A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes - SURPASS-2

Contribution To Literature:

The SURPASS-2 trial showed that tirzepatide is superior to semaglutide (both administered subcutaneously once-weekly) in improving glycemic control among patients with type 2 diabetes who were receiving metformin. 


The goal of the trial was to assess the safety and efficacy of tirzepatide versus semaglutide among patients with type 2 diabetes, who had been inadequately controlled with metformin monotherapy.

Study Design

Patients were randomized in an open-label 1:1:1:1 fashion to either tirzepatide 5 mg (n = 470), tirzepatide 10 mg (n = 469), tirzepatide 15 mg (n = 470), or semaglutide 1 mg (n = 469) for 40 weeks. Both drugs were administered as a subcutaneous injection once a week. Tirzepatide was initiated at a dose of 2.5 mg once weekly, and the doses were increased by 2.5 mg every 4 weeks until the randomly assigned dose was reached. Semaglutide was initiated at a dose of 0.25 mg once weekly, and the dose was doubled every 4 weeks until 1 mg was reached.

  • Total number screened: 2,526
  • Total number of enrollees: 1,878
  • Duration of follow-up: 40 weeks
  • Mean patient age: 56.6 years
  • Percentage female: 53%

Inclusion criteria:

  • Age ≥18 years
  • Type 2 diabetes
  • Glycated hemoglobin (HbA1c) 7.0-10.5%
  • Inadequate glycemic control on metformin (≥1500 mg/day)
  • Stable body weight over 3 months

Exclusion criteria:

  • Type 1 diabetes
  • Estimated glomerular filtration rate <45 ml/min/1.73 m2
  • History of pancreatitis
  • History of any of the following: nonproliferative diabetic retinopathy that warranted urgent treatment, proliferative diabetic retinopathy, or diabetic maculopathy

Other salient features/characteristics (mean):

  • Body weight: 93.7 kg (206.6 lbs)
  • HbA1c: 8.3%
  • Duration of type 2 diabetes: 8.6 years
  • Waist circumference: 109.3 cm (40.5 inches)
  • Blood pressure: 130/79 mm Hg

Principal Findings:

The primary endpoint, change in HbA1c levels from baseline to 40 weeks for tirzepatide 5 mg, tirzepatide 10 mg, tirzepatide 15 mg, or semaglutide 1 mg, was: -2.01% vs. -2.24% vs. -2.3% vs. -1.86%; p = 0.02, p < 0.001, p < 0.001, respectively.

Secondary outcomes:

  • Change in body weight: -7.6 vs. -9.3 vs. -11.2 vs. -5.7 kg (p < 0.001) for all doses of tirzepatide vs. semaglutide
  • Change in LDL-C: -7.7 vs. -5.6 vs. -5.2 vs. -6.4 mg/dl (p > 0.05)
  • All-cause mortality: 0.9% vs. 0.9% vs. 0.9% vs. 0.2% (p > 0.05)
  • Pancreatitis: 0% vs. 0.4% vs. 0.4% vs. 0.6% (p > 0.05)
  • Hypoglycemia: 0.6% vs. 0.2% vs. 1.7% vs. 0.4% (p > 0.05)
  • Increase in pulse rate: 2.3 vs. 2.2 vs. 2.6 vs. 2.5 bpm (p > 0.05)


The results of this trial indicate that injectable once a week tirzepatide is superior to semaglutide in improving glycemic control among patients with type 2 diabetes who were receiving metformin.

Semaglutide is a selective GLP-1 (glucagon-like peptide) agonist, with established efficacy in improving glycemic control and weight reduction (SUSTAIN [several] and STEP 2 trials). Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide–GLP-1 receptor agonist. This trial suggests that the glycemic and weight loss efficacy may be higher with tirzepatide compared with low-dose semaglutide (1 mg). The most frequent side effects were gastrointestinal related. Both agents appear to increase the resting pulse rate; the clinical impact of this finding is unclear. Two large cardiovascular outcomes trials of tirzepatide are ongoing.


Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide Versus Semaglutide Once Weekly in Patients With Type 2 Diabetes. N Engl J Med 2021;385:503-15.

Editorial: Tuttle KR. Breaking New Ground With Incretin Therapy in Diabetes. N Engl J Med 2021;385:560-1.

Presented by Dr. Juan P. Frías at the Virtual 81st Scientific Sessions of the American Diabetes Association (June 25-29, 2021).

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins

Keywords: Blood Pressure, Cholesterol, LDL, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Glucagon-Like Peptide 1, Heart Rate, Hypoglycemia, Metabolic Syndrome, Metformin, Primary Prevention, Waist Circumference, Weight Loss

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