Two recent studies assessed the safety and effectiveness of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes.
Both trials were funded by Eli Lilly, lasted 40 weeks, and were conducted at multiple sites around the world. Patients in both trials had inadequately controlled type 2 diabetes and were randomized to one of three doses of tirzepatide (5, 10, or 15 mg), injected once weekly. One trial, published by The Lancet on June 26, also randomized a group of patients to placebo, while the other trial, published by the New England Journal of Medicine (NEJM) on June 25, randomized a comparison group to semaglutide, a GLP-1 receptor agonist.
The placebo-controlled trial included 478 patients with a mean baseline HbA1c level of 7.9%, 121 assigned to each of the three dosing arms and 115 assigned to placebo. At 40 weeks, all tirzepatide doses were superior to placebo in reducing HbA1c level, fasting serum glucose, and body weight. Mean HbA1c decreased from baseline by 1.87% with tirzepatide 5 mg, 1.89% with 10 mg, and 2.07% with 15 mg, compared to an increase of 0.04% with placebo. Tirzepatide also induced dose-dependent weight loss ranging from 7.0 kg to 9.5 kg. The most common adverse events were mild to moderate and transient gastrointestinal events, including nausea (12% to 18% with tirzepatide vs. 6% with placebo), diarrhea (12% to 14% vs. 8%), and vomiting (2% to 6% vs. 2%). No clinically significant or severe hypoglycemia was reported.
In the other trial, 1,879 patients with a mean HbA1c level of 8.28% were assigned in equal numbers to 5, 10, or 15 mg of tirzepatide, or semaglutide. Mean HbA1c level decreased by 2.01 percentage points in the 5-mg group, 2.24 percentage points in the 10-mg group, and 2.30 percentage points in the 15-mg group, compared to 1.86 percentage points with semaglutide. All the doses of tirzepatide were noninferior and superior to semaglutide on the primary outcome of HbA1c reduction. Reductions in body weight were also greater with tirzepatide than with semaglutide. Adverse events were similar to those in the other trial: nausea (17% to 22% vs. 18% with semaglutide), diarrhea (13% to 16% vs. 12%), and vomiting (6% to 10% vs. 8%). Hypoglycemia (<54 mg/dL [<3.0 mmol/L]) was reported in 0.6% of the 5-mg group, 0.2% of the 10-mg group, 1.7% of the 15-mg group, and 0.4% of the semaglutide group. Serious adverse events occurred in 5% to 7% of patients on tirzepatide and in 3% of those on semaglutide.
The authors of both studies highlighted the HbA1c targets achieved with tirzepatide without significant hypoglycemia: an HbA1c level less than 7% in more than 80% of study patients and a normalized HbA1c level (less than 5.7%) in 31% to 52% of Lancet trial patients and 27% to 46% of NEJM study patients. Accompanying editorials noted the need for additional research, with more diverse patient populations and a focus on cardiovascular outcomes, but expressed optimism about the potential safety and effectiveness of the drug class. The NEJM editorial said, “In patients with type 2 diabetes, combination incretin therapy is poised to provide better glycemic efficacy than treatment with a GLP-1 receptor agonist alone while maintaining a good side-effect profile with respect to avoiding hypoglycemia.”