The SURPASS Program: Tirzepatide in Type 2 Diabetes

What the SURPASS program set out to answer

Tirzepatide is a once-weekly injectable peptide that activates both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor, making it the first dual incretin agonist to reach pivotal phase 3 testing. The SURPASS program (five trials, roughly 5,000 patients in total) was designed to answer three practical questions before regulatory submission: How much does tirzepatide lower HbA1c and body weight compared with placebo and against the current standard of care? Does performance hold up as background therapy intensifies? And is the safety profile acceptable when doses reach the maximum planned level of 15 mg per week?

Each trial addressed a specific niche in the T2DM treatment algorithm, from drug-naive patients eligible for monotherapy all the way to patients already on basal insulin with elevated cardiovascular risk.

Constituent trials at a structured glance

Results are approximate from published primary endpoints; follow-up was 40-52 weeks across trials. OADs = oral antidiabetic drugs; SGLT2i = sodium-glucose cotransporter 2 inhibitor.

SURPASS-1: Establishing monotherapy efficacy

The first trial (NCT03954834) enrolled approximately 480 drug-naive adults with T2DM and a baseline HbA1c of 7.5 to 9.5%. Patients were randomly assigned to tirzepatide 5, 10, or 15 mg once weekly or placebo for 40 weeks.^[1]

All three tirzepatide doses met the primary endpoint of HbA1c reduction versus placebo. The 15 mg dose produced a mean HbA1c reduction of approximately 2.07 percentage points from a baseline near 7.9%, placing the final mean HbA1c below 5.7% in many participants. Weight reductions were clinically meaningful even at monotherapy: roughly 7 kg at 5 mg and approximately 9.5 kg at 15 mg versus a modest reduction in the placebo group. Nausea and vomiting rates followed the dose-response pattern seen with other incretin agents but were generally transient.

SURPASS-1 served the simple but necessary role of establishing that tirzepatide's glycemic effect was not contingent on background pharmacotherapy. The dataset also generated the safety signal baseline used to interpret adverse events in subsequent trials with more complex backgrounds.

SURPASS-2: Head-to-head against semaglutide 1 mg

SURPASS-2 (NCT03987919) was the trial that drew the most clinical attention. It randomized approximately 1,880 patients on metformin to tirzepatide 5, 10, or 15 mg or semaglutide 1 mg subcutaneous for 40 weeks. Semaglutide 1 mg was the highest approved dose for T2DM at the time and represented the dominant GLP-1 receptor agonist class benchmark.^[2]

Tirzepatide was superior to semaglutide 1 mg on both co-primary endpoints. At 15 mg, the mean HbA1c reduction was 2.30 percentage points versus 1.86 for semaglutide; the difference was statistically significant. Body-weight reduction showed a more pronounced gap: approximately 12.4 kg with tirzepatide 15 mg compared with 6.2 kg for semaglutide 1 mg, a difference of about 6 kg between treatment arms. Even the lowest tirzepatide dose (5 mg) was non-inferior to semaglutide on HbA1c.

The weight gap in SURPASS-2 is frequently cited as evidence that dual GIP/GLP-1 receptor agonism provides meaningful incremental benefit beyond GLP-1 agonism alone, though the comparison was not at the maximum approved dose of semaglutide for obesity (2.4 mg, which was not yet approved for T2DM). Rates of gastrointestinal adverse events were broadly similar between tirzepatide 10-15 mg and semaglutide 1 mg, though direct tolerability comparisons are complicated by the different dose-escalation schedules.

SURPASS-3: Challenging basal insulin intensification

SURPASS-3 (NCT03882970) enrolled approximately 1,440 patients already on metformin with or without an SGLT2 inhibitor, who were not at target despite oral therapy. The comparator was titrated insulin degludec, reflecting a common escalation path in clinical practice.^[3]

Over 52 weeks, tirzepatide outperformed titrated insulin degludec on HbA1c (reductions of 1.93 to 2.37 percentage points depending on dose, versus a 1.34 percentage point reduction with degludec). The weight divergence was stark: tirzepatide produced weight losses of approximately 7 to 13 kg while insulin degludec was associated with a weight gain of roughly 2.3 kg, a separation of more than 15 kg at the high end. Rates of hypoglycemia were lower with tirzepatide, an expected finding given the glucose-dependent mechanism of incretin-mediated insulin secretion.

