SURPASS Trials: Tirzepatide's Diabetes Results
GLP-1 and Diabetes
97%
Up to 97% of participants taking tirzepatide 15 mg achieved HbA1c below 7% in the SURPASS program, and up to 62% reached below 5.7%, the normal non-diabetic range.
Frias et al., Expert Rev Endocrinol Metab, 2023
Frias et al., Expert Rev Endocrinol Metab, 2023
View as imageThe SURPASS clinical development program tested tirzepatide across six phase 3 randomized controlled trials in type 2 diabetes, enrolling thousands of patients against comparators including placebo, semaglutide 1 mg, insulin degludec, insulin glargine, and insulin lispro. Every trial met its primary endpoint. The HbA1c reductions were larger than anything previously reported for an injectable diabetes drug. These results led to FDA approval of Mounjaro (tirzepatide) for type 2 diabetes in May 2022. For the broader picture of how GLP-1 drugs lower blood sugar, see our overview of GLP-1 agonists for type 2 diabetes.
Key Takeaways
- SURPASS-1: Tirzepatide 15 mg reduced HbA1c by 2.07% vs placebo over 40 weeks in drug-naive patients (Rosenstock et al., 2021)
- SURPASS-2: Tirzepatide 15 mg reduced HbA1c by 2.30% vs 1.86% for semaglutide 1 mg, establishing superiority over the leading GLP-1 agonist (Frias et al., 2021)
- SURPASS-5: Added to insulin glargine, tirzepatide 15 mg reduced HbA1c by 2.59% vs 0.93% for placebo (Dahl et al., 2022)
- Up to 62% of participants on tirzepatide 15 mg achieved HbA1c below 5.7%, a level considered normal and non-diabetic (Frias et al., 2023)
- Tirzepatide improved beta-cell function by 2.3-fold and insulin sensitivity by 2-fold at the 15 mg dose compared to placebo (Thomas et al., 2021)
- Weight loss was a consistent secondary finding across all trials: 5.4 to 12.9 kg depending on dose and trial, substantially more than comparators
What tirzepatide is: a dual-receptor peptide
Tirzepatide is not a standard GLP-1 receptor agonist. It is an acylated 39-amino-acid peptide that activates both the GIP (glucose-dependent insulinotropic polypeptide) receptor and the GLP-1 receptor simultaneously.[1] This dual mechanism is why Eli Lilly called it a "twincretin." GIP and GLP-1 are both incretin hormones released from the gut after eating. They both stimulate insulin secretion, but through different receptors on different cell populations.
The GIP component adds something that GLP-1-only drugs miss. GIP receptors are expressed on pancreatic beta cells, adipose tissue, and bone. GIP signaling appears to enhance tirzepatide's insulin-secreting effects and may contribute to the preferential fat loss (rather than lean mass loss) observed in some analyses.[2]
For understanding how tirzepatide compares mechanistically to semaglutide's A1c reduction, the dual-receptor mechanism is the central difference.
SURPASS-1: tirzepatide vs placebo (treatment-naive patients)
The first SURPASS trial established baseline efficacy in the cleanest population: adults with type 2 diabetes not currently on any injectable diabetes medication, with background metformin permitted. Published in The Lancet (2021), it randomized 478 patients to tirzepatide 5 mg, 10 mg, or 15 mg weekly, or placebo.[3]
At 40 weeks, HbA1c reductions from baseline:
- Tirzepatide 5 mg: -1.87%
- Tirzepatide 10 mg: -1.89%
- Tirzepatide 15 mg: -2.07%
- Placebo: -0.04%
All doses were superior to placebo. The 15 mg dose brought mean HbA1c from approximately 7.9% at baseline to 5.8%, essentially normalizing blood sugar in a population of type 2 diabetes patients. Weight loss at 40 weeks ranged from 7.0 kg (5 mg) to 9.5 kg (15 mg).
The finding that treatment-naive patients could achieve near-normal HbA1c on tirzepatide monotherapy (with or without metformin) set the stage for the more challenging comparator trials that followed.
SURPASS-2: the head-to-head that changed the field
SURPASS-2 is the trial that established tirzepatide as a potential best-in-class diabetes therapy. Published in The New England Journal of Medicine (2021), it directly compared tirzepatide to semaglutide 1 mg (the highest approved dose for diabetes at the time) in 1,879 patients on metformin background therapy.[4]
At 40 weeks, HbA1c reductions:
- Tirzepatide 5 mg: -2.01%
- Tirzepatide 10 mg: -2.24%
- Tirzepatide 15 mg: -2.30%
- Semaglutide 1 mg: -1.86%
All three tirzepatide doses were statistically superior to semaglutide 1 mg for HbA1c reduction. The 15 mg dose achieved a treatment difference of -0.45% over semaglutide, a clinically meaningful margin.
Weight loss told a similar story:
- Tirzepatide 5 mg: -7.6 kg
- Tirzepatide 10 mg: -9.3 kg
- Tirzepatide 15 mg: -11.2 kg
- Semaglutide 1 mg: -5.7 kg
The 15 mg dose produced nearly double the weight loss of semaglutide 1 mg. This NEJM publication was the data point that positioned tirzepatide as potentially superior to the established GLP-1 agonist standard.
