The SURPASS-2 results, in one line: among adults with type 2 diabetes already on metformin, every dose of tirzepatide lowered blood sugar and weight more than semaglutide 1 mg over 40 weeks. HbA1c, a blood test that reflects your average sugar over about three months, fell 2.01 to 2.30 points on tirzepatide and 1.86 on semaglutide. Weight fell 7.6 to 11.2 kg against 5.7 kg.
The catch is the semaglutide dose. In 2019, 1 mg was as high as Ozempic went. It isn't anymore.
What question did SURPASS-2 ask?
By 2019, weekly semaglutide, sold as Ozempic, was an established diabetes shot. Tirzepatide, later sold as Mounjaro, was still experimental: one molecule acting on two gut-hormone receptors, GLP-1 and GIP, where semaglutide acts on one. Put head to head, which lowers blood sugar more?
Juan Frías and colleagues published the answer in the New England Journal of Medicine in 2021, and the trial is registered as NCT03987919. Eli Lilly, which makes tirzepatide, paid for it, and five of the paper's nine authors worked there.
Who was in the SURPASS-2 trial
The trial enrolled 1,879 adults whose diabetes wasn't controlled on metformin alone, with an HbA1c between 7.0% and 10.5% and a BMI (a height-to-weight screening number) of 25 or more. On average they were 57, weighed 93.7 kg (about 207 pounds) and had lived with diabetes for 8.6 years. People with past pancreatitis, a personal or family history of medullary thyroid cancer (a rare thyroid tumor), advanced diabetic eye disease or weak kidney function were kept out.
About a third enrolled in Argentina, and seven in ten identified as Hispanic or Latino.
Doses climbed in steps. Per the trial protocol, tirzepatide began at 2.5 mg and rose 2.5 mg every four weeks, so the 15 mg group reached full dose only at week 20; semaglutide reached 1 mg by week 8. Those were trial assignments. A prescriber sets any real person's dose.
How the trial measured blood sugar
The main result, fixed before the trial began, was the change in HbA1c at week 40. Tirzepatide first had to show it was no more than 0.3 points worse than semaglutide, then that it was better.
The headline figures count everyone as assigned, including people who stopped the drug or needed extra diabetes medicine; the protocol made that the primary analysis for the FDA. A second, "efficacy" count uses only time on the drug.
SURPASS-2 results by dose
| At week 40 | Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Semaglutide 1 mg |
|---|---|---|---|---|
| HbA1c change | −2.01 | −2.24 | −2.30 | −1.86 |
| Gap vs semaglutide | −0.15 | −0.39 | −0.45 | — |
| Weight change | −7.6 kg (17 lb) | −9.3 kg (21 lb) | −11.2 kg (25 lb) | −5.7 kg (13 lb) |
| Reached HbA1c under 7% | 82% | 86% | 86% | 79% |
The HbA1c figures come from the paper; weight and target rates from the table in Mounjaro's prescribing information, revised 08/2026.
Put plainly, every tirzepatide dose beat semaglutide on both counts. The blood-sugar gap was thin at 5 mg, 0.15 of a point, with a confidence interval (the range the true difference most likely sits in) of 0.03 to 0.28. At 10 and 15 mg it was about 0.4, and the weight gap ran 1.9 to 5.5 kg.
The efficacy count on the registry was a little larger: HbA1c −2.09, −2.37 and −2.46 against −1.86. By that count, 51% of the 15 mg group reached an HbA1c below 5.7%, a level a lab report treats as normal, against 20% on semaglutide.
Side effects in SURPASS-2
Stomach and bowel effects led on both drugs, mostly mild to moderate according to the paper. These rates are the registry's, for everyone who got at least one dose, about 470 per group.
| Event | Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Semaglutide 1 mg |
|---|---|---|---|---|
| Nausea | 17.4% | 19.2% | 22.1% | 17.9% |
| Diarrhea | 13.2% | 16.4% | 13.8% | 11.5% |
| Vomiting | 5.7% | 8.3% | 9.8% | 8.3% |
| Decreased appetite | 7.4% | 7.2% | 8.9% | 5.3% |
| Indigestion | 7.2% | 6.2% | 9.1% | 6.6% |
| Serious adverse events | 7.0% | 5.3% | 5.7% | 2.8% |
Blood sugar below 54 mg/dL was rare: 0.2% to 1.7% on tirzepatide, 0.4% on semaglutide. There were 13 deaths, four in each tirzepatide group and one on semaglutide; FDA's medical review notes six were related to COVID-19, five were cardiovascular and two were undetermined.
