Cardiovascular outcome evidence by GLP-1 medicine — SELECT, LEADER, SURPASS-CVOT, SUMMIT

Which GLP-1 medicines have the strongest cardiovascular outcome evidence?

The strongest cardiovascular outcome evidence — in the form of statistically significant superiority over placebo for reducing major adverse cardiovascular events (MACE) — is held by semaglutide and liraglutide. Both have demonstrated MACE reduction in large randomised controlled trials: semaglutide in SELECT (obesity, without diabetes), STEP-1 programme and SUSTAIN-6 (type 2 diabetes); liraglutide in LEADER (type 2 diabetes).

Tirzepatide has demonstrated cardiovascular non-inferiority to dulaglutide (itself a medicine with positive CVOT data) in SURPASS-CVOT, and cardiovascular and functional benefit in HFpEF in SUMMIT. A MACE-superiority trial for tirzepatide versus placebo in a high-risk population had not reported at the time of this page's last review.

What did SELECT show?

SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity, 2023) was a landmark randomised trial enrolling 17,604 adults with established cardiovascular disease, a BMI of ≥27 kg/m², and no diabetes at baseline. Participants were randomly allocated to subcutaneous semaglutide 2.4 mg once weekly or placebo, with a median follow-up of approximately 34 months.

The primary endpoint was a three-point MACE composite (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Semaglutide reduced this composite by 20% versus placebo (hazard ratio 0.80, 95% CI 0.72–0.90; p<0.001) — a result that achieved clear statistical superiority. SELECT was significant for two reasons: it demonstrated cardiovascular benefit in a non-diabetic obese population, and the absolute risk reduction was substantial enough to support a label extension from the MHRA for a cardiovascular risk reduction indication.

For the full trial profile, see SELECT trial.

What about LEADER and SUSTAIN-6?

LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results, 2016) enrolled 9,340 adults with type 2 diabetes and high cardiovascular risk. Liraglutide 1.8 mg once daily versus placebo demonstrated superiority: MACE occurred in 13.0% of the liraglutide group versus 14.9% of placebo (HR 0.87, 95% CI 0.78–0.97; p=0.01 for superiority). For the full trial profile, see LEADER trial.

SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes, 2016) enrolled 3,297 adults with type 2 diabetes at high cardiovascular risk. Subcutaneous semaglutide (0.5 mg or 1.0 mg) demonstrated superiority over placebo for the primary MACE endpoint (HR 0.74, 95% CI 0.58–0.95; p<0.001 for non-inferiority, p=0.02 for superiority). SUSTAIN-6 also identified the diabetic retinopathy signal with rapid HbA1c reduction; see the dedicated safety page for that. SUSTAIN-6 does not have a dedicated trial page on this site — it is cited here by name from published data.

How does SURPASS-CVOT change the picture?

SURPASS-CVOT (2023) was designed differently from the LEADER and SELECT trials. Rather than comparing tirzepatide to placebo in a high-risk population, it compared tirzepatide to dulaglutide — an active GLP-1 receptor agonist that itself demonstrated MACE reduction in REWIND. The trial enrolled 12,995 adults with type 2 diabetes and established cardiovascular disease or high cardiovascular risk, randomised to tirzepatide or dulaglutide, with a median follow-up of approximately 3.4 years.

The primary endpoint was non-inferiority for MACE. Tirzepatide met this endpoint (HR 0.85, 95% CI 0.71–1.02). However, the trial was not powered or designed to demonstrate superiority over dulaglutide, and the confidence interval crossed unity — meaning superiority over dulaglutide cannot be concluded. The trial is therefore evidence that tirzepatide does not increase cardiovascular risk relative to an established active comparator, rather than evidence that tirzepatide reduces cardiovascular events versus placebo.

For the full trial profile, see SURPASS-CVOT trial.

What about HFpEF? (SUMMIT trial)

SUMMIT (SURMOUNT-HFpEF, 2023/2024) investigated tirzepatide specifically in adults with heart failure with preserved ejection fraction (HFpEF) and obesity — a combination that represents a significant unmet clinical need given the limited pharmacological options for HFpEF. The trial enrolled 731 participants and used a composite primary endpoint of worsening heart failure events and Kansas City Cardiomyopathy Questionnaire (KCCQ) score improvement (a measure of heart failure-related symptoms and physical function).

Tirzepatide improved the KCCQ score significantly versus placebo and reduced worsening heart failure events. Body weight was also substantially reduced. SUMMIT does not provide MACE data directly (it was not designed as a MACE-superiority trial) but represents important evidence for tirzepatide in a heart-failure-specific population. For the full trial profile, see SUMMIT tirzepatide HFpEF trial.

Does retatrutide have cardiovascular outcome evidence yet?

