SURPASS-2: Tirzepatide Against Semaglutide in Diabetes
Last verified May 2026 · Phase 3 · Finished; published August 5, 2021 · NCT03987919 ↗
The comparison here is not quite like for like, and the asymmetry is worth naming: semaglutide was dosed at 1 mg, the Ozempic diabetes dose, not the 2.4 mg used for weight management. Tirzepatide was tested up to 15 mg, its maximum. That is a legitimate design — it compares the drugs as they are actually used in diabetes — but it means SURPASS-2 does not settle what happens at each drug's ceiling, which is what a weight-management reader usually wants to know. SURMOUNT-5 answered that later, in a different population, and found the same direction.
- Enrollment
- 1,879
- Duration
- 40 weeks of randomized treatment plus a 4-week safety check, with the last visit at week 44
- Drug
- Tirzepatide (vs semaglutide 1 mg head-to-head)
- Population
- Adults 18 and over with type 2 diabetes, an HbA1c between 7.0% and 10.5%, already on at least 1,500 mg of metformin daily for three months, a BMI of 25 or above and weight stable within 5% over the previous three months. ★ No other diabetes drug was permitted — no insulin, no sulfonylurea — which is why the low-blood-sugar rates below are so small and why they do not describe most real patients. Average starting HbA1c 8.28%, average weight 93.7 kg, average age 56.6, with roughly 470 people in each of the four arms.
Primary endpoint
How far three-month average blood sugar fell over 40 weeks, on tirzepatide against semaglutide
Treatment arm
10 mg: −2.24 percentage points; 15 mg: −2.30 percentage points
Comparator
Semaglutide 1 mg: −1.86 percentage points
Treatment difference: Estimated treatment difference vs semaglutide: −0.39 pp (10 mg) and −0.45 pp (15 mg); P<0.001 for noninferiority and superiority for both doses
⚠ The comparison is not ceiling against ceiling. Tirzepatide was tested to its maximum 15 mg; semaglutide was capped at 1 mg, which was the highest approved diabetes dose when this was designed. It is a fair comparison of how the two were prescribed for diabetes at the time, and it does not tell you what happens when both are pushed as far as they go.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| The same comparison at the lowest tirzepatide dose ★ Even the starting dose of tirzepatide beat semaglutide's maximum diabetes dose on blood sugar. | 5 mg tirzepatide: −2.01 percentage points | Semaglutide 1 mg: −1.86 percentage points | Treatment difference −0.15 pp (95% CI not in abstract); P=0.02 for superiority |
| Weight lost in kilograms ★ The result that launched a second drug program: 12.4 kg at the top dose against 6.2 kg — roughly double — in a trial where weight was not even the point. This is what convinced Lilly to run the obesity trials. | 5 mg: −7.8 kg; 10 mg: −10.3 kg; 15 mg: −12.4 kg (efficacy estimand) | Semaglutide 1 mg: −6.2 kg (efficacy estimand) | Published treatment-regimen estimated treatment differences: −1.9 kg (5 mg), −3.6 kg (10 mg), and −5.5 kg (15 mg); P<0.001 for all three comparisons |
| Got blood sugar under the standard 7% target Over nine in ten at the top dose, against about eight in ten on semaglutide. ⚠ Note that the comparator did well too — this is a gap between two effective drugs, not between a drug and nothing. | 5 mg: 85.5%; 10 mg: 88.9%; 15 mg: 92.2% | Semaglutide 1 mg: 81.1% | Higher proportion meeting ADA glycemic target at every tirzepatide dose; gap largest at 15 mg |
| Got blood sugar all the way back into the non-diabetic range ★ Half the top-dose group, against one in five on semaglutide. This row is what the 'diabetes remission' conversation is built on. ⚠ A blood sugar in the normal range while taking a drug is not the same as diabetes being gone — stop the drug and the question reopens. | 5 mg: 29.3%; 10 mg: 44.7%; 15 mg: 50.9% | Semaglutide 1 mg: 19.7% | Half of 15-mg tirzepatide participants returned HbA1c to the non-diabetic range vs ~1 in 5 on semaglutide |
| Lost at least 5% of body weight 86.2% at the top dose against 58.4%. | 5 mg: 68.6%; 10 mg: 82.4%; 15 mg: 86.2% | Semaglutide 1 mg: 58.4% | Nearly nine in ten 15-mg participants cleared the 5% clinical-relevance threshold for weight loss |
| Blood sugar after an overnight fast Down about 60 mg/dL at the higher doses against roughly 49 on semaglutide. | 5 mg: −56.0 mg/dL; 10 mg: −61.6 mg/dL; 15 mg: −63.4 mg/dL | Semaglutide 1 mg: −48.6 mg/dL | Treatment differences of −7.4 to −14.8 mg/dL favoring tirzepatide |
| Average of seven finger-prick readings taken across the day ★ A more honest picture than a single fasting number, because it captures what happens after meals — and it moved in the same direction and order. | 5 mg: −65.4; 10 mg: −70.6; 15 mg: −74.3 | Semaglutide 1 mg: −61.4 | Larger improvement in mean daily glucose at all tirzepatide doses |
| How often blood sugar dropped dangerously low ⚠ Vanishingly rare in every arm, and that is a fact about the trial design rather than the drugs: everyone was on metformin alone. Anyone on insulin or a sulfonylurea is not described by this row. | 5 mg: 0.0102; 10 mg: 0.0046; 15 mg: 0.0202 | Semaglutide 1 mg: 0.0046 | Clinically significant hypoglycemia was rare in both groups; absolute rates were a fraction of an episode per person-year |
