GLP Watchdog

SURPASS-2: Tirzepatide Against Semaglutide in Diabetes

Last verified November 2026 · Phase 3 · Finished; published August 5, 2021 · NCT03987919 ↗

By Ruth Calder · Enforcement Editor
Editorially reviewed. Not medical advice · How we verify contentLast reviewed

The comparison here is not quite like for like. Semaglutide was dosed at 1 mg, the Ozempic diabetes dose, not the 2.4 mg used for weight management, while tirzepatide was tested up to 15 mg, its maximum. That is a legitimate design, because it compares the drugs as they are 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.

The Tirzepatide drug page covers the drug itself: its dosing, cost and side effects.

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

SURPASS-2 secondary endpoints, treatment against comparator. Last verified November 2026.
EndpointTreatmentComparatorDifference
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 pointsSemaglutide 1 mg: −1.86 percentage pointsTreatment difference −0.15 pp (95% CI −0.28 to −0.03); P=0.02 for superiority
Weight lost in kilograms

12.4 kg at the top dose against 6.2 kg, roughly double, in a trial where weight was not even the point. Tirzepatide's obesity trials were already under way when this reported, and they went on to test the effect directly.

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. The comparator did well too, so 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/dLSemaglutide 1 mg: −48.6 mg/dLTreatment differences of −7.3 to −14.7 mg/dL favoring tirzepatide
Average of seven finger-prick readings taken across the day

A fuller picture than a single fasting number, because it captures what happens after meals. It moved in the same direction and order.

5 mg: −65.4; 10 mg: −70.6; 15 mg: −74.3Semaglutide 1 mg: −61.4Larger 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: 0.0202Semaglutide 1 mg: 0.0046Clinically significant hypoglycemia was rare in both groups; absolute rates were a fraction of an episode per person-year
Triglycerides, a blood fat

Down further on tirzepatide than on semaglutide, in step with the weight and blood-sugar results.

Fell on every tirzepatide doseFell on semaglutide 1 mgLarger reduction with tirzepatide
Top blood-pressure number

Down further on tirzepatide than on semaglutide, in step with the larger weight loss.

Fell on every tirzepatide doseFell on semaglutide 1 mgNumerical advantage for tirzepatide consistent with the larger weight-loss gradient

Adverse events

SURPASS-2 adverse events, rate on treatment against rate on comparator. Last verified November 2026.
EventTreatment rateComparator rate
Nausea

This row 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. The absolute numbers are small, but they are there.

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 showed the weight effect its obesity program was testing at the same time. 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, and 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 734 sellers on this register, 463 publish a standing monthly cash price for compounded semaglutide, from $47 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

On its primary endpoint — How far three-month average blood sugar fell over 40 weeks, on tirzepatide against semaglutide — the treatment arm recorded 10 mg: −2.24 percentage points; 15 mg: −2.30 percentage points against Semaglutide 1 mg: −1.86 percentage points for the comparator. 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.
1,879 participants, over 40 weeks of randomized treatment plus a 4-week safety check, with the last visit at week 44. It was a Phase 3 trial, finished; published August 5, 2021. Registered as NCT03987919, which you can look up yourself rather than taking anyone's summary for it.
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. ⚠ A trial result describes the population it was measured in. If you differ from it materially — in age, in baseline weight, in whether you have diabetes — the number is context rather than a prediction.
The most commonly reported were nausea (5 mg: 17.4% (82/470); 10 mg: 19.2% (90/469); 15 mg: 22.1% (104/470) against Semaglutide 1 mg: 17.9% (84/469) on comparator), diarrhea (5 mg: 13.2% (62/470); 10 mg: 16.4% (77/469); 15 mg: 13.8% (65/470) against Semaglutide 1 mg: 11.5% (54/469) on comparator), vomiting (5 mg: 5.7% (27/470); 10 mg: 8.3% (39/469); 15 mg: 9.8% (46/470) against Semaglutide 1 mg: 8.3% (39/469) on comparator). This row 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. Rates come from this trial's population under its own dose-escalation schedule; a faster or slower titration changes what people experience.
Secondary endpoints included the same comparison at the lowest tirzepatide dose (5 mg tirzepatide: −2.01 percentage points against Semaglutide 1 mg: −1.86 percentage points); weight lost in kilograms (5 mg: −7.8 kg; 10 mg: −10.3 kg; 15 mg: −12.4 kg (efficacy estimand) against Semaglutide 1 mg: −6.2 kg (efficacy estimand)); got blood sugar under the standard 7% target (5 mg: 85.5%; 10 mg: 88.9%; 15 mg: 92.2% against Semaglutide 1 mg: 81.1%). ⚠ Secondary endpoints are weaker evidence than the primary one — a trial is powered for its primary outcome, and the rest are read as supporting rather than as findings in their own right.
No, and this matters because the number gets used that way. SURPASS-2 tested Tirzepatide (vs semaglutide 1 mg head-to-head) — the FDA-approved product, made by its manufacturer under Good Manufacturing Practice, at the doses and schedule the protocol specified. A compounded preparation of semaglutide is a different product: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. ⛔ A seller quoting this trial's result beside a compounded price is quoting evidence that was generated on something they are not selling. That is not the same as saying compounded semaglutide does not work — it is saying nobody measured it here.
It cannot tell you that. A trial reports an average across a defined population under a fixed protocol, with monitoring and adherence support most people do not get. It is the best evidence available and it is still a distribution rather than a promise — some participants lost far more than the mean and some lost nothing. What it is genuinely good for is comparing options against each other, which is what the rest of this section is for.

References

  1. 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. 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. 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. 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.
  5. 5.Nicholls SJ, Pavo I, Bhatt DL, et al.; SURPASS-CVOT Investigators. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025. PMID: 41406444.
  6. 6.Aronne LJ, Horn DB, le Roux CW, et al.; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025. PMID: 40353578.

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