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Novel Agent Tirzepatide Superior to Semaglutide in Reducing A1c, Body Weight in Type 2 Diabetes


The much anticipated results from the SURPASS 2 clinical trial demonstrated reductions in A1c and body weight with tirzepatide that were significant and superior to those with semaglutide.

Tirzepatide, the novel injectable once-weekly dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 receptor agonist 1 (GLP-1 RA) led to superior reductions in baseline hemoglobin A1c (A1c) and body weight compared to GLP-1 RA semaglutide in patients with type 2 diabetes (T2D) on background treatment with metformin.

More than 90% (92%) of participants receiving tirzepatide reached an A1c <7% and up to 51% achieved an A1c <5.7%.

The findings, from the SURPASS 2 clinical trial sponsored by Eli Lilly, were simultaneously published on Friday, June 25, 2021, in The New England Journal of Medicine (NEJM)and presented in a late breaking poster presentation during the American Diabetes Association's® (ADA) 81st Scientific Sessions.

SURPASS 2, led by Juan Pablo Frias, MD, Medical Director of the National Research Institute, was a 40-week, multicenter, randomized, parallel, open-label trial designed to compare the efficacy and safety of 3 doses of tirzpeatide (5 mg, 10 mg, 15 mg) to semaglutide 1 mg adults with T2D inadequately controlled with ≥1500 mg/day metformin alone.

The primary objective, wrote Frias et al, was to demonstrate noninferiority in reduction of A1c with tirzepatide 10 and 15 mg compared to semaglutide 1 mg from baseline to week 40.

Key secondary endpoints included reductions noninferior to semaglutide in A1c from baseline for low-dose (5 mg) tirzepatide; superior reductions in body weight and A1c as well as a greater proportion of participants reaching A1c <7% for all 3 doses of terzepatide and greater percentages achieving A1c <5.7% for the 10 and 15 mg doses of tirzepatide.

SURPASS randomized 1 879 participants 1:1:1:1 to tirzepatide 5, 10, or 15 mg dose, or semaglutide 1 mg. Participants’ mean age was 56.6 years, mean A1c at baseline, 8.28%, mean baseline weight, 93.7 kg and BMI, 34.2 kg/m2. Average duration of T2D was 8.6 years.


Study authors report superior reductions from baseline in A1c and body weight for all 3 tirzepatide doses vs semaglutide. Specifically:

  • A1C reduction: -2.09% (5 mg), -2.37% (10 mg), -2.46% (15 mg) vs -1.86% (semaglutide)
  • Weight reduction: -7.8 kg (-8.5%, 5 mg), -10.3 kg (-11.0%, 10 mg), -12.4 kg (-13.1%, 15 mg) vs -6.2 kg (-6.7%, semaglutide)
  • Participants achieving A1C <7%: 85% (5 mg), 89% (10 mg), 92% (15 mg) vs 81% (semaglutide)
  • Participants achieving A1C <5.7%: 29% (5 mg, not controlled for type 1 error), 45% (10 mg), 51% (15 mg) vs 20% (semaglutide)

Estimated differences between tirzepatide groups and the semaglutide group were statistically significant for the 10 mg (−0.39 percentage points [95% CI, −0.51 to −0.26; P<.001]), and 15 mg (−0.45 percentage points [95% CI, −0.57 to −0.32; P<.001]) doses.

Frias et al also report that at all 3 doses, tirzepatide was noninferior and superior to semaglutide. Overall reductions in body weight from baseline were greater with tirzepatide vs semaglutide: (least-squares mean estimated treatment difference, −1.9 kg (5mg), −3.6 kg (10 mg), and −5.5 kg (15 mg); P<.001 for all comparisons).

Hypoglycemia (blood glucose <54 mg/dL) among all treated patients were reported to be low.

The most commonly reported side effects across treatment arms were gastrointestinal in nature and mostly mild-to-moderate.

Evaluation of an additional exploratory endpoint found that all 3 doses of tirzepatide led to reductions from baseline in fasting lipids including for the 15 mg dose a reduction in triglycerides of nearly 25%.

These results, which will also be featured during an ADA-sponsored symposium on Tuesday, June 29, showed that all three tirzepatide doses achieved greater A1C and weight reductions compared to semaglutide.

SURPASS-2 is the second of five global registration studies for tirzepatide in type 2 diabetes, all of which have been completed. Lilly intends to submit the full registration package to regulatory authorities by the end of 2021.

SURPASS 2 results also will be featured during an ADA-sponsored symposium, Next Chapter in Incretin-Based Therapies—Tirzepatide, a Novel Dual GIP/GLP-1 Receptor Agonist—Results from the First Phase 3 SURPASS Clinical Trials , on Tuesday, June 29, 2021, from 8-9:30 am, EST.

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