Incretin analogues as cardiovascular agents: a state-of-the-art review.

Narrative literature review synthesizing cardiovascular evidence for incretin analogues

“This state-of-the-art review synthesizes the cardiovascular evidence base for incretin analogues, organized by clinical scenario, and addresses the structural challenges that constrain their deployment in low- and middle-income countries (LMICs).”

Patients with type 2 diabetes, obesity, heart failure with preserved ejection fraction, chronic kidney disease, and peripheral artery disease

“We summarize the evidence in five clinical scenarios: type 2 diabetes with established atherosclerotic cardiovascular disease or high cardiovascular risk; overweight or obesity with established cardiovascular disease but without diabetes; obesity-related heart failure with preserved ejection fraction; chronic kidney disease; and symptomatic peripheral artery disease.”

Varies by specific trial reviewed, ranging from 529 to 17,604 participants

“Eleven dedicated cardiovascular outcome trials, enrolling more than 95,000 patients with type 2 diabetes, now constitute the foundational evidence (Table 1).”

Trial follow-up periods typically range from 1.6 to 5.4 years

“Long-term durability of the cardiovascular benefit beyond the trial follow-up periods (typically 2–5 years) remains to be established.”

GLP-1 receptor agonists and tirzepatide reduce major adverse cardiovascular events in patients with type 2 diabetes and established cardiovascular disease

“Across placebo-controlled cardiovascular outcome trials in type 2 diabetes, meta-analyses have produced consistent estimates: a 14% relative reduction in MACE (HR ~0.86), 13% reduction in cardiovascular mortality, 12% reduction in all-cause mortality, 11% reduction in heart-failure hospitalization, and 21% reduction in composite kidney outcomes (36).”

Semaglutide reduces major adverse cardiovascular events in patients with obesity and established cardiovascular disease but without diabetes

“The primary 3-point MACE composite occurred in 6.5% of the semaglutide arm and 8.0% of the placebo arm (HR 0.80; 95% CI 0.72–0.90; P<0.001 for superiority).”

Tirzepatide reduces the composite of cardiovascular death or worsening heart failure events in patients with obesity-related heart failure with preserved ejection fraction

“Tirzepatide reduced the primary composite (cardiovascular death or worsening heart failure event) by 38% (HR 0.62; 95% CI 0.41–0.95; P = 0.026), driven primarily by a 46% reduction in worsening heart-failure events (HR 0.54; 95% CI 0.34–0.85).”

Limited representation of low- and middle-income country populations in pivotal trials, high cost, and lack of evidence for heart failure with reduced ejection fraction

“The representation of populations from LMICs — including Latin American, African, South Asian, and Southeast Asian populations — in pivotal trials remains modest, and the assumption of class effect across populations rests on biological plausibility rather than direct demonstration.”