How much more A1C lowering does tirzepatide provide compared to semaglutide 1 mg?

At the highest dose (15 mg), tirzepatide lowered A1C by approximately 0.45 to 0.60 percentage points more than semaglutide 1 mg, depending on the estimand used. At 10 mg, the difference was about 0.39 to 0.48 points. At 5 mg, the difference was 0.15 to 0.20 points.

Did SURPASS-2 compare tirzepatide to the highest dose of semaglutide?

No. SURPASS-2 used semaglutide 1 mg, which was the maximum approved diabetes dose at trial design. The 2.4 mg dose (branded as Wegovy for obesity) was not included. A comparison against semaglutide 2.4 mg has not been conducted in a completed randomized trial in type 2 diabetes as of this review.

How much weight did patients lose on tirzepatide vs semaglutide in SURPASS-2?

Tirzepatide 15 mg produced an average weight loss of 11.2 kg (about 12.4% of body weight), compared to 5.7 kg (about 6.2%) with semaglutide 1 mg. The 10 mg dose yielded 9.3 kg, and 5 mg yielded 7.6 kg.

Were GI side effects worse with tirzepatide than semaglutide?

GI side effects were broadly similar. Nausea occurred in 17 to 22% of tirzepatide-treated patients versus 18% with semaglutide. The 15 mg tirzepatide arm had a higher discontinuation rate (8% vs 4%), but at lower doses, tolerability was comparable.

What was the rate of hypoglycemia in SURPASS-2?

Clinically significant hypoglycemia (glucose below 54 mg/dL) was rare across all arms, occurring in 0.4 to 0.8% of participants. All patients were on metformin monotherapy, which has low intrinsic hypoglycemia risk.

How long did SURPASS-2 last?

The treatment period was 40 weeks. This is shorter than some comparator trials in the GLP-1 space (SUSTAIN trials ran 30 to 56 weeks; STEP trials ran 68 weeks). Whether results hold or shift beyond 40 weeks remains an open question from this study.

What percentage of patients reached a normal A1C on tirzepatide?

In the 15 mg group, 46% of participants achieved an A1C below 5.7% (the threshold for normoglycemia), compared to 19% with semaglutide 1 mg. This was one of the most clinically notable findings of the trial.

Is tirzepatide FDA-approved based on SURPASS-2?

Tirzepatide (Mounjaro) received FDA approval for type 2 diabetes in May 2022. The approval was based on the full SURPASS program (trials 1 through 5), of which SURPASS-2 was one component. SURPASS-2 was particularly influential because it provided the only active GLP-1 RA comparator data.

Did SURPASS-2 measure cardiovascular outcomes?

No. SURPASS-2 was a glycemic efficacy trial, not a cardiovascular outcomes trial. The dedicated cardiovascular trial, SURPASS-CVOT, was reported separately in 2024 and used a placebo comparator rather than semaglutide.

Was the trial blinded?

Partially. Assignment to tirzepatide versus semaglutide was open-label (participants knew which drug they received). Assignment among the three tirzepatide dose levels was blinded. This design was chosen because the injection devices differ between the two drugs.

SURPASS-2 Results in Detail: Numbers, Subgroups, and Time Course

By HealthRX.com Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

Clinical image for SURPASS-2 Results in Detail: Numbers, Subgroups, and Time Course Image: HealthRX.com clinical image

At a glance

Trial: SURPASS-2 (NCT03987919)
N: 1,879 adults with type 2 diabetes inadequately controlled on metformin
Intervention: Tirzepatide 5 mg, 10 mg, or 15 mg subcutaneous once weekly
Comparator: Semaglutide 1 mg subcutaneous once weekly
Duration: 40 weeks
Primary endpoint: Change from baseline in HbA1c
Key result: Tirzepatide was superior to semaglutide 1 mg at all three doses for A1C lowering and weight reduction

What SURPASS-2 Actually Tested

SURPASS-2 was the first completed head-to-head randomized trial comparing tirzepatide, a dual GIP/GLP-1 receptor agonist, against the established GLP-1 receptor agonist semaglutide in people with type 2 diabetes. The trial enrolled 1,879 participants across 128 sites in 13 countries. All participants were already taking metformin (at least 1 to 500 mg/day) with baseline A1C between 7.0% and 10.5%.

Randomization was 1:1:1:1 to tirzepatide 5 mg, 10 mg, 15 mg, or semaglutide 1 mg. Both drugs followed escalation schedules: tirzepatide started at 2.5 mg and increased by 2.5 mg every four weeks until the assigned dose was reached; semaglutide started at 0.25 mg, moved to 0.5 mg at week 4, and reached the target 1 mg at week 8. This is important because the escalation timelines differ, and the 15 mg tirzepatide arm did not reach full dose until week 20, halfway through the trial.

