SURMOUNT-1 deep dive: tirzepatide 5/10/15 mg vs placebo at 72 weeks
Last verified 2026-05-27 · 3 · Completed; primary results reported · NCT04184622 ↗
SURMOUNT-1 is the registrational phase-3 trial that supported the November 2023 FDA approval of tirzepatide (Zepbound) for chronic weight management. Eli Lilly randomized 2,539 adults with obesity (BMI at least 30, or at least 27 with a weight-related complication) and without type 2 diabetes to once-weekly subcutaneous tirzepatide at 5 mg, 10 mg, or 15 mg or matching placebo, all on top of lifestyle counseling, for 72 weeks with a 20-week dose-escalation period. The coprimary endpoints were percentage change in body weight and the percentage of participants achieving at least 5% weight loss. Results published in the New England Journal of Medicine in July 2022 (Jastreboff et al., PMID 35658024) showed a placebo-subtracted weight loss of roughly 18 percentage points at the 15-mg dose, the largest pharmacologic weight loss reported in a pivotal obesity trial at that time.
- Enrollment
- 2,539
- Duration
- 72 weeks (primary treatment period), with a 20-week dose-escalation phase; an additional treatment period extended follow-up to week 176 in participants with prediabetes
- Drug
- Tirzepatide
- Population
- Adults aged 18 or older with a body-mass index of 30 or higher, or 27 or higher with at least one weight-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). Type 2 diabetes was an exclusion. Mean baseline body weight 104.8 kg, mean BMI 38.0, 94.5% had a BMI of 30 or higher, and prediabetes was present in roughly 40% of participants.
Primary endpoint
Percent change in body weight at week 72 (treatment-regimen estimand, ITT)
Treatment arm
-20.9% (95% CI -21.8 to -19.9)
Comparator
-3.1% (95% CI -4.3 to -1.9)
Treatment difference: Placebo-subtracted -17.8 percentage points at 15 mg; P<0.001 for all three doses vs placebo
Largest weight loss observed at the time of publication in a pivotal obesity trial without diabetes; the dose-response between 5 mg (-15.0%), 10 mg (-19.5%), and 15 mg (-20.9%) was monotonic.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Percent change in body weight at week 72 — 5 mg and 10 mg arms (treatment-regimen estimand) Monotonic dose-response across all three tirzepatide arms. | 5 mg: -15.0% (95% CI -15.9 to -14.2); 10 mg: -19.5% (95% CI -20.4 to -18.5) | -3.1% (95% CI -4.3 to -1.9) | Placebo-subtracted -11.9 percentage points at 5 mg and -16.4 at 10 mg; P<0.001 for both |
| ≥5% body weight reduction at week 72 Nearly every participant on tirzepatide met the conventional clinical threshold for meaningful weight loss. | 5 mg: 85%; 10 mg: 89%; 15 mg: 91% | 35% | Odds ratio favored every tirzepatide dose; P<0.001 |
| ≥20% body weight reduction at week 72 More than half of participants on 15 mg achieved weight loss in a range previously associated only with bariatric surgery. | 10 mg: 50%; 15 mg: 57% | 3% | P<0.001 for both 10 mg and 15 mg vs placebo |
| Change in waist circumference at week 72 (15 mg arm) | -19.9 cm (5 mg: -14.6, 10 mg: -19.4, 15 mg: -19.9) | -3.4 cm | Placebo-subtracted -16.5 cm at 15 mg |
| Change in systolic blood pressure at week 72 (pooled tirzepatide doses) Magnitude comparable to a low-dose antihypertensive added to standard care. | -8.1 mmHg (pooled 5/10/15 mg) | -1.3 mmHg | Placebo-subtracted -6.8 mmHg |
| Percent change in fasting insulin at week 72 (pooled tirzepatide doses) Reflects a sharp drop in hyperinsulinemia, consistent with restored insulin sensitivity. | -46.9% (pooled 5/10/15 mg) | -9.7% | Placebo-subtracted -37.2 percentage points |
