mL per minute per 1.73 m squared less steep per year on semaglutide.

FLOW shifted GLP-1 prescribing in T2D plus CKD into territory previously occupied by SGLT2 inhibitors and finerenone. The mechanism is not fully resolved (weight loss, blood pressure, direct renal effects, and reduced inflammation are all candidates), but the outcome data are robust enough that updated diabetes-and-kidney guidelines are incorporating GLP-1s into CKD pathways.

The glycemic-era foundations: LEADER, SUSTAIN-6, REWIND

The cardiovascular case for GLP-1s did not start with SELECT. The 2008 FDA guidance on cardiovascular safety in T2D drugs forced every new diabetes drug to demonstrate non-inferiority on cardiovascular endpoints. The GLP-1 class was the first oral or injectable diabetes class beyond metformin to demonstrate not just safety but benefit on three-point MACE in T2D populations.

• LEADER (Marso 2016 NEJM) randomized 9,340 patients with T2D and high cardiovascular risk to liraglutide 1.8 mg daily or placebo. Three-point MACE was reduced from 14.9 percent to 13.0 percent (HR 0.87) .
• SUSTAIN-6 (Marso 2016 NEJM) randomized 3,297 patients with T2D and high cardiovascular risk to once-weekly injectable semaglutide (0.5 or 1.0 mg) or placebo. Three-point MACE was reduced from 8.9 percent to 6.6 percent (HR 0.74) .
• REWIND (Gerstein 2019 Lancet) randomized 9,901 patients with T2D and either prior CV disease or risk factors to dulaglutide 1.5 mg weekly or placebo. Three-point MACE was reduced from 13.4 percent to 12.0 percent (HR 0.88) over a median 5.4 years and importantly included a primary-prevention subgroup .
• Earlier exenatide (EXSCEL) and lixisenatide (ELIXA) trials were neutral on MACE; the class signal is real but not uniform across molecules and dose levels .

FDA label changes that followed

In March 2024 the FDA approved a labeling expansion for Wegovy (semaglutide 2.4 mg) to include reducing the risk of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in adults with established cardiovascular disease and either obesity or overweight. This was the first time an obesity drug carried a CV outcomes claim on its label .

Practical implication for prescribers and payers: a patient with established CVD and BMI 27 or higher, with or without diabetes, now has a label-supported indication for semaglutide 2.4 mg specifically for cardiovascular risk reduction. This changes coverage logic: prior-authorization criteria that previously turned on weight-loss-as-cosmetic framing now have a hard MACE endpoint to anchor on.

What the trials do not yet answer

• Whether tirzepatide (a GLP-1 plus GIP co-agonist) produces equivalent or larger MACE reductions. The SURPASS-CVOT trial in T2D plus high CV risk is ongoing; topline results are anticipated.
• Whether retatrutide (GLP-1 plus GIP plus glucagon) shifts the cardiometabolic outcome profile further. Phase 3 outcome programs are in progress.
• Whether primary-prevention populations (no prior CVD, lower baseline risk) gain a similar relative risk reduction. SELECT was secondary prevention.
• Whether the cardiovascular benefit persists after discontinuation. Trial protocols required ongoing therapy; weight regain after stopping is well-documented and the cardiometabolic implications of the regain phase are not yet resolved.
• How GLP-1s combine with SGLT2 inhibitors and finerenone in cardiorenal patients. There are no head-to-head outcome trials.
• Whether oral GLP-1 formulations (oral semaglutide, orforglipron) reproduce injectable outcomes. SOUL (oral semaglutide CVOT) reported in 2025 and is the closest existing data.

Editorial summary

The 2023 to 2024 cardio-renal-metabolic trials moved GLP-1s from glycemic drugs to multi-organ-protective drugs. SELECT, STEP-HFpEF, and FLOW are independently strong; together they reframe the prescribing case. The FDA label change for Wegovy formalizes that shift. Open questions on tirzepatide CV outcomes, retatrutide outcomes, primary-prevention populations, and post-discontinuation persistence remain meaningful and will likely shape the next 24 months of trial readouts.