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Section 5 of 6

Landmark Trials

The six cardiovascular outcome trials that proved GLP-1 medications do far more than manage weight — establishing heart protection as a core therapeutic benefit across diabetic and non-diabetic populations.

SuperiorSemaglutide 2.4mg

SELECT

n=17,604 · Obesity without T2D · ~3.4 years

0.80
Hazard Ratio
20%
MACE Reduction
17,604
Patients

First trial to demonstrate CV benefit in obesity without diabetes — expanding GLP-1 therapy from "diabetes drug" to "cardiometabolic drug."

Full trial detail
Superior vs. Placebo

SELECT

Semaglutide 2.4mg weekly · n=17,604 · Adults ≥45 with CVD, BMI ≥27, no T2D

Primary Outcome

CV death, nonfatal MI, or nonfatal stroke: 6.5% (semaglutide) vs. 8.0% (placebo). HR 0.80 (95% CI: 0.72–0.90; p<0.001).

Key Insight

SELECT was the first trial to demonstrate that a GLP-1 RA reduces cardiovascular events in patients with obesity but without diabetes — fundamentally expanding the therapeutic paradigm and establishing obesity itself as an independent target for pharmacological CV risk reduction.

Reference
  • Lincoff AM et al. N Engl J Med. 2023;389(24):2221-2232. PMID: 37952131
SuperiorSemaglutide 0.5/1.0mg

SUSTAIN-6

n=3,297 · T2D, high CV risk · 2 years

0.74
Hazard Ratio
26%
MACE Reduction
3,297
Patients

Established semaglutide's cardiovascular superiority in type 2 diabetes — positioning GLP-1 RAs as cardiovascular protective therapies.

Full trial detail
Superior vs. Placebo

SUSTAIN-6

Semaglutide 0.5/1.0mg weekly · n=3,297 · T2D with high CV risk · 104 weeks

Primary Outcome

CV death, nonfatal MI, or nonfatal stroke: 6.6% vs. 8.9%. HR 0.74 (95% CI: 0.58–0.95; p<0.001 for noninferiority).

Key Insight

SUSTAIN-6 established semaglutide's CV benefit in T2D with a 26% MACE reduction — fundamentally changing treatment guidelines to position GLP-1 RAs as first-line for diabetic patients with established or high-risk cardiovascular disease.

Reference
  • Marso SP et al. N Engl J Med. 2016;375(19):1834-1844. PMID: 27633186
SuperiorLiraglutide 1.8mg

LEADER

n=9,340 · T2D, high CV risk · 3.8 years

0.87
Hazard Ratio
13%
MACE Reduction
9,340
Patients

The first major CVOT to demonstrate cardiovascular superiority for a GLP-1 RA — establishing the cardiovascular class effect.

Full trial detail
Superior vs. Placebo

LEADER

Liraglutide 1.8mg daily · n=9,340 · T2D with high CV risk · 3.8 years

Primary Outcome

First occurrence of CV death, nonfatal MI, or nonfatal stroke: HR 0.87 (95% CI: 0.78–0.97; p=0.01 for superiority).

Key Insight

LEADER was the first major CVOT to prove cardiovascular superiority for a GLP-1 RA, demonstrating 13% MACE reduction and fundamentally altering treatment guidelines — making GLP-1 RAs first-line for diabetic patients with CV disease.

Reference
  • Marso SP et al. N Engl J Med. 2016;375(4):311-322. PMID: 27295427
NoninferiorOral Semaglutide

PIONEER-6

n=3,183 · T2D, high CV risk · 1.3 years

0.79
Hazard Ratio
21%
MACE Reduction (NS)
3,183
Patients

Proved oral semaglutide achieves cardiovascular safety comparable to injectable — formulation route doesn't compromise protection.

Full trial detail
Noninferior vs. Placebo

PIONEER-6

Oral semaglutide (Rybelsus) · n=3,183 · T2D with CVD/CKD or CV risk factors

Primary Outcome

CV death, nonfatal MI, or nonfatal stroke: HR 0.79 (95% CI: 0.57–1.09; p<0.001 for noninferiority). Point estimate numerically similar to SUSTAIN-6, but not powered for superiority.

