Triple Agonism Based Therapies for Obesity.
This review examines the rationale and emerging clinical evidence for triple receptor agonist therapies targeting GLP-1, GIP, and glucagon receptors as next-generation treatments for obesity and type 2 diabetes (T2D). The authors focus primarily on retatrutide, the most clinically advanced triple agonist, which has completed Phase 2 trials. In people with obesity, retatrutide achieved up to 24.2% mean weight loss over 48 weeks; in people with T2D, it produced 16.9% mean weight loss over 36 weeks, alongside a 2.2% reduction in HbA1c and 82% of participants reaching HbA1c ≤ 6.5%. The review also highlights improvements in blood pressure, lipid profiles, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal side effects were the most commonly reported adverse events, with no major safety signals identified in Phase 2. The authors also briefly discuss other unimolecular triple agonists and combination regimens in development. Key limitations include that this is a narrative review of Phase 2 data; Phase 3 confirmatory trials are still ongoing. Conclusions about long-term efficacy, safety, and cardiovascular/renal outcomes remain premature pending those results.
Why this grade: This is a narrative review synthesizing Phase 2 clinical trial data rather than an original controlled study, so it does not independently generate primary human evidence.
Purpose of the review Glucagon-like peptide 1 (GLP-1) receptor agonists (RA) have transformed obesity and type 2 diabetes (T2D) management. Tirzepatide, the first dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA approved for both conditions, has paved the way for next-generation incretin-based therapies. Among these, triple agonists targeting GLP-1, GIP, and glucagon receptors represent a promising next step. This review outlines the rationale for their development and summarizes clinical trial data, focusing on retatrutide, the most advanced candidate. Recent findings Retatrutide is the first triple agonist (acting on GLP-1/GIP/glucagon receptors) with published phase 2 data in people with obesity as well as in people with T2D. Retatrutide achieved up to 24.2% mean weight loss after 48 weeks in individuals with obesity and 16.9% in those with T2D after 36 weeks. In the T2D study, HbA1c improved by 2.2%, with 82% of participants reaching HbA1c ≤ 6.5%. Retatrutide also improved multiple cardiometabolic parameters, including blood pressure, lipids, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal symptoms were the most common side effects; no major safety concerns were observed. A comprehensive phase 3 program is ongoing to evaluate efficacy, safety, and cardiovascular/renal outcomes in people with obesity and/or T2D. Other unimolecular triple agonists and combination regimens involving tirzepatide with additional mono agonists are also in development. Summary Retatrutide, a triple agonist now in phase 3 trials, has the potential to become the most effective pharmacological treatment for obesity while also offering substantial benefits in T2D management and other cardiometabolic risk factors.
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