The SURPASS Trials Decoded: Tirzepatide for Type 2 Diabetes

Before tirzepatide became widely known for weight loss under the Zepbound brand, it was approved for type 2 diabetes as Mounjaro — and the clinical trial program that got it there is among the most comprehensive in GLP-1 drug development history.

The SURPASS trials (Tirzepatide versus Various Comparators in Adults with T2D) enrolled more than 10,000 people with type 2 diabetes across six trials. They produced head-to-head comparisons against semaglutide, multiple forms of insulin, and placebo. The results established tirzepatide's position in diabetes treatment — and they illuminate something important about how to read GLP-1 trial data.

The SURPASS Program at a Glance

Each trial targeted a different segment of the T2D population, which makes the SURPASS program unusually useful for clinicians making individualized treatment decisions.

SURPASS-1: Tirzepatide vs. Placebo

The foundational trial (Rosenstock et al., 2021, Lancet) enrolled adults on diet and exercise alone, with no background diabetes medications. This is the cleanest look at tirzepatide's intrinsic glucose-lowering effect.

At 40 weeks:

• 5 mg: A1c reduction of 1.87 percentage points vs. 0.04 pp for placebo
• 10 mg: A1c reduction of 1.89 pp
• 15 mg: A1c reduction of 2.07 pp

Weight loss tracked proportionally: 7.0, 7.8, and 9.5 kg respectively across dose levels.

Notably, more than 80% of participants at 10 mg and 15 mg achieved A1c below 7.0% — the standard glycemic target for most T2D patients. In a drug-naive population, that is a high response rate.

SURPASS-2: The Head-to-Head With Semaglutide

SURPASS-2 (Frias et al., 2021, NEJM) is the most-cited trial in the program because it directly compared tirzepatide to semaglutide 1 mg weekly — the most commonly prescribed GLP-1 receptor agonist for T2D at the time. All participants were on metformin.

A1c reductions at 40 weeks:

All tirzepatide doses were statistically superior to semaglutide on A1c reduction. The difference was largest at 15 mg.

Weight loss at 40 weeks:

The weight difference at 15 mg — roughly 5.9 kg more lost than semaglutide — is large for a drug comparison. This gap has since been studied extensively, with the dual GIP/GLP-1 mechanism widely credited.

One important note: SURPASS-2 used semaglutide 1 mg, not the 2 mg dose that became available later. The 2 mg dose is more potent, particularly for weight loss. A fully matched comparison against semaglutide 2 mg would narrow the gap to an unknown degree.

SURPASS-3: Tirzepatide vs. Insulin Degludec

SURPASS-3 (Ludvik et al., 2021, Lancet) compared tirzepatide to insulin degludec (a long-acting basal insulin) in participants who were insulin-naive and on one or two oral agents. This is clinically important because tirzepatide is increasingly considered as an alternative to starting insulin in patients progressing on oral therapy.

At 52 weeks:

• Tirzepatide achieved comparable or superior A1c reductions to insulin degludec across all doses
• Tirzepatide 15 mg produced significantly greater A1c reduction
• Weight: tirzepatide participants lost 7.5–12.9 kg; insulin degludec participants gained 2.3 kg

The weight trajectory difference is striking. Initiating basal insulin typically means weight gain — a clinical headache in a population that is usually already overweight. Tirzepatide reversed this pattern.

Hypoglycemia rates were also meaningfully lower with tirzepatide than insulin degludec, which is an important safety consideration given that hypoglycemia is the primary risk of insulin therapy.

SURPASS-4: High Cardiovascular Risk

SURPASS-4 (Del Prato et al., 2021, Lancet) enrolled participants with established cardiovascular disease or high CV risk — a population historically underrepresented in trials. Comparator was insulin glargine titrated to target.

At 52 weeks, tirzepatide 15 mg reduced A1c by 2.58 pp vs. 1.44 pp for insulin glargine. Weight loss vs. weight gain patterns mirrored SURPASS-3.

The trial also reported a safety signal monitoring major adverse cardiovascular events (MACE), though it was not powered to detect differences in CV outcomes — that question requires dedicated cardiovascular outcomes trials, which are ongoing.

What This Means for A1c Trajectory

A key insight from reading the SURPASS data together: A1c reduction is dose-dependent but the differences between doses narrow at the higher end. Going from 5 mg to 10 mg produces a larger A1c improvement than going from 10 mg to 15 mg. For many patients with moderate A1c elevation, 7.5 or 10 mg hits the target without needing to push to the maximum dose.

The relationship between dose and weight loss, however, remains more linear through the higher doses — which is why tirzepatide's dosing strategy often looks different in obesity vs. diabetes management.

The Comparison Context: What SURPASS Doesn't Settle

A few things the SURPASS program does not tell us:

• How tirzepatide compares to semaglutide 2 mg: SURPASS-2 used 1 mg. A higher-dose semaglutide arm would change the comparison.
• Long-term durability beyond 1 year: most SURPASS trials were 40–52 weeks. STEP-5's two-year data for semaglutide suggests durability; we don't have an equivalent long-duration SURPASS trial yet.
• Cardiovascular mortality outcomes: the SELECT trial demonstrated semaglutide reduces CV events in people with obesity + established cardiovascular disease. Tirzepatide's SURPASS CVOT (SURPASS-CVOT) will address this question.

The trial data positions tirzepatide as the more potent glucose-lowering and weight-reducing agent compared to semaglutide 1 mg. Whether that advantage in A1c and weight translates to equivalent advantages in cardiovascular, renal, and mortality endpoints is the central open question.

Related reading

• Tirzepatide: the complete guide
• Semaglutide vs tirzepatide
• GLP-1 weight loss: realistic timelines
• STEP trial results decoded