SURMOUNT-3: Tirzepatide After a Lifestyle Run-In
Last verified November 2026 · Phase 3 · Finished; headline results reported 2023 · NCT04657016 ↗
The most common objection to these drugs is that people should try diet and exercise first, and the most common defense is that they usually have. SURMOUNT-3 is the trial that speaks to both positions, because everyone in it did the lifestyle work and did it successfully enough to enter the randomized phase. What happened next (continued substantial loss on the drug, gradual regain on placebo) is a fairly direct measurement of what the medication contributes to someone who has already done everything they were told to do.
- Enrollment
- 579
- Duration
- A 12-week intensive lifestyle lead-in, then 72 weeks of randomized treatment — 84 weeks in all, with side-effect monitoring to week 76
- Drug
- Tirzepatide
- Population
- Adults 18 and over with a BMI of 30 or more, or 27 or more if a weight-related condition came with it. Diabetes ruled people out. So did previous pancreatitis, medullary thyroid cancer or MEN-2 in the family or the person, major depression inside two years, and a suicide attempt at any time in life. Of the 806 people who started the 12-week lifestyle program, only the 579 who lost at least 5% went forward. That means 28% never reached randomization, and everyone in the trial proper had already shown they could lose weight without a drug. At that point they averaged 101.87 kg, 63% women, 86% white, mean age 45.6.
The Tirzepatide drug page covers the drug itself: its dosing, cost and side effects.
Primary endpoint
How much MORE weight came off in the 72 weeks after the lifestyle program had already worked
Treatment arm
-18.4% (SE 0.7)
Comparator
+2.5% (SE 1.0)
Treatment difference: Estimated treatment difference -20.8 percentage points (95% CI -23.2 to -18.5; P<0.001)
Note the starting line: this is measured from randomization, not from the beginning. Add the roughly 7% already lost during the lead-in and the drug group finished about 24% down overall, against about 4.5% for placebo. You cannot add 18.4% to another trial's 20.9%, because the starting points differ and nobody in either trial lost that much.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Kept losing: at least another 5% after the lifestyle phase Nearly nine in ten on the drug kept going, against roughly one in six on placebo. | 87.5% (SE 2.2) | 16.5% (SE 3.0) | Odds ratio 34.6 (95% CI 19.2 to 62.6; P<0.001) |
| Still holding most of what the lifestyle program had achieved, a year and a half later The most important result in this trial, and the one insurers should read. Without the drug, fewer than half of people who had successfully lost weight still held most of it. With it, nearly everyone did (94.0%). | 94.0% | 43.8% | Odds ratio 19.7 (95% CI 10.3 to 37.6); P<0.001 |
| Lost at least another tenth 76.7% against 8.9%. The gap widens sharply as the target rises. | 76.7% (SE 2.7) | 8.9% (SE 2.4) | Odds ratio 34.7 (95% CI 17.6 to 68.3; P<0.001) |
| Lost at least another 15% About two thirds against 4.2%. | 65.4% (SE 3.0) | 4.2% (SE 1.8) | Odds ratio 48.2 (95% CI 19.2 to 121.0; P<0.001) |
| Lost at least another fifth Nearly half shed another fifth beyond what they had already lost. On placebo, 2.2% did. | 44.7% (SE 3.0) | 2.2% (SE 1.3) | Odds ratio 40.4 (95% CI 12.2 to 133.8; P<0.001) |
| Inches off the waist Nearly 15 cm off on the drug while the placebo group's waist barely changed. | -14.6 cm (SE 0.7) | +0.2 cm (SE 1.0) | Estimated treatment difference -14.8 cm (95% CI -17.2 to -12.5; P<0.001) |
| Top blood-pressure number On placebo, blood pressure went back up as the weight came back, which is why the gap here is over 10 points. Regain has its own costs. This row and the ones below count people while they were still taking their assigned treatment (the efficacy estimand), as the paper does for these additional endpoints; the rows above count everyone randomized. | -5.8 mmHg (SE 0.73) | +4.4 mmHg (SE 0.76) | Estimated treatment difference roughly -10.2 mmHg |
