Cardiovascular and renal outcomes across the GLP-1 class

Why this matters

For most pharmacologic classes used in metabolic disease, the goal is glycemic or weight benefit — outcomes that, while important, are intermediate. The relevant terminal outcomes are cardiovascular events, kidney disease progression, and mortality. The GLP-1 class is increasingly distinguished by direct evidence at those terminal endpoints.

The cardiovascular outcomes trials

LEADER (liraglutide) — Marso et al., NEJM 2016

9,340 adults with T2D and high CV risk over a median 3.8 years. Liraglutide reduced 3-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke) by 13% (HR 0.87). The first major positive CV outcomes trial in the modern GLP-1 era.

SUSTAIN-6 (semaglutide) — Marso et al., NEJM 2016

Semaglutide reduced MACE by 26% (HR 0.74) in T2D with CV risk. Smaller trial than LEADER; remained directionally consistent.

REWIND (dulaglutide) — Gerstein et al., Lancet 2019

9,901 adults with T2D and CV risk over 5.4 years. Dulaglutide reduced MACE by 12% (HR 0.88). Notably included a higher proportion of primary-prevention patients than LEADER, broadening the applicable population.

SELECT (semaglutide) — Lincoff et al., NEJM 2023

17,604 adults with overweight/obesity and pre-existing CV disease, but without diabetes. Semaglutide 2.4 mg reduced MACE by 20% (HR 0.80) over 3.3 years median follow-up. The first large trial to establish CV benefit for a GLP-1 in a primary obesity population without diabetes.

The kidney outcomes trial

FLOW (semaglutide) — Perkovic et al., NEJM 2024

Adults with T2D and chronic kidney disease randomized to semaglutide 1.0 mg vs placebo. Stopped early for efficacy. Reported a 24% reduction in the composite primary endpoint of major kidney and cardiovascular outcomes. Established semaglutide as having renal-specific benefits beyond what would be expected from glycemic control alone.

The heart-failure-with-preserved-ejection-fraction trial

STEP-HFpEF (semaglutide) — Kosiborod et al., NEJM 2023

Obesity-related HFpEF. Semaglutide 2.4 mg improved Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance vs placebo. Companion trials in HFpEF with diabetes and reduced ejection fraction with obesity-related component have been advancing.

What we don't yet have

• Tirzepatide CV outcomes — SURPASS-CVOT is ongoing. The class effect would predict a positive result, but it has not yet been formally demonstrated.
• Retatrutide CV outcomes — TRIUMPH-OUTCOMES is part of the Phase 3 program; results pending.
• Newer co-agonists (survodutide, pemvidutide, MariTide) — CV outcomes data is not yet at the scale of the established GLP-1s.

Synthesis

The cardiovascular and renal outcomes data positions the GLP-1 class as a cardiometabolic therapy rather than a glycemic or weight-management drug class alone. The breadth of the SELECT, FLOW, and STEP-HFpEF results — across CV death, MI, stroke, kidney function, and HF symptoms — is unusual in pharmacology and explains much of why GLP-1s have shifted from "diabetes drugs" to "core cardiometabolic agents" over the past five years.

Bottom line

For practitioners and engaged readers, the GLP-1 class's place in cardiometabolic medicine rests less on weight loss alone than on the accumulating evidence that the same molecules reduce hard cardiovascular and renal outcomes. The next wave — tirzepatide and retatrutide CV outcomes — will determine whether these benefits remain a class effect or vary by molecule.