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.