Mounjaro vs Ozempic: the dose problem
SURPASS-2 set tirzepatide's full range against semaglutide 1 mg, Ozempic's top dose at the time. On March 28, 2022, the FDA signed a letter adding a 2 mg dose, and Ozempic's prescribing information, revised 05/2026, lists 2 mg as the maximum. So the trial shows how tirzepatide compared with 1 mg, not with today's top dose.
The step to 2 mg added a little on its own. In SUSTAIN FORTE, a 40-week trial of 961 adults, HbA1c fell 2.1 points on 2 mg against 1.9 on 1 mg, counting everyone (Frías et al., Lancet Diabetes & Endocrinology 2021). A Lilly-authored statistical comparison, built "in the absence of a head-to-head clinical trial," estimated tirzepatide 10 and 15 mg still ahead of semaglutide 2 mg by about 0.4 of a point, with 5 mg no different (Vadher et al., Diabetes, Obesity and Metabolism 2022). Stitching two trials together is weaker evidence than one trial.
As of September 23, 2026, the day this article was written, that gap is in court. Novo Nordisk sued Lilly on July 21, 2026, alleging that Mounjaro ads set its 15 mg dose against Ozempic 1 mg and leave out the 2 mg dose (Novo's announcement). Those are allegations, not findings. The judge reserved decision on Novo's request to pause the ads after a hearing that ended August 28 (hearing minutes); the lawsuit explainer covers the rest.
What critics and later studies said
It was open-label. People knew whether they were on tirzepatide or semaglutide; only the tirzepatide dose was hidden. A lab test is hard to fool, but knowing your drug can shape who drops out and which side effects get reported.
The volunteers weren't a mirror of US patients. A 2022 analysis of national survey data estimated that about 3 million US adults would qualify for the trial, but only 18.5% of them were Hispanic, against 70.1% of the people actually enrolled.
Forty weeks is short. The trial measured blood sugar and weight, not heart attacks, kidney failure or deaths.
An outside reanalysis agreed. Researchers in Porto, using the trial's shared data, found 34% on semaglutide met at least three standard targets for blood sugar, blood pressure, LDL cholesterol and weight, against 42% to 57% on tirzepatide (Neves et al., Diabetologia 2026).
The dose argument now cuts both ways. As of September 23, 2026, the day this article was written, the newest diabetes head-to-head came from Novo. On September 21 it reported that its investigational combination CagriSema produced 12.4% weight loss against 9.1% on tirzepatide 5 mg, the lowest dose SURPASS-2 tested, over 60 weeks, with HbA1c falls judged no worse, 1.71 against 1.67 points (Novo's announcement). That's a company release, not a peer-reviewed paper, and its weight figures use the on-drug count.
What happened after SURPASS-2
Mounjaro's approval letter, for blood-sugar control in adults with type 2 diabetes, was signed on May 13, 2022, with SURPASS-2 among the five phase 3 trials behind it. A later heart trial against dulaglutide, SURPASS-CVOT, led to a heart-risk indication on Mounjaro's label in August 2026, explained in tirzepatide heart benefits. The obesity rematch is SURMOUNT-5; tirzepatide for type 2 diabetes and the tirzepatide clinical trials overview cover the rest.
What SURPASS-2 means for a person, and for compounded versions
For adults with type 2 diabetes on metformin, SURPASS-2 is solid evidence that tirzepatide lowered HbA1c and weight more, on average, than semaglutide 1 mg over 40 weeks. It can't say who will respond to or tolerate either drug, how tirzepatide compares with semaglutide 2 mg, or what switching does. Tirzepatide vs semaglutide weighs the wider choice.
SURPASS-2 used the manufacturers' own products. Through Promise, tirzepatide and semaglutide are dispensed as compounded medications, which is different from an FDA-approved product: the formulations offered here are not FDA-approved. The FDA says it does not verify compounded drugs' safety, effectiveness or quality before they are marketed, so the trial's averages can't show a compounded preparation will do the same.
A licensed provider may still prescribe a compounded formulation; that decision is between the patient and the doctor. At Promise, a licensed provider reviews every request, and not everyone qualifies.