Key Insight

PIONEER-6 demonstrated that oral semaglutide achieves CV safety comparable to injectable forms — expanding the GLP-1 landscape by proving formulation route does not compromise cardiovascular protection.

Reference
  • Husain M et al. N Engl J Med. 2019;381(9):841-851. PMID: 31185157
SuperiorDulaglutide 1.5mg

REWIND

n=9,901 · T2D, mixed CV risk · 5.4 years

0.88
Hazard Ratio
12%
MACE Reduction
9,901
Patients

Broadest population of any GLP-1 CVOT — extended CV protection evidence to primary prevention in lower-risk patients.

Full trial detail
Superior vs. Placebo

REWIND

Dulaglutide 1.5mg weekly · n=9,901 · T2D with CV risk factors · 5.4 years

Primary Outcome

CV death, nonfatal MI, or nonfatal stroke: 12.0% vs. 13.4%. HR 0.88 (95% CI: 0.79–0.99; p=0.026).

Key Insight

REWIND had the broadest population — most participants had CV risk factors but no established CVD. By demonstrating benefit in this lower-risk group, it extended the evidence to primary prevention, suggesting GLP-1 RAs may prevent first cardiovascular events — not just recurrent ones.

Reference
  • Gerstein HC et al. Lancet. 2019;394(10193):121-130. PMID: 31189511
NoninferiorTirzepatide vs. Dulaglutide

SURPASS-CVOT

n=13,165 · T2D, ASCVD · ~4 years

0.92
HR vs. Dulaglutide
0.84
Expanded MACE
13,165
Patients

First head-to-head CVOT between a dual agonist and a GLP-1 monagonist — active comparator design makes absolute benefit likely larger.

Full trial detail
Noninferior vs. Active Comparator

SURPASS-CVOT

Tirzepatide (up to 15mg) vs. Dulaglutide 1.5mg · n=13,165 · T2D with ASCVD · ~4 years

Primary Outcome

CV death, MI, or stroke: 12.2% (tirzepatide) vs. 13.1% (dulaglutide). HR 0.92 (95% CI: 0.83–1.03; p=0.003 noninferiority; p=0.09 superiority — not met). Expanded MACE (including revascularization): HR 0.84 (95% CI: 0.76–0.92; p<0.001).

Key Insight

The first head-to-head CV comparison between a dual GLP-1/GIP agonist and a GLP-1 monagonist. Tirzepatide demonstrated noninferiority and superiority for expanded endpoints. The active comparator design means the absolute CV benefit versus placebo is likely larger than the relative comparison suggests.

Reference
  • Nicholls SJ et al. N Engl J Med. 2025;393(25):2409-2420. PMID: 41406444

Trial Summary

Cardiovascular Outcomes — At a Glance

Cardiovascular outcome trial summary
Trial Drug Population n Follow-up MACE HR (95% CI) Result
SELECT Semaglutide 2.4mg Obesity, no T2D 17,604 ~3.4 yr 0.80 (0.72–0.90) Superior
SUSTAIN-6 Semaglutide 0.5/1.0mg T2D, high CV risk 3,297 2 yr 0.74 (0.58–0.95) Superior
LEADER Liraglutide 1.8mg T2D, high CV risk 9,340 3.8 yr 0.87 (0.78–0.97) Superior
PIONEER-6 Oral Semaglutide T2D, high CV risk 3,183 1.3 yr 0.79 (0.57–1.09) Noninferior
REWIND Dulaglutide 1.5mg T2D, mixed CV risk 9,901 5.4 yr 0.88 (0.79–0.99) Superior
SURPASS-CVOT Tirzepatide vs. Dulaglutide T2D, ASCVD 13,165 ~4 yr 0.92 (0.83–1.03) vs. DU Noninferior

All trials placebo-controlled except SURPASS-CVOT (active comparator: dulaglutide). MACE = cardiovascular death, nonfatal MI, or nonfatal stroke. Educational content — treatment decisions should be made with a healthcare provider.

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