The study used an open-label design for drug administration but blinded the tirzepatide dose assignments across the three tirzepatide arms. The primary estimand was a treatment-policy approach (all randomized participants, regardless of rescue medication or adherence), with a secondary estimand analyzing only data from on-treatment periods without rescue medication.

Primary Endpoint: A1C Change at Week 40

The primary results showed clear dose-dependent superiority for tirzepatide over semaglutide on A1C reduction.

HRX Dose-Response Framework: A1C Reduction by Arm

To understand how tirzepatide performed, it helps to see the raw reductions alongside the estimated treatment differences and their confidence intervals. The table below presents both the treatment-policy estimand (intention-to-treat, with rescue medication data included) and the efficacy estimand (on-treatment, no rescue), side by side.

Treatment-policy estimand (ITT-like):

| Arm | Baseline A1C (%) | LS Mean Change (%) | Difference vs Semaglutide (%) | 95% CI | P value | |---|---|---|---|---|---| | Tirzepatide 5 mg | 8.33 | −2.01 | −0.15 | −0.28 to −0.03 | 0.02 | | Tirzepatide 10 mg | 8.31 | −2.24 | −0.39 | −0.51 to −0.26 | <0.001 | | Tirzepatide 15 mg | 8.25 | −2.30 | −0.45 | −0.57 to −0.32 | <0.001 | | Semaglutide 1 mg | 8.24 | −1.86 |, |, |, |

Efficacy estimand (on-treatment, no rescue):

| Arm | LS Mean Change (%) | Difference vs Semaglutide (%) | 95% CI | |---|---|---|---| | Tirzepatide 5 mg | −2.09 | −0.20 | −0.29 to −0.11 | | Tirzepatide 10 mg | −2.37 | −0.48 | −0.57 to −0.39 | | Tirzepatide 15 mg | −2.46 | −0.60 | −0.41 to −0.78 | | Semaglutide 1 mg | −1.86 |, |, |

A few details worth noting. The treatment difference at the 5 mg dose was statistically significant but clinically modest (0.15 percentage points). At 10 mg and 15 mg the gaps widened to roughly 0.4 and 0.5 to 0.6 percentage points, depending on estimand. These are not trivial differences. For context, the FDA approved semaglutide itself partly on a 0.4-point advantage over placebo-equivalent comparators in earlier SUSTAIN trials.

A1C Target Achievement Rates

Proportion reaching clinically meaningful A1C thresholds at week 40 (treatment-policy estimand):

| Target | Tirz 5 mg | Tirz 10 mg | Tirz 15 mg | Sema 1 mg | |---|---|---|---|---| | A1C <7.0% | 82% | 86% | 86% | 79% | | A1C <6.5% | 69% | 80% | 83% | 64% | | A1C <5.7% | 27% | 40% | 46% | 19% |

The <5.7% target (normoglycemia) stands out. Nearly half of the tirzepatide 15 mg group reached a non-diabetic A1C, compared to roughly one in five on semaglutide. That gap (46% vs 19%) is clinically striking and was one of the results that received the most attention in endocrinology discussions following publication.

Time-Course Pattern: When the Curves Separated

A1C reductions in all four arms were steep through the first 12 to 16 weeks, reflecting the dose-escalation period for both drugs. By week 12, semaglutide had already been at its target dose (1 mg) for four weeks, while tirzepatide 10 mg and 15 mg arms were still escalating.

Between weeks 16 and 24, the curves separated more clearly. The semaglutide arm's A1C trajectory began to flatten, while the two higher tirzepatide arms continued declining. By week 28, the separation was essentially stable through week 40. This pattern suggests the effect difference was not simply a matter of tirzepatide needing more time to reach full dose; even after both drugs had been at target dose for 20+ weeks, the gap persisted.

For body weight, the separation was even more sustained. Weight loss curves did not show a clear plateau in any arm by week 40, raising the question (addressed in the longer SURMOUNT trials) of whether an even longer treatment period would widen the gap further.

Secondary Endpoint: Body Weight

Weight loss was a key secondary endpoint and showed clear tirzepatide superiority across all doses.

Body weight change from baseline at week 40 (treatment-policy estimand):

| Arm | Baseline Weight (kg) | LS Mean Change (kg) | Difference vs Semaglutide (kg) | 95% CI | |---|---|---|---|---| | Tirzepatide 5 mg | 93.0 | −7.6 | −1.9 | −2.8 to −1.0 | | Tirzepatide 10 mg | 94.2 | −9.3 | −3.6 | −4.5 to −2.7 | | Tirzepatide 15 mg | 94.0 | −11.2 | −5.5 | −6.4 to −4.6 | | Semaglutide 1 mg | 93.7 | −5.7 |, |, |

In percentage terms, the 15 mg tirzepatide arm lost approximately 12.4% of baseline body weight versus 6.2% for semaglutide. This degree of weight loss at 15 mg approaches what the tirzepatide obesity label later demonstrated in the SURMOUNT-1 trial at 72 weeks in people without diabetes.

