GLP-1 cardiovascular outcomes trials, what the named studies actually showed

Key takeaways

• LEADER (liraglutide, type 2 diabetes, 9,340 patients, 3.8 year median follow-up): 13 percent relative reduction in major adverse cardiovascular events (MACE) and 22 percent relative reduction in cardiovascular death.
• SUSTAIN-6 (semaglutide once-weekly, type 2 diabetes, 3,297 patients, 2.1 year median follow-up): 26 percent relative reduction in MACE, driven primarily by non-fatal stroke.
• REWIND (dulaglutide, type 2 diabetes, 9,901 patients, 5.4 year median follow-up): 12 percent relative reduction in MACE; first GLP-1 outcomes trial enrolling a majority primary-prevention population.
• SELECT (semaglutide 2.4 mg, no diabetes, 17,604 adults with overweight or obesity and prior cardiovascular disease, 39.8 month follow-up): 20 percent relative reduction in MACE. The first cardiovascular outcomes trial to demonstrate benefit in non-diabetic adults with obesity.
• FLOW (semaglutide 1.0 mg, type 2 diabetes with chronic kidney disease, 3,533 patients): 24 percent relative reduction in major kidney disease events; trial stopped early for benefit.
• Tirzepatide CVOT (SURPASS-CVOT vs dulaglutide, ongoing) is expected to read out in 2025; SUMMIT (tirzepatide in HFpEF with obesity, 731 patients) reported a 38 percent relative reduction in the composite of cardiovascular death or worsening heart failure events at 52 weeks.

Why cardiovascular outcomes trials matter

After the rosiglitazone safety signal in 2008, the FDA required new type 2 diabetes drugs to demonstrate that they did not increase cardiovascular risk. The cardiovascular outcomes trial (CVOT) became the standard postmarketing study: large, randomized, placebo-controlled, with a primary endpoint of major adverse cardiovascular events (the three-point MACE composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). The CVOT framework is documented in the FDA guidance on cardiovascular outcomes for type 2 diabetes drug development .

The result for the GLP-1 receptor agonist class was a series of trials that demonstrated not just safety but benefit. Several of those trials produced label additions for cardiovascular risk reduction, which is now part of how the drugs are used outside the original glycemic-control indication.

LEADER: liraglutide in type 2 diabetes

LEADER randomized 9,340 adults with type 2 diabetes and high cardiovascular risk to liraglutide (titrated to 1.8 mg daily) or placebo, with a median follow-up of 3.8 years. The primary endpoint (3-point MACE) occurred in 13.0 percent of the liraglutide arm versus 14.9 percent of placebo, a hazard ratio of 0.87 (95 percent CI 0.78 to 0.97, p less than 0.001 for non-inferiority and p equal to 0.01 for superiority). Cardiovascular death was reduced 22 percent (HR 0.78) and all-cause mortality 15 percent (HR 0.85) .

LEADER is the trial that supported the cardiovascular indication added to the Victoza (liraglutide) label in 2017. The Saxenda (liraglutide 3.0 mg) obesity label does not carry the same indication; LEADER was conducted at the diabetes dose .

SUSTAIN-6: semaglutide in type 2 diabetes

SUSTAIN-6 randomized 3,297 adults with type 2 diabetes and high cardiovascular risk to subcutaneous semaglutide (0.5 mg or 1.0 mg weekly) or placebo. The primary 3-point MACE endpoint occurred in 6.6 percent of the semaglutide arm versus 8.9 percent of placebo, a hazard ratio of 0.74 (95 percent CI 0.58 to 0.95). The reduction was driven primarily by non-fatal stroke (HR 0.61). Cardiovascular death was numerically lower but did not reach statistical significance individually .

SUSTAIN-6 was conducted at semaglutide doses below the 2.4 mg weight-management dose used in STEP-1 and SELECT. The Ozempic (semaglutide injection) label cardiovascular indication is supported by SUSTAIN-6 .