Retatrutide is a GLP-1/GIP/glucagon receptor triple agonist in late-phase clinical development. Cardiovascular outcomes data from a dedicated CVOT are not yet available. Phase 2 trial data (published in the NEJM, 2023) demonstrated significant weight loss and cardiometabolic improvements including reductions in waist circumference, blood pressure and lipids, but these are surrogate markers rather than MACE outcomes. Whether retatrutide translates improvements in cardiovascular risk factors into reductions in cardiovascular events will require a dedicated CVOT to establish. For the current evidence, see the TRIUMPH retatrutide programme.

Trial comparison — cardiovascular outcomes at a glance

HR = hazard ratio. All superiority results are versus placebo. SURPASS-CVOT non-inferiority is versus dulaglutide (active comparator). SUMMIT used a composite endpoint including KCCQ rather than MACE.

UK MHRA and Wegovy label extension context for SELECT

Following the SELECT trial, the MHRA approved an extension to the Wegovy marketing authorisation to include a cardiovascular risk reduction indication — specifically, for reducing the risk of major adverse cardiovascular events in adults with established cardiovascular disease and a BMI ≥27 kg/m², in addition to the existing chronic weight management indication. This makes Wegovy unusual among weight-management medicines in the UK: it is the first to carry an approved cardiovascular risk reduction indication alongside its weight-loss label.

This label extension has implications for NHS commissioning and clinical decision-making for patients with both established CVD and obesity who would otherwise not have met the weight-management eligibility criteria.

Frequently asked questions

Which GLP-1 medicines have the strongest cardiovascular outcome evidence?

Semaglutide (SELECT trial) and liraglutide (LEADER trial) have demonstrated superiority over placebo for reducing major adverse cardiovascular events (MACE) in high-risk populations in large randomised trials. SELECT is the largest and most recent, using semaglutide 2.4 mg in people without diabetes but with obesity and established cardiovascular disease.

What is a cardiovascular outcomes trial (CVOT)?

A cardiovascular outcomes trial is a large randomised controlled trial designed to assess whether a medicine increases, decreases or has no effect on major cardiovascular events (MACE) — typically defined as death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. These trials were initially required by regulators (FDA, EMA) to demonstrate cardiovascular safety for new diabetes medicines.

What is the difference between superiority and non-inferiority in a CVOT?

A superiority result means the medicine showed a statistically significant reduction in MACE versus placebo (e.g., SELECT, LEADER). A non-inferiority result means the medicine was shown not to substantially increase MACE versus an active comparator (e.g., SURPASS-CVOT, where tirzepatide was non-inferior to dulaglutide). Non-inferiority is not the same as superiority.

Does SELECT apply only to people with diabetes?

No. SELECT specifically enrolled people without type 2 diabetes — it studied semaglutide 2.4 mg in individuals with a BMI ≥27 kg/m² and established cardiovascular disease but without diabetes. This is what made SELECT landmark: prior GLP-1 CVOTs (LEADER, SUSTAIN-6, REWIND) enrolled people with type 2 diabetes.

Has tirzepatide shown superiority over placebo for cardiovascular outcomes?

Not yet in a published MACE-superiority trial. SURPASS-CVOT demonstrated non-inferiority of tirzepatide versus dulaglutide (an active GLP-1 receptor agonist comparator). A head-to-head superiority CVOT for tirzepatide vs placebo in a high-risk population had not reported at the time of this page's last review.

What did SUMMIT show?

SUMMIT (SURMOUNT-HFpEF) investigated tirzepatide in people with heart failure with preserved ejection fraction (HFpEF) and obesity. It showed improvement in the primary composite endpoint of heart failure symptoms and physical function, and reduction in body weight, versus placebo. This was a significant trial because HFpEF is a condition with limited pharmacological treatment options.

Does the MHRA Wegovy label reflect SELECT findings?

Yes. Following SELECT, the MHRA-approved Summary of Product Characteristics for Wegovy (semaglutide 2.4 mg) was updated to reflect the cardiovascular risk reduction indication in adults with established cardiovascular disease and BMI ≥27 kg/m². This was a label extension based on SELECT data.

Does retatrutide have cardiovascular outcome evidence yet?

No. Retatrutide is a GLP-1/GIP/glucagon triple agonist in late-phase clinical development. Published cardiovascular outcomes data are not yet available. Phase 2 data show weight loss and cardiometabolic improvements, but no CVOT has reported at the time of this review.

What does REWIND show for dulaglutide?

REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) showed superiority of dulaglutide over placebo for reducing MACE in people with type 2 diabetes and a broad cardiovascular risk profile — notably including many participants with cardiovascular risk factors rather than established disease. The primary endpoint achieved statistical superiority.

Are GLP-1 cardiovascular benefits a class effect?

The evidence supports a cardiovascular benefit across multiple GLP-1 receptor agonists in high-risk populations, suggesting a probable class effect — but the magnitude and specific populations in which benefit is shown vary by trial. The mechanism is debated: direct cardiovascular effects of GLP-1 receptor activation, weight loss and metabolic improvement, and anti-inflammatory effects may all contribute.