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

Jun 28, 2021
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Eli Lilly
Date Presented:
06/25/2021
Date Published:
06/25/2021
Date Updated:
06/28/2021
Original Posted Date:
06/28/2021
References

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. 

Description:

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)

Interpretation:

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.

References:

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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