peplexicon

EP 101:50

Semaglutide vs tirzepatide: the only fair comparison

The headline weight-loss numbers come from different trials. What a head-to-head trial shows, and why an average does not predict one person's result.

Transcript and sources
  1. You've seen the numbers. Tirzepatide, about twenty-one percent weight loss. Semaglutide, about fifteen. But those came from two different trials.
  2. Semaglutide, in the STEP 1 trial: down fourteen point nine percent over sixty-eight weeks. Tirzepatide's top dose, in SURMOUNT-1: down twenty point nine percent over seventy-two.
  3. Even one trial can give two averages. That twenty point nine counts everyone. If everyone had stayed on treatment, it's twenty-two point five.
  4. And diabetes changes the numbers on both drugs. Semaglutide: fourteen point nine percent without diabetes, nine point six with it. Tirzepatide: twenty point nine, and fourteen point seven.
  5. The fair test puts both drugs in one trial. In SURMOUNT-5, seven hundred fifty-one adults without diabetes were randomly assigned. After seventy-two weeks: tirzepatide, twenty point two percent. Semaglutide, thirteen point seven.
  6. A gap of six point five percentage points, close to what the separate trials suggested. But you couldn't know until they were tested side by side.
  7. An average isn't a forecast. In that trial, more than a quarter of people on semaglutide lost at least twenty percent, more than the tirzepatide average. And more than one in ten on tirzepatide lost less than ten.
  8. The fine print: the trial was open-label, funded by Eli Lilly, and everyone was raised to the highest dose they could tolerate. Nausea was the most common side effect, about forty-four percent in each group.
  9. One number rarely settles it. See every trial, with its population and dates, at peplexicon.com.

Sources

  1. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021;384:989–1002
  2. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022;387:205–216
  3. Davies M, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). Lancet. 2021;397:971–984
  4. Garvey WT, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2). Lancet. 2023;402:613–626
  5. Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025;393:26–36
  6. ClinicalTrials.gov NCT05822830 (SURMOUNT-5), posted results incl. adverse events
  7. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). N Engl J Med. 2021;385:503–515
  8. Wegovy (semaglutide) injection and tablets prescribing information, DailyMed, version 19, effective 18 Jun 2026 (Sections 1, 6.1, 14.2; Study 2 = STEP 1, Study 3 = STEP 2, Study 4 = STEP 3, Study 8 = higher dose)
  9. Zepbound (tirzepatide) prescribing information, DailyMed, version 40, effective 28 Aug 2026 (Sections 1, 6.1, 14.1; Study 1 = SURMOUNT-1, Study 2 = SURMOUNT-2)
  10. ICH E9(R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials, final, adopted 20 Nov 2019
  11. Wharton S, et al. Estimating and reporting treatment effects in clinical trials for weight management: using estimands… Int J Obes. 2021
  12. FDA. FDA's concerns with unapproved GLP-1 drugs used for weight loss (content current 1 Sep 2026)
Go deeperRead the GLP-1 guide