REWIND: dulaglutide in primary prevention

REWIND randomized 9,901 adults with type 2 diabetes to dulaglutide 1.5 mg weekly or placebo, with a median follow-up of 5.4 years. Unlike LEADER and SUSTAIN-6, REWIND enrolled a majority primary-prevention population (approximately 69 percent without prior cardiovascular disease). The primary 3-point MACE endpoint occurred in 12.0 percent of the dulaglutide arm versus 13.4 percent of placebo, a hazard ratio of 0.88 (95 percent CI 0.79 to 0.99) .

REWIND was important because it extended the GLP-1 cardiovascular benefit signal into a primary-prevention population, broadening the population in which the drug class might be reasonable beyond glycemic control.

SELECT: semaglutide 2.4 mg without diabetes

SELECT was the first cardiovascular outcomes trial of a GLP-1 agonist in adults without diabetes. It randomized 17,604 adults aged 45 or older with overweight or obesity (BMI 27 or higher) and pre-existing cardiovascular disease to semaglutide 2.4 mg weekly or placebo, with a mean follow-up of 39.8 months. The primary 3-point MACE endpoint occurred in 6.5 percent of the semaglutide arm versus 8.0 percent of placebo, a hazard ratio of 0.80 (95 percent CI 0.72 to 0.90, p less than 0.001) .

SELECT supported the FDA's 2024 expansion of the Wegovy (semaglutide 2.4 mg) indication to include reduction of major cardiovascular events in adults with established cardiovascular disease and overweight or obesity. The label update was the first to formally separate weight-loss-mediated cardiovascular risk reduction from glycemic-control benefits .

FLOW: semaglutide and kidney outcomes

FLOW randomized 3,533 adults with type 2 diabetes and chronic kidney disease (eGFR 50 to 75 with elevated albuminuria, or eGFR 25 to 50) to semaglutide 1.0 mg weekly or placebo. The trial was stopped early for benefit. The primary kidney endpoint (composite of kidney failure, sustained 50 percent eGFR decline, or kidney or cardiovascular death) was reduced 24 percent (HR 0.76, 95 percent CI 0.66 to 0.88, p equal to 0.0003). Cardiovascular event rates were also reduced .

FLOW supported a subsequent label expansion for Ozempic to include reduction of kidney disease progression in adults with type 2 diabetes and chronic kidney disease, a separate indication from glycemic control or cardiovascular risk reduction. The current Ozempic prescribing information should be consulted for the precise indication wording .

Tirzepatide cardiovascular and heart-failure data

Tirzepatide is a dual GLP-1/GIP receptor agonist approved for type 2 diabetes (Mounjaro) and obesity (Zepbound). The dedicated cardiovascular outcomes trial SURPASS-CVOT (NCT04255433) randomizes adults with type 2 diabetes and atherosclerotic cardiovascular disease to tirzepatide vs dulaglutide; results are expected in 2025 .

SUMMIT randomized 731 adults with heart failure with preserved ejection fraction (HFpEF) and obesity to tirzepatide 15 mg weekly or placebo. At 52 weeks, the composite of cardiovascular death or worsening heart failure events was reduced 38 percent (HR 0.62, 95 percent CI 0.41 to 0.95). Kansas City Cardiomyopathy Questionnaire score, six-minute walk distance, and weight all improved . Tirzepatide was approved for HFpEF in adults with obesity in late 2024, the first GLP-1 class agent with that specific heart-failure indication.

What the evidence does and does not support

• Within the GLP-1 class, liraglutide, semaglutide, and dulaglutide all have completed CVOTs showing MACE reduction in adults with type 2 diabetes; semaglutide additionally has SELECT for non-diabetic adults with obesity and prior cardiovascular disease.
• Lixisenatide (ELIXA) and exenatide once-weekly (EXSCEL) showed cardiovascular safety but not statistically significant MACE reduction. Not every GLP-1 agonist has shown the same magnitude of cardiovascular benefit; the class label is not uniform.
• Effects on heart failure and kidney outcomes (SUMMIT, FLOW) are now driving label additions beyond MACE.
• Compounded GLP-1 products do not inherit the cardiovascular indications of their labeled counterparts. The FDA has issued repeated cautions on compounded GLP-1 products, including dosing errors and quality concerns .