SURMOUNT-1

Tirzepatide for chronic weight management in adults with obesity without diabetes
Tirzepatide produced dose-dependent weight loss of 15–21% at 72 weeks. More than half of patients receiving 15 mg lost at least 20% of baseline body weight

Study design

  • Randomized, double-blind, placebo-controlled phase 3 trial
  • 2,539 patients randomized 1:1:1:1
  • 72-week treatment period including 20 weeks of dose escalation
  • All groups received lifestyle intervention
  • Co-primary outcomes: percentage change in body weight and proportion achieving ≥5% weight loss

Population

Included
  • Age ≥18 years
  • BMI ≥30 kg/m²
  • Or BMI ≥27 kg/m² with ≥1 weight-related complication
  • At least 1 unsuccessful prior dietary weight-loss attempt
  • No diabetes
Baseline
  • Mean weight 104.8 kg
  • Mean BMI 38.0 kg/m²
  • 94.5% had BMI ≥30 kg/m²
  • Approximately 68% female

Interventions

Tirzepatide
  • 5 mg, 10 mg, or 15 mg subcutaneous once weekly
  • Started at 2.5 mg weekly
  • Dose increased by 2.5 mg every 4 weeks
  • 20-week dose-escalation period
  • Plus lifestyle intervention
5 mg: n = 630 10 mg: n = 636 15 mg: n = 630
Placebo
  • Matching subcutaneous placebo once weekly
  • Same lifestyle intervention
n = 643

Primary outcome

Mean body-weight change at week 72
−15.0%, −19.5%, and −20.9% with tirzepatide vs −3.1% with placebo
P < 0.001 for all tirzepatide doses vs placebo
≥5% body-weight reduction
85.1%, 88.9%, and 90.9% with tirzepatide vs 34.5% with placebo
P < 0.001 for all comparisons

Mean weight loss

Percentage change from baseline at 72 weeks

21% 16% 11% 6% 0%
−15.0%
Tirzepatide 5
mg weekly
−19.5%
Tirzepatide 10
mg weekly
−20.9%
Tirzepatide 15
mg weekly
−3.1%
Placebo
lifestyle
5 mg: −15.0%  |  10 mg: −19.5%  |  15 mg: −20.9%  |  Placebo: −3.1%

Weight loss increased substantially with higher tirzepatide doses

Weight-loss thresholds

≥5% weight loss

85.1%, 88.9%, 90.9%
vs 34.5% with placebo

≥10% weight loss

68.5%, 78.1%, 83.5%
vs 18.8%

≥15% weight loss

48.0%, 66.6%, 70.6%
vs 8.8%

≥20% weight loss

30.0%, 50.1%, 56.7%
vs 3.1%

≥25% weight loss

15.3%, 32.3%, 36.2%
vs 1.5%

Waist circumference

−14.0, −17.7, and −18.5 cm
vs −4.0 cm

Safety

Most common adverse events

Nausea, diarrhea, and constipation
Mostly mild to moderate and concentrated during dose escalation

Stopped treatment for adverse events

4.3%, 7.1%, and 6.2% with tirzepatide
2.6% with placebo

Overall adverse events

Common with both tirzepatide and placebo
GI events predominated with tirzepatide

Timing

GI adverse effects occurred mainly during dose escalation

Clinical interpretation

  • Tirzepatide produced large, dose-dependent weight loss in adults with obesity without diabetes
  • Mean weight loss approached 21% with the 15 mg dose
  • More than half of patients receiving 10 or 15 mg lost ≥20% of baseline body weight
  • Higher doses produced greater weight loss but also more treatment discontinuation from adverse effects
  • GI adverse effects were common and occurred mainly during dose escalation
  • SURMOUNT-1 established tirzepatide as a highly effective pharmacologic treatment for obesity

Limitations

  • Patients with diabetes were excluded
  • 72-week primary trial did not determine long-term weight maintenance after stopping treatment
  • Trial assessed weight loss rather than cardiovascular outcomes
  • All groups received lifestyle intervention
  • Population was predominantly female
  • Funded by Eli Lilly, the manufacturer of tirzepatide
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038. NEJM