Tirzepatide vs Semaglutide Once Weekly in Patients with Type 2 Diabetes

Tirzepatide vs Semaglutide Once Weekly in Patients with Type 2 Diabetes
Anna Lange, PharmD, Goodrich Pharmacy

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective agents in the treatment of type 2 diabetes. GLP-1 agonists work by stimulating insulin secretion in hyperglycemic states, suppressing glucagon secretion in hyperglycemic or euglycemic states, delaying gastric emptying, decreasing appetite, and aiding in weight loss. Additionally, they are known for their cardio-protective and renal-protective effects. Unlike semaglutide, tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. GlP is insulinotropic as well as glucagonotropic in a glucose-dependent manner and has abundant receptors in adipose tissue. Its dual activity may provide a greater effect on hemoglobin A1C and weight loss than GLP-1 receptor agonists alone. 

Objective: The objective of this study was to assess the safety and efficacy of once weekly tirzepatide (GIP/GLP-1 receptor agonist) compared to once weekly semaglutide (GLP-1 agonist) in reducing hemoglobin A1C levels from baseline to 40 weeks. 

Study Design: This was an open-label, parallel-group, randomized, active-controlled, phase III trial conducted at 128 sites. Patient inclusion criteria: ≥18 years old, type 2 diabetes with hemoglobin A1C of 7.0-10.5%, on at least 1,500 mg metformin/day, BMI >25, and stable weight over the last three months. A total of 1,789 patients were randomly assigned into four treatment groups to receive a once-weekly subcutaneous injection of either tirzepatide 5 mg, 10 mg or 15 mg, or semaglutide 1 mg for a 40-week treatment period, followed by a 4-week safety follow-up period. The primary outcome was the change in hemoglobin A1C from baseline to 40 weeks. The key secondary outcomes were change in weight from baseline to 40 weeks and target hemoglobin A1C of less than 7.0% and less than 5.7%. 

Results: Tirzepatide was found to be superior to semaglutide in terms of change in hemoglobin A1C and weight from baseline to 40 weeks. The mean change in A1C was -2.01% with the 5 mg dose (P=0.02), -2.24% with the 10 mg dose (P<0.001), and -2.30% with the 15 mg dose of tirzepatide (P<0.001). Patients randomized to tirzepatide 15 mg lost an average of 11.2 kg, compared with 5.7 kg on maximum dose semaglutide (P<0.001). In addition to the weight loss, 82 to 86% of patients on tirzepatide reached an A1C of <7%, while 79% of patients on semaglutide reached an A1C of <7%. The most common side effects were gastrointestinal in nature. Nausea was reported in 17 to 22% of patients who received tirzepatide and in 18% who received semaglutide, diarrhea was reported in 13 to 16% and 12%, vomiting in 6 to 10% and 8%, and decreased appetite in 7 to 9% and 5%, respectively. Gastrointestinal upset increased with higher doses. Hypoglycemia occured at a rate of 1.7% in tirzepatide 15 mg compared to 0.4% in semaglutide, with two instances of severe hypoglycemia in the 5 mg and 15 mg tirzepatide groups. Both patients were able to continue the rest of the trial safely after treating the hypoglycemia. 

Conclusion: Tirzepatide, a dual GIP/GLP-1 receptor agonist, exhibits A1C lowering and weight loss effects similar to semaglutide, but to a greater extent. Regarding safety, severe hypoglycemia occured at a higher rate in tirzepatide, but all patients recovered and finished the trial. Tirzepatide demonstrated superior efficacy in comparison to maximum dose semaglutide in both lowering of hemoglobin A1C and weight from baseline to 40 weeks. 

Key Point: Tirzepatide is a promising new therapy for use in type 2 diabetes and showed significant A1C and weight loss benefits. Further studies comparing it to other GLP-1 receptor agonists are needed.



  1. Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-515. doi: 10.1056/NEJMoa2107519