| Triglycerides, a blood fat Down roughly 16 to 24% across the tirzepatide arms against about 10%, tracking the weight and blood-sugar gradients. No lipid measure got worse in any arm. | Reductions of approximately −16% to −24% across the tirzepatide arms in the published manuscript | Roughly −10% with semaglutide 1 mg | Larger reduction with tirzepatide; LDL fell modestly in all arms and HDL rose modestly in all arms, with directional advantage favoring tirzepatide |
| Top blood-pressure number Down 4 to 6 points on tirzepatide against 2 to 3 — the sort of change a low-dose blood-pressure tablet produces. | Mean systolic BP fell ~4-6 mmHg across the three tirzepatide arms | Mean systolic BP fell ~2-3 mmHg with semaglutide 1 mg | Numerical advantage for tirzepatide consistent with the larger weight-loss gradient |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea ★ Worth reading closely, because it contradicts the assumption that the stronger drug must be harder to take: 17.4% at tirzepatide 5 mg against 17.9% on semaglutide. It climbs to 22.1% at the top dose, but the drugs are close. | 5 mg: 17.4% (82/470); 10 mg: 19.2% (90/469); 15 mg: 22.1% (104/470) | Semaglutide 1 mg: 17.9% (84/469) |
| Diarrhea 13 to 16% across the tirzepatide arms against 11.5% — a few percentage points apart. | 5 mg: 13.2% (62/470); 10 mg: 16.4% (77/469); 15 mg: 13.8% (65/470) | Semaglutide 1 mg: 11.5% (54/469) |
| Vomiting Effectively the same at tirzepatide's higher doses as on semaglutide. | 5 mg: 5.7% (27/470); 10 mg: 8.3% (39/469); 15 mg: 9.8% (46/470) | Semaglutide 1 mg: 8.3% (39/469) |
| Indigestion Much the same in all four arms. | 5 mg: 7.2% (34/470); 10 mg: 6.2% (29/469); 15 mg: 9.1% (43/470) | Semaglutide 1 mg: 6.6% (31/469) |
| Constipation ★ Lower at the higher tirzepatide doses than the lower one — the reverse of nausea. Side effects in this class do not all scale together. | 5 mg: 6.6% (31/470); 10 mg: 4.5% (21/469); 15 mg: 4.5% (21/470) | Semaglutide 1 mg: 5.8% (27/469) |
| Loss of appetite Recorded as a side effect, though it is the mechanism doing its job. | 5 mg: 7.4% (35/470); 10 mg: 7.2% (34/469); 15 mg: 8.9% (42/470) | Semaglutide 1 mg: 5.3% (25/469) |
| Blood sugar dropping dangerously low ⛔ Under 2% anywhere, because background treatment was metformin alone. Add insulin or a sulfonylurea and this changes completely — those doses generally need reducing when you start. | 5 mg: 0.6%; 10 mg: 0.2%; 15 mg: 1.7% (of participants ever) | Semaglutide 1 mg: 0.4% |
| Serious adverse events of any kind ⚠ Roughly twice as common on tirzepatide — 5 to 7% against 2.8% — with nothing concentrated in one body system. Small absolute numbers, and worth knowing rather than skipping. | 5 mg: 7.0% (33/470); 10 mg: 5.3% (25/469); 15 mg: 5.7% (27/470) | Semaglutide 1 mg: 2.8% (13/469) |
| Stopped the drug for good over a side effect 6 to 8.5% on tirzepatide against 4.1%, with stomach and bowel problems the reason in every arm. | 5 mg: 6.0%; 10 mg: 8.5%; 15 mg: 8.5% (per Frias 2021 manuscript) | Semaglutide 1 mg: 4.1% |
| Deaths during the trial ⚠ Twelve across the three tirzepatide arms against one on semaglutide. Investigators judged all of them unrelated to treatment, and the trial was far too small to measure mortality — but the imbalance is visible and we would rather you saw it here than found it later. | 5 mg: 4 (0.9%); 10 mg: 4 (0.9%); 15 mg: 4 (0.9%) | Semaglutide 1 mg: 1 (0.2%) |
Clinical significance
SURPASS-2 established tirzepatide as the more potent glucose-lowering agent of the two and demonstrated the weight effect that later drove its obesity program. For someone reading it as a weight-loss comparison, the dose asymmetry is the thing to hold onto — this is 15 mg against 1 mg, not ceiling against ceiling. ⚠ It is also a diabetes trial: weight loss is consistently smaller in people with type 2 diabetes than in people without, so neither figure here transfers cleanly to an obesity population.
Who sells semaglutide, and for how much
This trial tested Tirzepatide (vs semaglutide 1 mg head-to-head). Across the 556 sellers on this register, 283 publish a standing monthly cash price for compounded semaglutide, from $79 a month, with a median of $174.
⛔ 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 semaglutide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
References
- 1.Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021. PMID: 34170647.
- 2.Eli Lilly and Company. Study Results: A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2, NCT03987919). ClinicalTrials.gov. 2022. https://clinicaltrials.gov/study/NCT03987919?tab=results
- 3.U.S. Food and Drug Administration. FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes (Mounjaro, tirzepatide). FDA Press Announcement, May 13, 2022. 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes
- 4.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.