SURPASS-3 was important for the prescribing community because it addressed the real-world decision of whether to intensify with injectable GLP-1-class therapy or proceed to insulin. The trial suggested tirzepatide can meaningfully delay or reduce the need for insulin intensification in a broad population.

SURPASS-4: High cardiovascular risk and the insulin comparison

SURPASS-4 (NCT03730662) was the largest and longest trial in the program, enrolling approximately 2,000 patients with T2DM and increased cardiovascular risk who were receiving one to three oral antidiabetic agents. The comparator was titrated insulin glargine U-100. The primary endpoint was HbA1c change at 52 weeks, but the protocol pre-specified 104-week follow-up specifically to capture cardiovascular events for an exploratory MACE (major adverse cardiovascular events) analysis.^[4]

Tirzepatide was superior to insulin glargine on HbA1c across all doses tested, with the 15 mg arm reducing HbA1c by approximately 2.58 percentage points versus a 1.44 percentage point reduction with glargine. Weight loss with tirzepatide 15 mg was approximately 12.9 kg; insulin glargine was associated with a 2.0 kg gain. The exploratory cardiovascular analysis, while not powered for this purpose, showed a hazard ratio favoring tirzepatide for MACE, providing directional signal without definitive confirmation. That confirmation is expected from SURPASS-CVOT (NCT04255433), the dedicated outcomes trial that was underway during regulatory review.

SURPASS-5: Adding tirzepatide on top of basal insulin

SURPASS-5 (NCT04039503) enrolled approximately 475 patients who were already on a stable dose of insulin glargine with or without metformin and whose HbA1c remained 7.0 to 10.5%. Tirzepatide 5, 10, or 15 mg was added versus placebo while glargine dosing was maintained.^[5]

All three tirzepatide doses significantly reduced HbA1c from baseline compared with placebo, with the 15 mg arm achieving approximately a 2.1 percentage point reduction versus a 0.86 percentage point reduction with placebo. Weight fell by approximately 9.5 kg with 15 mg while placebo patients gained 1.6 kg. Rates of clinically significant hypoglycemia (below 54 mg/dL) were numerically higher with tirzepatide than placebo, which is expected when an efficacious agent is added on top of existing insulin. Investigators could adjust the glargine dose to mitigate this risk, though the protocol allowed insulin reduction only after hypoglycemia occurred rather than proactively.

SURPASS-5 established that tirzepatide provides meaningful benefit as an add-on to basal insulin, an important data point for patients who are already partially managed with injectable therapy and need additional glucose lowering without switching regimens entirely.

Regulatory outcome

The FDA approved tirzepatide as Mounjaro (5, 10, and 15 mg weekly doses) for the treatment of type 2 diabetes in adults in May 2022, relying principally on the SURPASS program as its pivotal evidence base. The EMA granted a conditional marketing authorisation later in 2022 under the brand name Mounjaro for T2DM in Europe. The MHRA followed with UK approval in 2023, with NICE subsequently issuing technology appraisal guidance (TA924) for use in the NHS.

The FDA's approval label carries a boxed warning for the risk of thyroid C-cell tumors observed in rodent carcinogenicity studies, a class warning that applies to all GLP-1 receptor agonists. No cases of medullary thyroid carcinoma were attributed to tirzepatide in the clinical program. The product is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

The SURPASS-CVOT trial (NCT04255433) remains the outstanding piece of the tirzepatide cardiovascular evidence base for the T2DM indication. Until those data mature, the cardiovascular label language reflects the exploratory signal from SURPASS-4 rather than a confirmed outcome benefit.

What came after SURPASS

The SURMOUNT program was initiated in parallel to SURPASS, specifically to generate the evidence for the obesity indication that became Zepbound in 2023. SURMOUNT built directly on SURPASS's efficacy signals, noting that weight losses in T2DM populations were already large and hypothesizing that even larger reductions were achievable in participants with obesity but without diabetes.

As of the last review date, SURPASS-CVOT is the key open question for the T2DM indication. Results from that trial are anticipated to either confirm cardiovascular benefit (as liraglutide and semaglutide achieved in LEADER and SUSTAIN-6) or provide a more nuanced neutral outcome picture.