SURPASS-2

Tirzepatide vs semaglutide for glycemic control and weight loss in type 2 diabetes
Tirzepatide 5, 10, and 15 mg produced greater A1c reduction and weight loss than semaglutide 1 mg at 40 weeks

Study design

  • Randomized, open-label, phase 3 trial
  • 1,879 patients randomized 1:1:1:1
  • 40-week treatment period
  • Patients remained on background metformin
  • Primary outcome: change in A1c from baseline to week 40
  • Noninferiority margin 0.3 percentage points

Population

Included
  • Adults with type 2 diabetes inadequately controlled on metformin
  • Mean age 56.6 years
  • Mean diabetes duration 8.6 years
  • Mean baseline A1c 8.28%
  • Mean baseline weight 93.7 kg
Key exclusions
  • Type 1 diabetes
  • eGFR <45 mL/min/1.73 m²
  • History of pancreatitis
  • Proliferative diabetic retinopathy
  • Diabetic maculopathy
  • Retinopathy requiring urgent treatment

Interventions

Tirzepatide
  • 5 mg, 10 mg, or 15 mg subcutaneous once weekly
  • Started at 2.5 mg weekly
  • Increased by 2.5 mg every 4 weeks until assigned dose
5 mg: n = 470 10 mg: n = 469 15 mg: n = 470
Semaglutide
  • 1 mg subcutaneous once weekly
  • Started at 0.25 mg weekly
  • Dose doubled every 4 weeks to 1 mg
n = 470 randomized

Primary outcome

Mean change in A1c at week 40
−2.01%, −2.24%, and −2.30% with tirzepatide vs −1.86% with semaglutide
All tirzepatide doses were noninferior and superior to semaglutide 1 mg

A1c reduction

Mean change from baseline at 40 weeks

2.3% 1.8% 1.2% 0.6% 0%
−2.01%
Tirzepatide 5
mg weekly
−2.24%
Tirzepatide 10
mg weekly
−2.30%
Tirzepatide 15
mg weekly
−1.86%
Semaglutide
1 mg weekly
ETD vs semaglutide: −0.15% with 5 mg  |  −0.39% with 10 mg  |  −0.45% with 15 mg

Tirzepatide was superior to semaglutide 1 mg for A1c reduction at every tested dose

Weight loss

Tirzepatide 5 mg

−7.6 kg
1.9 kg greater loss than semaglutide

Tirzepatide 10 mg

−9.3 kg
3.6 kg greater loss than semaglutide

Tirzepatide 15 mg

−11.2 kg
5.5 kg greater loss than semaglutide

Semaglutide 1 mg

−5.7 kg

Additional outcomes

A1c <7%

82–86% with tirzepatide
79% with semaglutide

A1c ≤6.5%

69–80% with tirzepatide
64% with semaglutide

A1c <5.7%

27–46% with tirzepatide
19% with semaglutide

≥15% weight loss

15–36% with tirzepatide
8% with semaglutide

Safety

Nausea

17–22% with tirzepatide
18% with semaglutide

Diarrhea

13–16% with tirzepatide
12% with semaglutide

Vomiting

6–10% with tirzepatide
8% with semaglutide

Hypoglycemia <54 mg/dL

0.6%, 0.2%, and 1.7% with tirzepatide
0.4% with semaglutide

Serious adverse events

5–7% with tirzepatide
3% with semaglutide

Overall tolerability

GI adverse effects were most common and usually mild to moderate

Clinical interpretation

  • Tirzepatide lowered A1c more than semaglutide 1 mg at all tested doses
  • Weight loss increased substantially with higher tirzepatide doses
  • Hypoglycemia was uncommon with both therapies in patients receiving metformin without insulin or sulfonylureas
  • GI adverse effects were common with both incretin-based therapies
  • SURPASS-2 established strong glycemic and weight-loss efficacy for tirzepatide in T2DM

Limitations

  • Open-label trial
  • Only 40 weeks of treatment
  • Semaglutide was tested at 1 mg rather than the subsequently approved 2 mg diabetes dose
  • Trial was designed for glycemic efficacy rather than cardiovascular outcomes
  • Patients were receiving background metformin, limiting extrapolation to other treatment settings
  • Funded by Eli Lilly, the manufacturer of tirzepatide
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(6):503–515. doi:10.1056/NEJMoa2107519. NEJM