Tirzepatide vs. Semaglutide

Tirzepatide dual-action may significantly impact a person’s weight management and blood glucose compared to GLP-1 receptor agonists.

Tirzepatide is a unique medication formulated as a new type 2 diabetes (T2D) agent that is both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. Previous studies have discovered that when combined, GIP and GLP-1 agonists have a synergistic effect of lowering glucose when compared to when either agent is used alone. Another name coined from this combination is twincretin. GLP-1 receptor agonists such as semaglutide have already been recognized as effective agents in patients with T2D to reduce blood glucose. In addition, they have been demonstrated to cause weight loss. In healthy individuals, GIP is the primary incretin hormone and is insulinotropic, distinct from GLP-1 receptor agonists. Therefore, it has been hypothesized that the action of the GIP in the dual GIP/GLP-1 agonism is to enhance GLP-1 induced reduction of food intake. Tirzepatide has a relatively long half-life of approximately five days. Similar to semaglutide, it is delivered subcutaneously once weekly. Furthermore, tirzepatide’s dual-action may significantly impact a person’s weight management and blood glucose compared to GLP-1 receptor agonists.

At 26 weeks, a phase IIb trial by Frias et al. showed tirzepatide had a dose-dependent reduction on HbA1c levels and body weight. Recent tests of semaglutide had demonstrated mean reductions of HbA1c up to -1.8% and mean weight reductions up to 6.5kg. The SURPASS-2 trial is a phase III study that assessed tirzepatide’s and semaglutide’s efficacy and safety supplementary to metformin monotherapy in patients whose T2D was poorly controlled. The trial was carried out in the United States and seven other countries. It was an open-label, 40 weeks, randomized, active control trial where 1879 participants were randomized in a 1:1:1:1 ratio to be administered once weekly via subcutaneous injection of either tirzepatide 5mg, 10, 15mg, or semaglutide 1mg. The average age of the participants was 56.6 years, the average baseline HbA1c was 8.28%, and 93.7kg was the mean weight. The change in HbA1c at week 40 was the primary endpoint. Primary, secondary endpoints were a change of body weight from baseline to week 40 and achieving HbA1c targets of <5.7% to <7%.

Discontinuing either medication as a result of adverse events and adverse events occurring were the safety endpoints. Participants had to be ≥18 years old with poorly controlled T2D with metformin up to 1500mg a day, HbA1c 7% to 10.5%, BMI of ≥25, and a stable weight (+/-5%) in the prior three months to be eligible for the trial. 

The calculated mean change of HbA1c from baseline was -2.01%, -2.24%, and -2.30% from 5mg, 10mg, 15mg of tirzepatide; For semaglutide, the mean change was -1.86%. The calculated differences between tirzepatide 5mg, 10mg, and 15mg arms and semaglutide arm were -0.15% (p=0.02), -0.39% (p<0.001), and -0.45% (p<0.001). Interestingly, 82% to 86% of participants who were administered tirzepatide and 79% who were administered semaglutide attained HbA1c <7%; 69% to 80% who received tirzepatide and 64% who received semaglutide attained HbA1c ≤6.5%; 27% to 46% who received tirzepatide and 19% who received semaglutide attained HbA1c <5.7%. Bodyweight reductions were dose-dependent and greater in the tirzepatide arms in contrast with the semaglutide arm (mean LSE difference -1.9kg, -3.6kg, and -5.5kg (p<0.001) for all doses. The most prevalent adverse effects reported were gastrointestinal (GI), severity from mild to moderate in all treatment groups, including nausea, vomiting, and diarrhea. Hypoglycemia, <54mg/dL was reported among patients who were given tirzepatide 0.6% with 5mg, 0.2% with 10mg, and 1.75% with 15mg. In contrast, 0.4% (2 participants) reported hypoglycemia in the semaglutide arm. 3% of severe adverse events were noted in the semaglutide arm, while 5% to 7% were reported using tirzepatide. All doses demonstrated tirzepatide to be non-inferior and superior to semaglutide.

Practical Pearls

• 5mg, 10mg, and 15mg of tirzepatide were non-inferior and superior compared to 1mg semaglutide concerning the reduction of HbA1c in patients with T2D receiving metformin.
• Weight reduction is dose-dependent and was superior with tirzepatide compared to semaglutide 1mg at all doses.
• Adverse effects were GI-related in the tirzepatide arms and semaglutide arms: diarrhea, nausea, and vomiting.

Frías, Juan P et al. “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.” The New England Journal of Medicine

Min, Thinzar, “The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials.” DiabetesTherapy

Trina Maglalang RPh, PharmD Candidate 2022 University of Colorado Skaggs School of Pharmacy

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