Before Mounjaro became a household name for weight loss, it was a diabetes medication. The clinical programme that built its case to regulators was called SURPASS, and it consisted of six major trials run between 2019 and 2022. The programme tested tirzepatide at three doses (5 mg, 10 mg, and 15 mg weekly) against placebo, against semaglutide, against insulin, and as add-on therapy. It was designed to be comprehensive, and it was. The results across the six trials told a consistent story: tirzepatide produced larger reductions in blood sugar and body weight than any of the comparators, with a side effect profile consistent with the GLP-1 class.
This is a close reading of what the six trials actually showed.
SURPASS-1: Monotherapy Vs Placebo
What it tested: Tirzepatide alone (no other diabetes medication) compared to placebo in adults with type 2 diabetes. About 478 participants. 40 week follow up.
Headline finding: At 40 weeks, HbA1c reduction was approximately 1.9 percent at 5 mg, 1.9 percent at 10 mg, and 2.1 percent at 15 mg, compared to 0.04 percent on placebo. Weight reduction was 7 to 9.5 kg compared to 1 kg on placebo.
Why it mattered: Demonstrated that tirzepatide alone produces meaningful diabetes control without other medications. This is unusual for new diabetes medications, which are typically tested as add-ons.
SURPASS-2: Head To Head Vs Semaglutide
What it tested: Tirzepatide at three doses against semaglutide 1 mg weekly in patients on metformin. About 1,879 participants. 40 week follow up.
Headline finding: HbA1c reduction was 2.0 percent at tirzepatide 5 mg, 2.2 percent at 10 mg, and 2.3 percent at 15 mg, compared to 1.9 percent on semaglutide 1 mg. Weight reduction was 7.6 kg, 9.3 kg, and 11.2 kg respectively, compared to 5.7 kg on semaglutide.
Why it mattered: The first direct head to head trial of tirzepatide against another GLP-1 medication. Tirzepatide outperformed semaglutide at every dose, and the difference was greatest at the highest dose. This established the practical implication of the dual receptor mechanism.
SURPASS-3: Tirzepatide Vs Insulin Degludec
What it tested: Tirzepatide compared to long acting insulin (insulin degludec) in patients inadequately controlled on metformin with or without an SGLT2 inhibitor. About 1,444 participants. 52 weeks.
Headline finding: HbA1c reduction was 1.93 percent at tirzepatide 5 mg, 2.20 percent at 10 mg, 2.37 percent at 15 mg, compared to 1.34 percent on insulin degludec titrated to glycaemic target. Weight reduction with tirzepatide; weight gain with insulin.
Why it mattered: Compared tirzepatide directly to insulin, the traditional escalation step in type 2 diabetes. Tirzepatide produced stronger HbA1c reduction with weight loss instead of weight gain, and crucially with a substantially lower hypoglycaemia risk. This positioned tirzepatide as an alternative to insulin initiation rather than just as add-on therapy.
SURPASS-4: Tirzepatide Vs Insulin Glargine In High Cardiovascular Risk
What it tested: Tirzepatide compared to insulin glargine in patients with type 2 diabetes and elevated cardiovascular risk. About 2,002 participants. 52 weeks for the primary endpoint, with extended follow up.
Headline finding: HbA1c reduction was 2.11 percent at tirzepatide 5 mg, 2.30 percent at 10 mg, 2.42 percent at 15 mg, compared to 1.44 percent on insulin glargine. Weight reduction of 7 to 11 kg vs weight gain of about 1.6 kg on insulin.
Why it mattered: Provided initial safety data in a population at high cardiovascular risk, paving the way for the SURPASS-CVOT cardiovascular outcomes trial. Confirmed superiority over basal insulin in efficacy and weight outcomes.
SURPASS-5: Added To Insulin Glargine
What it tested: Tirzepatide added on top of existing insulin glargine therapy, in patients whose blood sugar was inadequately controlled despite insulin. About 475 participants. 40 weeks.
Headline finding: Added HbA1c reduction of 2.11, 2.40, and 2.34 percent at the three tirzepatide doses, compared to 0.86 percent on placebo. Reduced insulin requirements over time. Reduced body weight.
Why it mattered: Showed that tirzepatide combines well with insulin and often allows insulin dose reduction. For patients already on insulin who needed more glycaemic control, this provided an alternative to escalating insulin doses.
For Type 2 Diabetes Patients
A consultation reviews how tirzepatide might fit with your current diabetes treatment.
Start ConsultationSURPASS-CVOT: Cardiovascular Outcomes
What it tested: Tirzepatide compared to dulaglutide (an older GLP-1 medication with established cardiovascular benefit) in adults with type 2 diabetes and elevated cardiovascular risk. Over 13,000 participants. Multi-year follow up.
Headline finding: Tirzepatide was non-inferior to dulaglutide on the composite endpoint of cardiovascular death, non-fatal heart attack, or non-fatal stroke. Secondary analyses suggested possible superiority on individual endpoints, though not powered for definitive demonstration.
Why it mattered: Established the cardiovascular safety profile that regulators require for new diabetes medications. Non-inferiority against an active comparator (dulaglutide) that already reduces cardiovascular events is a more rigorous standard than non-inferiority against placebo.
The Pattern Across The Programme
Six trials, varied designs, consistent results. Tirzepatide produced:
- HbA1c reductions of approximately 2 to 2.4 percentage points at the 15 mg dose
- Weight reductions of approximately 7 to 12 kg depending on duration and population
- Superior outcomes compared to placebo, semaglutide, and insulin
- Side effect profile consistent with the GLP-1 class (gastrointestinal effects most prominent)
- Lower hypoglycaemia risk than insulin or sulfonylurea based regimens
- Cardiovascular safety non-inferior to dulaglutide
The consistency is what made the regulatory case overwhelming. SAHPRA approval for type 2 diabetes in December 2024 followed straightforwardly.
What The Programme Did Not Test
SURPASS was a diabetes programme. It did not directly answer:
- Tirzepatide in adults with obesity but without diabetes (that was the parallel SURMOUNT programme)
- Tirzepatide in adolescents (still in trial)
- Long term outcomes beyond 2 to 3 years
- Comparison to the newer Wegovy 2.4 mg dose specifically (a separate SURMOUNT-5 trial compared the higher semaglutide dose for weight management)
How To Read These Numbers
For a patient considering tirzepatide for type 2 diabetes, the SURPASS numbers translate into rough practical expectations. An HbA1c reduction of around 2 percentage points at maximum dose is significant for most patients with poorly controlled diabetes. A weight reduction of 8 to 12 kg accompanying glucose improvement is unusual for diabetes medications (most either are weight neutral or cause weight gain).
Individual results vary considerably. The SURPASS averages are starting points, not promises. But the consistency of the programme means the direction of effect is reliable, even if the magnitude in any given patient cannot be predicted exactly. The diabetes-specific guidance lives here.