| Percent change in triglycerides at week 72 (pooled tirzepatide doses) | -27.6% (pooled 5/10/15 mg) | -6.3% | — |
| Percent change in LDL cholesterol at week 72 (pooled tirzepatide doses) | -6.9% (pooled 5/10/15 mg) | -0.9% | — |
| Percent change in HDL cholesterol at week 72 (pooled tirzepatide doses) | +7.9% (pooled 5/10/15 mg) | +0.3% | — |
| Change in HbA1c at week 72 (15 mg arm) Participants had no diabetes; HbA1c shifted from upper-normal toward mid-normal range, with implications for prediabetes regression. | -0.51 percentage points (5 mg: -0.40, 10 mg: -0.49, 15 mg: -0.51) | -0.07 percentage points | — |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea (most-common AE) Most cases mild-to-moderate; clustered during the 20-week dose-escalation phase. Rates from CT.gov registry over the full trial period (week 193). | 25.4% (5 mg), 34.1% (10 mg), 31.9% (15 mg) | 9.8% |
| Diarrhoea | 20.3% (5 mg), 22.5% (10 mg), 23.7% (15 mg) | 7.9% |
| Constipation Lower at higher dose, opposite of the dose-response seen with nausea. | 17.9% (5 mg), 18.4% (10 mg), 12.7% (15 mg) | 5.9% |
| Vomiting | 9.2% (5 mg), 11.6% (10 mg), 12.9% (15 mg) | 1.9% |
| Dyspepsia | 9.4% (5 mg), 10.1% (10 mg), 11.7% (15 mg) | 4.8% |
| Decreased appetite Reported as an AE, but is part of the mechanism rather than a complication. | 9.5% (5 mg), 11.8% (10 mg), 8.7% (15 mg) | 3.4% |
| Alopecia (hair loss) Predominantly female participants; typically transient and tied to the rate of weight loss rather than the drug per se. | 5.2% (5 mg), 5.0% (10 mg), 5.9% (15 mg) | 1.1% |
| Injection-site reaction | 2.9% (5 mg), 5.7% (10 mg), 4.6% (15 mg) | 0.3% |
| Discontinuation due to adverse event From the 72-week primary period in the NEJM publication. | 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) | 2.6% |
| Serious adverse events (any) Rates from CT.gov over the full trial period; not concentrated in any single organ system. | 9.0% (5 mg), 9.4% (10 mg), 7.9% (15 mg) | 8.2% |
Subgroup analyses
- Participants with prediabetes at baseline (continued through week 176): Sustained mean weight loss of -22.9% at week 176 in the 15-mg arm vs -2.1% with placebo; onset of type 2 diabetes was 1.2% with pooled tirzepatide vs 12.6% with placebo at week 176
Prediabetes-to-diabetes conversion was reduced by roughly 90% on tirzepatide — the basis for the regulatory case that GLP-1/GIP therapy modifies natural history, not just weight.
- Body weight loss sustained beyond 72 weeks: Weight loss in the 15-mg arm was 22.9% at week 176, similar to the 22.5% efficacy-estimand value at week 72 in the same cohort
The plateau-then-maintenance pattern matches what STEP-5 showed for semaglutide and undermines the 'rebound is inevitable' narrative as long as the drug is continued.
Clinical significance
SURMOUNT-1 reset the ceiling for pharmacologic weight loss. Before this trial, liraglutide and semaglutide had shown about 8% and 15% mean weight loss respectively in placebo-controlled phase-3 obesity trials; tirzepatide 15 mg produced about 21% on the treatment-regimen estimand and about 23% on the efficacy estimand, with 57% of participants losing at least 20% of body weight. The cardiometabolic profile — meaningful reductions in waist circumference, systolic blood pressure, fasting insulin, triglycerides, LDL, and HbA1c — supported a benefit beyond weight alone. The trial's design also enabled the prediabetes-to-diabetes conversion analysis at week 176, which contributed to the case that adding GIP agonism to GLP-1 agonism produces a categorically different metabolic effect, not just a stronger version of GLP-1 monotherapy.
Frequently asked questions
Who qualified for SURMOUNT-1?
