PMID-35658024 — SURMOUNT-1: Tirzepatide Once Weekly for the Treatment of Obesity

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi: 10.1056/NEJMoa2206038. PMID: 35658024.

Study Design

Phase: 3
Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group
Randomization: 1:1:1:1 to tirzepatide 5 mg, 10 mg, 15 mg, or placebo, once weekly subcutaneous
Blinding: Double-blind
Duration: 72 weeks on treatment
N: 2,539 adults with obesity (without type 2 diabetes)
Setting: 119 sites across 9 countries

Population

Inclusion criteria:
- BMI ≥30 kg/m², OR BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, excluding diabetes)
- Adults ≥18 years
- Prior unsuccessful attempt at dietary weight loss
Exclusion criteria:
- Type 2 diabetes or HbA1c ≥6.5%
- Self-reported change in body weight >5 kg in preceding 3 months
- Prior weight-loss medication in preceding 3 months
- Bariatric surgery history
- Personal/family history of MTC or MEN 2
Demographics:
- Mean age: ~45 years
- Mean baseline weight: ~105 kg
- Mean BMI: ~38 kg/m²
- Female: ~67%
- Obesity-related comorbidities: hypertension ~36%, dyslipidemia ~34%

Intervention

Tirzepatide arms: 5 mg, 10 mg, or 15 mg once weekly subcutaneous, with standard 4-week dose titration (2.5 mg weeks 1–4, then escalation per protocol)
Control: Matching placebo subcutaneous once weekly
Concomitant therapy: All participants received counseling on lifestyle modification (reduced-calorie diet, 150 min/week physical activity)

Outcomes

Primary

Percent change in body weight from baseline to week 72
Proportion of participants achieving ≥5% weight reduction

Results (mean percent change in body weight, efficacy estimand):

Tirzepatide 5 mg: −15.0% (95% CI, −15.9 to −14.2)
Tirzepatide 10 mg: −19.5% (95% CI, −20.4 to −18.5)
Tirzepatide 15 mg: −20.9% (95% CI, −21.8 to −19.9), with higher efficacy analyses reporting up to −22.5%
Placebo: −3.1% (95% CI, −4.3 to −1.9)

P < 0.001 for all tirzepatide doses vs. placebo.

Proportion achieving ≥5% weight reduction:

Tirzepatide 5 mg: 85%
Tirzepatide 10 mg: 89%
Tirzepatide 15 mg: 91%
Placebo: 35%

Secondary

≥10%, ≥15%, and ≥20% weight reduction — significantly higher in all tirzepatide arms
Waist circumference: reduced by 14.6–18.5 cm in tirzepatide arms vs. 4.0 cm placebo
Cardiometabolic parameters: improvements in blood pressure, lipids, fasting insulin, HbA1c (below threshold for diabetes)
Physical functioning (IWQOL-Lite-CT) and patient-reported outcomes: superior in tirzepatide arms
Body composition (subset with DEXA): approximately one-third of weight loss was lean mass, two-thirds fat mass

Key Findings

SURMOUNT-1 established tirzepatide as the most efficacious weight-loss pharmacotherapy approved by the FDA at the time of publication. The magnitude of weight loss (~20% body weight at 15 mg) approached that of bariatric surgery in select subpopulations, significantly exceeding the ~15% ceiling for semaglutide 2.4 mg established in the STEP program (PMID: 33567185). The approval of Zepbound (tirzepatide) for chronic weight management in November 2023 was based primarily on SURMOUNT-1 data, alongside supportive evidence from SURMOUNT-2, -3, and -4.

Safety findings aligned with the GLP-1 class profile: gastrointestinal adverse events (nausea 24–33%, diarrhea 17–22%, vomiting 10–15%, constipation 6–12%) were most common, largely mild-to-moderate, and typically emerged during titration. Pancreatitis occurred in <0.2% of tirzepatide-treated participants. Gallbladder disease (cholelithiasis, cholecystitis) occurred at 0.6–0.7%. No deaths were attributed to tirzepatide.

The 15 mg dose produced notably high rates of ≥20% weight loss (36% of participants), which represents a new therapeutic benchmark and created the basis for the subsequent SURMOUNT-5 head-to-head comparison with semaglutide (PMID: 40353578).

Limitations (Author-acknowledged)

Absence of a diabetes or prediabetes cohort — SURMOUNT-2 addressed this in a T2DM population (PMID: 37385280).
No active-comparator arm (placebo only) — the head-to-head against semaglutide came later (SURMOUNT-5, PMID: 40353578).
72-week duration — longer-term weight maintenance and safety signals require extended observation; SURMOUNT-4 addressed discontinuation patterns (PMID: 38078870).
Underrepresentation of Black and Hispanic populations; majority non-Hispanic White (~70%).
Body composition (DEXA) was assessed in a subset only; population-level lean mass data remain an area for further research.
Most participants also received lifestyle counseling; isolation of pharmacologic from behavioral effects is not clean.

Evidence Level

Level Ib (Oxford CEBM) — single, large, well-conducted, adequately-powered Phase 3 RCT with double-blinding and low risk of bias.

Linked Peptides

Tirzepatide
Semaglutide (comparator class reference)
Liraglutide (older comparator in same class)
CJC-1295 NO DAC, Ipamorelin (lean mass preservation adjunct per body composition sub-analysis)

Orchestrator Notes

Industry relationship: Trial funded by Eli Lilly; majority of authors have Lilly financial relationships disclosed.
Regulatory context: This trial, combined with SURMOUNT-2, supported FDA approval of Zepbound for chronic weight management (November 2023).
Follow-on trials: SURMOUNT-3 (post-lifestyle run-in, PMID: 37840095), SURMOUNT-4 (maintenance withdrawal, PMID: 38078870), SURMOUNT-5 (head-to-head vs semaglutide, PMID: 40353578), SURMOUNT-OSA (sleep apnea indication, PMID: 38912654), SUMMIT (HFpEF indication, PMID: 39555826).
Clinical significance: Re-set the weight-loss-pharmacotherapy benchmark from ~15% (semaglutide STEP-1) to ~20–22% body weight reduction, narrowing the gap with bariatric surgery in select populations.

PMID-35658024 – SURMOUNT-1 Tirzepatide for Obesity