Other Secondary and Exploratory Endpoints

Fasting plasma glucose dropped by 54.4 to 65.2 mg/dL across tirzepatide doses versus 44.4 mg/dL with semaglutide. The between-group differences at 10 mg and 15 mg were roughly 15 to 20 mg/dL (p <0.001 for both).

Fasting serum insulin decreased more with tirzepatide at the two higher doses than with semaglutide, despite greater glucose lowering. This observation aligns with the proposed mechanism whereby the GIP component improves beta-cell insulin secretion efficiency rather than simply increasing total insulin output.

Lipid parameters: Triglycerides fell more with tirzepatide (19 to 24% reductions versus 12% with semaglutide). LDL changes were modest and similar across arms. VLDL cholesterol showed greater reductions with tirzepatide 10 mg and 15 mg.

Waist circumference decreased by 7.0 to 8.4 cm with tirzepatide versus 5.1 cm with semaglutide, consistent with the weight findings and suggesting meaningful visceral fat loss.

Safety and Tolerability Comparison

Gastrointestinal adverse events were the most common reason for discontinuation in all arms. Nausea rates were 17 to 22% across tirzepatide doses and 18% with semaglutide. Diarrhea was reported in 13 to 16% of tirzepatide-treated participants versus 12% with semaglutide. Vomiting ranged from 5 to 9% with tirzepatide and 8% with semaglutide.

Discontinuation rates due to adverse events were 4 to 8% with tirzepatide versus 4% with semaglutide. The 15 mg tirzepatide arm had the highest discontinuation rate (8%), which the study authors noted was consistent with other incretin-based therapy trials.

Hypoglycemia (glucose <54 mg/dL) occurred in 0.4 to 0.8% across tirzepatide arms and 0.4% with semaglutide. These rates reflect the metformin-only background, which carries minimal hypoglycemia risk.

Limitations the Authors Acknowledged

Several limitations directly affect how to interpret these results.

Open-label comparator. Participants and investigators knew whether the drug was tirzepatide or semaglutide (though tirzepatide dose was blinded). This could influence subjective adverse-event reporting, though A1C and weight are objective outcomes unlikely to be affected by knowledge of treatment assignment.

Semaglutide dose ceiling. The trial used semaglutide 1 mg, which was the maximum approved dose in 2019 when the trial was designed. The 2.4 mg semaglutide dose (Wegovy) and the oral semaglutide 50 mg formulation were not available as comparators. This is the single most common criticism of SURPASS-2: it compared three escalating doses of the new drug against one fixed dose of the established drug. A head-to-head against semaglutide 2.4 mg would answer a different and arguably more relevant clinical question.

40-week duration. Many patients remain on these medications for years. Whether the A1C and weight advantages persist, widen, or narrow beyond 40 weeks cannot be determined from this trial alone. The SURPASS-4 trial (vs. insulin glargine) extended to 52 weeks but did not include a semaglutide arm.

Population characteristics. Mean baseline A1C was approximately 8.3%, and mean diabetes duration was 8 to 9 years. Patients with more advanced disease, higher baseline A1C, or insulin-requiring type 2 diabetes may respond differently.

No cardiovascular outcomes. SURPASS-2 was a glycemic control trial. The SURPASS-CVOT trial, reported in 2024, subsequently assessed tirzepatide's cardiovascular effects but used placebo rather than an active comparator.

What These Numbers Mean for Prescribing Decisions

The SURPASS-2 results established that tirzepatide at 10 mg and 15 mg provides clinically meaningful additional A1C lowering and weight reduction compared to semaglutide 1 mg. The 5 mg dose showed statistically significant but smaller advantages. For clinicians choosing between these two agents, the data supports tirzepatide when maximal glycemic control and weight reduction are priorities, provided the patient tolerates the GI side-effect profile.

The ADA Standards of Care now list both tirzepatide and semaglutide as preferred options for patients with type 2 diabetes who need weight management, without specifying one over the other. Cost, insurance coverage, and patient preference for injection device remain practical factors the trial data cannot address.

Frequently asked questions

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References

Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. PubMed
U.S. Food and Drug Administration. Mounjaro (tirzepatide) prescribing information. FDA Label
U.S. Food and Drug Administration. Ozempic (semaglutide) prescribing information. FDA Label
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(4):327-340. PubMed
Nicholls SJ, Bhatt DL, Buse JB, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT. Circulation. 2024;149(4):267-278. PubMed
American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes, 2024. Diabetes Care. 2024;47(Suppl 1). PubMed