Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

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Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment option for patients with type 2 diabetes. These agents act by stimulating insulin secretion in hyperglycemic states, suppressing glucagon secretion in hyperglycemic or euglycemic states, delaying gastric emptying, decreasing appetite, and reducing body weight.1-3

Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

Glucose-dependent insulinotropic polypeptide, the main incretin hormone in healthy persons, is insulinotropic; however, unlike GLP-1, it is glucagonotropic in a glucose-dependent manner. Under hyperglycemic conditions, glucose-dependent insulinotropic polypeptide stimulates the release of insulin, thereby lowering glucagon levels, and under euglycemic or hypoglycemic conditions, glucagon levels are increased.4Glucose-dependent insulinotropic polypeptide receptors are abundant in adipose tissue,5and glucose-dependent insulinotropic polypeptide enhances both the postprandial lipid-buffering capacity of white adipose tissue and the sensitivity of adipose tissue to insulin, which may prevent ectopic fat deposition.6The glucose-dependent insulinotropic polypeptide component of dual glucose-dependent insulinotropic polypeptide–GLP-1 agonism is hypothesized to act centrally to potentiate a GLP-1–induced reduction in food intake.6-8In patients with type 2 diabetes, a single molecule combining the glucose-dependent insulinotropic polypeptide receptor and GLP-1 receptor agonism may have a greater effect on glucose levels and weight control than selective GLP-1 receptor agonists.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide–GLP-1 receptor agonist. Its structure is primarily based on the glucose-dependent insulinotropic polypeptide amino acid sequence and includes a C20 fatty diacid moiety.7Its half-life of approximately 5 days allows once-weekly subcutaneous administration.7A phase 2b trial involving patients with type 2 diabetes showed that those who received tirzepatide had dose-dependent reductions in the glycated hemoglobin level and weight at 26 weeks.9

Once-weekly injectable semaglutide, a selective GLP-1 receptor agonist, is approved for the treatment of type 2 diabetes at doses up to 1 mg. In trials involving patients who received semaglutide, the mean reductions in the glycated hemoglobin level have been reported to be as high as 1.8 percentage points and the mean reductions in body weight have been reported to be as high as 6.5 kg.10-19

We conducted the SURPASS-2 trial (A Study of Tirzepatide [LY3298176] versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants with Type 2 Diabetes) to compare the efficacy and safety of tirzepatide at doses of 5 mg, 10 mg, and 15 mg with those of semaglutide at a dose of 1 mg in patients with type 2 diabetes that had been inadequately controlled with metformin monotherapy.