Executive Summary
SELECT randomized 17,604 people with established cardiovascular disease, overweight/obesity and no diabetes. Semaglutide 2.4 mg reduced the primary MACE endpoint from 8.0% to 6.5% (HR 0.80), establishing cardiovascular event reduction outside diabetes.
FLOW enrolled 3,533 people with type 2 diabetes and CKD. Semaglutide reduced the primary kidney/CV composite by 24%, major cardiovascular events by 18% and all-cause mortality by 20%.
SOUL enrolled 9,650 people with type 2 diabetes and ASCVD, CKD or both. Oral semaglutide reduced MACE by 14% versus placebo (HR 0.86).
ADA 2026 recommends GLP-1 receptor agonists with demonstrated cardiovascular benefit in type 2 diabetes with established ASCVD, multiple risk factors or CKD.
Tirzepatide reduced weight and glycemia more than dulaglutide in SURPASS-CVOT and was noninferior for MACE (HR 0.92; superiority not reached). Its dedicated obesity morbidity/mortality trial SURMOUNT-MMO is still ongoing.
The cardiovascular benefit of GLP-1 therapy probably reflects multiple pathways: weight loss, blood pressure, glycemia, lipids, inflammation and direct vascular/metabolic effects. The exact fraction attributable to weight loss remains debated.
Figure 1. Selected outcome-trial signals. The bars summarize relative changes in different endpoints and are not directly comparable across trials.
1. SELECT: the landmark obesity outcome trial
SELECT was the first large randomized trial to prove that a GLP-1-based obesity therapy could reduce cardiovascular events in people without diabetes. The effect size was a 20% relative reduction in MACE, with an absolute event difference of 1.5 percentage points over the trial.
2. FLOW and kidney disease
FLOW established that semaglutide can reduce clinically important kidney outcomes in type 2 diabetes with CKD. This moved GLP-1 therapy deeper into cardiorenal prevention rather than treating it purely as a glucose or weight intervention.
3. SOUL and oral semaglutide
SOUL showed that oral semaglutide also reduces MACE in high-risk type 2 diabetes, important because earlier oral-semaglutide trials were primarily designed for safety rather than superiority.
4. Tirzepatide: what is proven in 2026?
SURPASS-CVOT compared tirzepatide with the proven GLP-1 agonist dulaglutide in 13,299 patients with type 2 diabetes and ASCVD. Tirzepatide was noninferior for MACE (12.2% vs 13.1%; HR 0.92) but did not meet the prespecified superiority criterion.
For obesity without diabetes, the definitive placebo-controlled morbidity/mortality evidence is still pending from SURMOUNT-MMO, which enrolled 15,374 participants and is estimated to complete in October 2027.
| Trial | Population | Main result |
|---|---|---|
| SELECT | Overweight/obesity + established CVD, no diabetes | Semaglutide 2.4 mg: MACE HR 0.80 |
| FLOW | T2D + CKD | Semaglutide: kidney/CV primary HR 0.76; MACE HR 0.82 |
| SOUL | T2D + ASCVD/CKD | Oral semaglutide: MACE HR 0.86 |
| SURPASS-CVOT | T2D + ASCVD | Tirzepatide noninferior to dulaglutide: MACE HR 0.92 |
| SURMOUNT-MMO | Obesity/overweight | Ongoing; no results posted as of Aug 2026 |
5. FAQ
Are GLP-1 drugs substitutes for statins?
No. They reduce risk through different pathways. Patients with elevated LDL-C/ApoB still need lipid-directed therapy when indicated.
Do they lower Lp(a)?
Not enough to treat genetically high Lp(a) as a primary target.
Does every GLP-1 drug prevent heart attacks?
No. Outcome evidence is molecule- and population-specific.
Is the benefit only from losing weight?
Weight loss contributes, but outcome benefits likely involve multiple metabolic and vascular mechanisms.
References
1. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389:2221-2232.
2. Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024.
3. McGuire DK, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025.
4. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025.
5. American Diabetes Association. Standards of Care in Diabetes—2026.
6. ClinicalTrials.gov NCT05556512. SURMOUNT-MMO.