Adults aged 18 or older with a BMI of 30 or higher, or 27 or higher with at least one weight-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or established cardiovascular disease). Type 2 diabetes was an exclusion criterion, which is why the diabetes-specific SURMOUNT-2 trial was run separately. Mean baseline body weight was 104.8 kg and mean BMI was 38.0; 94.5% of participants had a BMI of 30 or higher, and roughly 40% had prediabetes at randomization. Participants had to be willing to inject themselves weekly for 72 weeks and to receive lifestyle counseling in all four arms.
Why did the 15 mg arm lose more weight than the 10 mg or 5 mg arms?
Tirzepatide engages both the GIP and GLP-1 receptors, and both receptor effects appear to be dose-dependent on appetite, gastric emptying, and adipose-tissue insulin sensitivity. The 5-mg, 10-mg, and 15-mg arms produced -15.0%, -19.5%, and -20.9% mean weight loss respectively on the treatment-regimen estimand, a roughly monotonic dose response without a clear plateau. The marginal gain between 10 mg and 15 mg was smaller than between 5 mg and 10 mg, suggesting that the curve begins to flatten near the top of the tested range, which is consistent with the dose-response seen in earlier tirzepatide diabetes trials.
How did SURMOUNT-1 compare to STEP-1?
STEP-1 tested semaglutide 2.4 mg weekly vs placebo over 68 weeks in 1,961 adults without diabetes and reported mean weight loss of about 14.9% with semaglutide vs 2.4% with placebo. SURMOUNT-1 tested tirzepatide 5/10/15 mg weekly vs placebo over 72 weeks in 2,539 adults under broadly similar entry criteria and reported about 15.0%, 19.5%, and 20.9% mean weight loss in the three tirzepatide arms vs 3.1% with placebo (treatment-regimen estimand). The trials were not head-to-head, but the placebo-subtracted differences favor tirzepatide at the higher doses by roughly 5 to 8 percentage points; the head-to-head SURMOUNT-5 trial published in 2025 later confirmed the gap.
Are these results sustained beyond 72 weeks?
The trial included an additional treatment period for participants with prediabetes at baseline that extended follow-up to week 176. In that cohort, weight loss in the 15-mg arm was -22.9% at week 176, essentially identical to the 22.5% at week 72 on the efficacy estimand. Onset of type 2 diabetes through week 176 was 1.2% on pooled tirzepatide vs 12.6% on placebo, a roughly 90% relative reduction. The plateau-then-maintenance pattern is consistent with how chronic-disease drugs work: continued use preserves the effect, discontinuation predicts regain — as the separate SURMOUNT-4 withdrawal trial later demonstrated.
Why do GIP and GLP-1 combined work better than GLP-1 alone?
GLP-1 receptor agonism reduces appetite, slows gastric emptying, and improves first-phase insulin secretion. Adding GIP receptor agonism appears to amplify the appetite and energy-balance effect while also acting directly on adipocytes to improve insulin sensitivity, which may explain the larger drop in fasting insulin and waist circumference seen with tirzepatide compared with semaglutide in matched populations. The clinical signal in SURMOUNT-1 — roughly 5 to 8 percentage points more weight loss than the comparable semaglutide trial at matched durations — is consistent with a dual-incretin advantage rather than a coincidental dose-equivalence difference. SURMOUNT-5 later confirmed the gap in a head-to-head design.
Sources
References
- 1.Jastreboff AM, Aronne LJ, Ahmad NN, et al.; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity N Engl J Med. 2022. PMID: 35658024.
- 2.Eli Lilly and Company. Study Results: A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1, NCT04184622) ClinicalTrials.gov. 2024. https://clinicaltrials.gov/study/NCT04184622?tab=results
- 3.U.S. Food and Drug Administration. FDA Approves New Medication for Chronic Weight Management (Zepbound, tirzepatide) FDA Press Announcement. 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
- 4.Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1) N Engl J Med. 2021. PMID: 33567185.
- 5.Aronne LJ, Sattar N, Horn DB, et al.; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial JAMA. 2024. PMID: 38078870.