Beyond GLP-1: Multiorgan Efficacy of Dual and Triple Incretin Agonists in Cardiometabolic Syndrome
DOI:
https://doi.org/10.66201/ss.v1.26Keywords:
Tirzepatide, Retatrutide, Survodutide, Incretin Agonists, Cardiometabolic Syndrome, Obesity, Type 2 Diabetes Mellitus, Heart Failure, Chronic Kidney Disease, MASLDAbstract
Background: Dual GIP/GLP-1 receptor agonists (tirzepatide) and triple agonists (retatrutide, survodutide) have redefined the expected efficacy thresholds in the pharmacotherapy of obesity and type 2 diabetes mellitus (T2DM), with emerging evidence of multiorgan benefits in populations at high cardiometabolic risk.
Methods: An integrative review (Whittemore and Knafl, 2005) was conducted using searches in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Web of Science (January 2020–March 2026). Thirty-five studies involving more than 320,000 participants were included, evaluating dual or triple incretin agonists in adults with obesity, T2DM, or cardiometabolic comorbidities.
Results: Tirzepatide demonstrated weight loss of up to 20.9% (SURMOUNT-1) and reductions in HbA1c of 2.30 percentage points compared with 1.86 percentage points with semaglutide in SURPASS-2 (difference: −0.45 percentage points; 95% CI: −0.57 to −0.32). In heart failure with preserved ejection fraction (HFpEF), tirzepatide reduced the composite outcome of cardiovascular death or worsening heart failure by 38% (HR 0.62; SUMMIT). In chronic kidney disease (CKD), it reduced the composite renal outcome by 42% (HR 0.58; SURPASS-4). In metabolic dysfunction-associated steatohepatitis (MASH), histological resolution was achieved in 62% versus 10% with placebo (SYNERGY-NASH), with fibrosis improvement in 51–55% of cases. Retatrutide achieved weight loss of up to 24.2% in phase 2 trials. The safety profile was favorable, with predominantly mild to moderate gastrointestinal adverse effects.
Conclusion: Dual and triple incretin agonists represent the most significant pharmacological advance in cardiometabolic medicine over the past decade. Current evidence supports their priority incorporation into clinical guidelines, with equity of access emerging as a central ethical challenge.
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Copyright (c) 2026 Elizabeth Valinotti Delmás, Luz Diana Vázquez Vera, Helen López Ovelar, Fabiola Romero Gómez, Andrés Giménez Benítez, Federico Fariña Mendieta, Nadia Liz García Fernández (Autor/a)
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