Triple Hormone Receptor Agonism: The Role of Retatrutide in Addressing Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Comprehensive Review

Retatrutide is a first-in-class, unimolecular triple hormone receptor agonist targeting glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. By synergizing incretin-mediated central satiety with glucagon-driven thermogenesis, retatrutide circumvents the compensatory metabolic resistance that often limits traditional weight-loss therapies. Phase 2 clinical data demonstrate that a 12-mg maximal weekly dose yields a 24.2% reduction in total body weight at 48 weeks, with 63% of participants achieving a total body weight loss of ≥20%. In patients with type 2 diabetes, retatrutide achieved an absolute HbA1c reduction of 2.02%, with 27% of participants reaching normoglycemia (HbA1c < 5.7%). Beyond global weight reduction, dual-energy X-ray absorptiometry substudies confirm a 23.2% reduction in fat mass, comparable to bariatric surgery. Retatrutide demonstrates potent efficacy in resolving metabolic dysfunction-associated steatotic liver disease, achieving an 82.4% relative reduction in hepatic fat and normalization of liver fat in 86% of patients. These metabolic improvements are accompanied by systemic hemodynamic unloading, including an 8.79 mm Hg reduction in systolic blood pressure and significant attenuation of the urine albumin-to-creatinine ratio. The safety profile is consistent with established incretins: clinicians must monitor for a dose-dependent chronotropic effect. De-escalation of concurrent antihypertensive therapies may also be required.