In type 2 diabetes, tirzepatide reduced HbA1c vs. semaglutide

This industry-funded trial of tirzepatide, a unimolecular dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, heralds a new era of “twincretins” in diabetes management, an ACP Journal Club commentary said.

An industry-funded trial found tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist that is under development for the treatment of type 2 diabetes, to be superior to semaglutide for glucose control and equally safe. The phase 3, open-label trial randomized 1,879 patients with type 2 diabetes to 5, 10, or 15 mg of tirzepatide, or semaglutide for 40 weeks.

The study was published online by the New England Journal of Medicine on June 25 and summarized in the July ACP Diabetes Monthly. The following commentary by Gunjan Y. Gandhi, MD, MSc, was published in the ACP Journal Club section of Annals of Internal Medicine on Nov. 2.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones secreted from the upper (GIP, K cells) and lower (GLP-1, L cells) gut, respectively. Analogues of GLP-1 have transformed type 2 diabetes treatment by improving glycemia and weight loss and reducing mortality, cardiovascular (CV) events, and progression of diabetic kidney disease. Tirzepatide is a unimolecular dual agonist of GLP-1 and GIP receptors, heralding a new era of “twincretins” in diabetes management.

In the trial by Frias and colleagues of patients with diabetes treated with metformin, tirzepatide showed greater dose-dependent reductions in HbA1c vs. the GLP-1 receptor agonist semaglutide. Tirzepatide also reduced weight more than semaglutide (mean, −8.5% to −13.1% depending on dose vs. −6.7%; P<0.001), which did not plateau at 40 weeks. These results suggest that tirzepatide may potentially be used for weight loss, similar to higher-dose GLP-1 analogues, which are approved in people with obesity and without diabetes. Wilding and colleagues found that semaglutide, 2.4 mg/wk, reduced weight by a mean 15% at 68 weeks in patients with obesity but without diabetes. Semaglutide dose was lower in the trial by Frias and colleagues, so we cannot ascertain the relative weight-reducing effectiveness of tirzepatide vs. semaglutide at the higher approved dose.

Overall, side effects were similar between groups and were primarily gastrointestinal, although serious adverse events and death were numerically more frequent in the tirzepatide group. Although few, the increased deaths were mainly due to CV disease, which may be related to mixed effects of GIP on atherogenesis. A trial of the effects of tirzepatide vs. dulaglutide on CV outcomes in patients with type 2 diabetes and atherosclerotic CV disease is underway. If CV- and kidney-protective benefits are found, this class of medication would be potentially superior to GLP-1 receptor agonists given its effect on diabetes control and weight loss without increased risk for hypoglycemia.