| Triglycerides, a blood fat Down about a quarter on the drug, up slightly on placebo. | -25.8% (SE 1.61) | +3.0% (SE 2.34) | Estimated treatment difference roughly -29 percentage points |
| Total cholesterol Down modestly on the drug, up about 5% on placebo, again because of the regain. | -3.0% (SE 0.97) | +5.2% (SE 1.11) | Estimated treatment difference roughly -8 percentage points |
| Three-month average blood sugar Nobody here had diabetes, so this shifts within the normal-to-prediabetic band. | -0.46% (SE 0.020) | +0.01% (SE 0.022) | Estimated treatment difference roughly -0.47 percentage points |
| Blood sugar after an overnight fast Down about 9 mg/dL on the drug, up slightly on placebo. | -8.8 mg/dL (SE 0.82) | +2.4 mg/dL (SE 0.86) | Estimated treatment difference roughly -11.2 mg/dL |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea The leading complaint, mostly mild to moderate, and bunched into the 20 weeks while the dose was being raised. | 39.7% (114/287) | 14.0% (41/292) |
| Diarrhea Roughly three times the placebo rate. | 31.0% (89/287) | 9.2% (27/292) |
| Constipation About 23% against 7% on placebo. | 23.0% (66/287) | 6.8% (20/292) |
| Vomiting The widest relative gap of any stomach effect: 18.1% against 1.4%, about 13 times the placebo rate. If one side effect is going to decide whether you stay on this drug, it is likely this one. | 18.1% (52/287) | 1.4% (4/292) |
| Reaction where the injection went in About one in nine, against 1% on placebo. | 11.1% (32/287) | 1.0% (3/292) |
| Stomach pain Around four times the placebo rate. | 10.5% (30/287) | 2.4% (7/292) |
| Indigestion About 9% against 3% on placebo. | 9.4% (27/287) | 3.1% (9/292) |
| Loss of appetite Recorded as a side effect, though it is the mechanism rather than a complication. | 9.4% (27/287) | 4.1% (12/292) |
| Headache Barely above the placebo rate, one of the few complaints that is mostly not about the drug. | 9.4% (27/287) | 7.5% (22/292) |
| Hair loss 7.0% against 1.4%. It tracks how much weight is coming off rather than the drug itself, and the same rate showed up in the other trials of this drug. | 7.0% (20/287) | 1.4% (4/292) |
| Serious adverse events of any kind Close to the placebo rate, with no single problem affecting more than two people on the drug. One death occurred in each arm, neither judged related to treatment. | 5.9% (17/287) | 4.8% (14/292) |
Clinical significance
This is the strongest evidence that the drug and the behavioral work are additive rather than alternatives, and it is useful against both the argument that medication replaces effort and the argument that effort makes medication unnecessary. The 18.4% is measured from randomization, after the lead-in loss, so it is not comparable to SURMOUNT-1's 20.9% measured from baseline. Adding the two together would overstate what anyone achieved.
Who sells tirzepatide, and for how much
This trial tested Tirzepatide. Across the 734 sellers on this register, 453 publish a standing monthly cash price for compounded tirzepatide, from $69 a month, with a median of $228.28.
⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for tirzepatide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
References
- 1.Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, Halpern B, Zhang S, Chen J, Bunck MC, Ahmad NN, Forrester T. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023. PMID: 37840095.
- 2.U.S. National Library of Medicine. A Study of Tirzepatide (LY3298176) In Participants After A Lifestyle Weight Loss Program (SURMOUNT-3) — Study Results. ClinicalTrials.gov, NCT04657016. 2024. https://clinicaltrials.gov/study/NCT04657016
- 3.Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021. PMID: 33567185.
- 4.Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, Lingvay I, O'Neil PM, Rubino DM, Skovgaard D, Wallenstein SOR, Garvey WT; STEP 3 Investigators. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021. PMID: 33625476.
- 5.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. PMID: 35658024.