The Tirzepatide

Tirzepatide is a combined glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. This review will summarize the pharmacological aspects of tirzepatide with a focus on the clinical efficacy and safety reported in the trial programs underlying the regulatory approval for the treatment of type 2 diabetes (T2D) and obesity in the U.S. and Europe. In a range of trials, tirzepatide has been compared to placebo, insulin and GLP-1 mono-receptor ago-nists. The trials have included participants with T2D (SURPASS) and obesity (SURMOUNT-1) and have examined tirzepatide in doses ranging from 5 to 15 mg administered once weekly. In the SURPASS trials, tirzepatide led to dose-dependent clinically rel-evant reductions in HbA1c of up to 20-28 mmol/mol. A head-to -head trial comparing tirzepatide (5-15 mg once weekly) to the GLP-1 mono-receptor agonist semaglutide (1 mg once weekly) demonstrated all doses of tirzepatide to be superior with respect to HbA1c reduction. In terms of body weight, tirzepatide 5-15 mg caused reductions from baseline of up to 13% in patients with T2D in the SURPASS trials and up to 21% in nondi-abetic participants in the SURMOUNT-1 trial. The most frequent adverse events were gastrointestinal symptoms with nausea as the most frequently observed adverse event in up to 33% of tirzepatide (15 mg)-treated patients. These gastrointestinal symptoms were dose-dependent and often self-limiting with a lower occurrence compared to GLP-1 mono-receptor agonists at conditions with similar efficacy (i.e., with similar HbA1c and body weight reduction). Adverse events resulted in trial drop-out rates from 3-11% of all patients treated with tirzepatide. The potential superior efficacy of tirzepatide compared to GLP-1 mono-receptor agonists is hypothesized to be a result of the unique dual GLP-1 and GIP receptor agonism. At present, there is no data to support long-term efficacy and safety of tirzepatide. Ongoing trials reporting results the coming years on cardiovas-cular effects as well as the clinical use in specific populations will unravel the full clinical potential for tirzepatide.