Tirzepatide

Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist developed by Eli Lilly. Unlike semaglutide, which targets only the GLP-1 receptor, tirzepatide simultaneously activates both the GIP and GLP-1 receptors, producing synergistic effects on glucose metabolism, appetite regulation, and body weight. This dual mechanism represents an important innovation in incretin-based therapy.

In the SURMOUNT-1 clinical trial, tirzepatide at its highest dose (15 mg weekly) produced mean weight loss of 22.5% over 72 weeks in participants with obesity but without diabetes — the highest weight loss achieved by any anti-obesity medication in pivotal trials at the time. Participants in the SURPASS trial program for type 2 diabetes also showed superior HbA1c reductions compared to semaglutide 1 mg, with many achieving HbA1c levels below 5.7%, effectively reaching normoglycemia.

The mechanism by which GIP receptor agonism contributes to weight loss was initially surprising to researchers, as GIP was historically considered an obesogenic hormone. Current understanding suggests that at pharmacological levels, GIP receptor activation in the brain may complement GLP-1 effects on appetite suppression, while also improving lipid metabolism and fat distribution. Tirzepatide has also shown favorable effects on cardiovascular risk factors including blood pressure, triglycerides, and inflammatory markers.

Tirzepatide is marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management. Like semaglutide, it has experienced enormous demand and periodic supply constraints. Ongoing research is evaluating tirzepatide for heart failure with preserved ejection fraction, obstructive sleep apnea, NASH, and other obesity-related conditions.