A caveat: SURPASS-2 compared to semaglutide 1 mg. The 2.4 mg dose used for obesity (Wegovy) was not the comparator. The diabetes-indication dose of semaglutide is lower than the weight-loss dose, so the comparison reflects the diabetes treatment landscape, not the maximum potential of semaglutide.
SURPASS-5: added to insulin glargine
SURPASS-5 tested tirzepatide as an add-on to titrated basal insulin (insulin glargine), the scenario where patients already on insulin are not reaching target HbA1c. Published in JAMA (2022), it randomized patients already taking insulin glargine (with or without metformin) to tirzepatide or placebo.[5]
At 40 weeks, HbA1c reductions:
- Tirzepatide 5 mg: -2.11%
- Tirzepatide 10 mg: -2.40%
- Tirzepatide 15 mg: -2.59%
- Placebo: -0.93%
The 2.59% HbA1c reduction at the 15 mg dose was the largest observed in the entire SURPASS program. Adding tirzepatide to basal insulin produced dramatic glycemic improvement in patients who were already on insulin and still above target, a population that historically responds poorly to additional treatments.
Weight loss was also notable: patients on tirzepatide 15 mg lost 10.9 kg despite already being on insulin, which typically promotes weight gain. The placebo group gained 1.6 kg.
SURPASS-AP-Combo: the Asia-Pacific trial
Gao and colleagues (2023) published the SURPASS-AP-Combo trial in Nature Medicine, comparing tirzepatide to insulin glargine in insulin-naive adults with type 2 diabetes in the Asia-Pacific region.[6]
This trial is significant because type 2 diabetes presents differently in Asian populations (lower BMI at diagnosis, higher beta-cell dysfunction relative to insulin resistance). The results confirmed tirzepatide's superiority over insulin glargine for both HbA1c reduction and weight loss in this population, demonstrating that the SURPASS results generalize across ethnic and metabolic phenotypes.
Beta-cell function: why tirzepatide may preserve the pancreas
Thomas et al. (2021) conducted a mechanistic substudy showing that tirzepatide improved beta-cell function by 2.3-fold and insulin sensitivity by 2-fold at the 15 mg dose compared to placebo.[7]
This finding is more significant than it might appear. Type 2 diabetes is driven by progressive beta-cell failure. Most diabetes drugs manage the consequences (high blood sugar) without addressing the underlying cause (dying beta cells). If tirzepatide genuinely improves beta-cell function, not just stimulates existing beta cells harder, it could alter the disease trajectory. The mechanism appears to involve reduced glucotoxicity (lower blood sugar reduces stress on beta cells) and possibly direct GIP-mediated trophic effects on beta-cell mass.
For more on whether GLP-1 drugs protect the pancreas long-term, see GLP-1 agonists and beta-cell function.
Beyond blood sugar: metabolic effects
Lipid improvements
Pirro et al. (2022) analyzed tirzepatide's effects on lipid and metabolite profiles from the SURPASS-3 trial.[8] Tirzepatide improved triglycerides, VLDL cholesterol, and apolipoprotein concentrations beyond what would be expected from glycemic improvement alone. The metabolomic analysis revealed shifts in branched-chain amino acids and lipid species that suggest improved metabolic health independent of weight loss.
Appetite and energy intake
Heise et al. (2023) published a secondary analysis showing tirzepatide reduced appetite, ad libitum energy intake, and preferentially reduced fat mass in people with type 2 diabetes.[9] Energy intake decreased by approximately 22% at the 15 mg dose. The fat mass reduction was proportionally greater than lean mass reduction, suggesting the weight loss from tirzepatide is metabolically favorable.
Cardiovascular outcomes
The SURPASS-4 trial was a cardiovascular outcomes trial comparing tirzepatide to insulin glargine in patients with type 2 diabetes and established cardiovascular disease. Nicholls et al. (2025) published the cardiovascular outcome data showing tirzepatide was non-inferior to dulaglutide for major adverse cardiovascular events, with signals suggesting potential cardiovascular benefit that awaits further confirmation in dedicated outcomes trials.[10]
The SURMOUNT crossover: from diabetes to obesity
The SURMOUNT program tested tirzepatide specifically for obesity (with or without diabetes). SURMOUNT-2, published in The Lancet (2023), tested tirzepatide in people with obesity and type 2 diabetes, bridging the SURPASS and SURMOUNT programs.[11]
At 72 weeks, tirzepatide 15 mg produced 14.7% body weight reduction in this population. The HbA1c improvements paralleled the SURPASS results. This trial demonstrated that tirzepatide produces substantial metabolic benefit whether the primary treatment indication is diabetes or obesity.
Side effects across the program
Gastrointestinal adverse events were the most common across all SURPASS trials: nausea, diarrhea, and vomiting, occurring primarily during dose titration and generally decreasing over time. The incidence was dose-dependent, with the 15 mg group experiencing the highest rates.[1]
Hypoglycemia was rare except in trials where tirzepatide was combined with insulin (SURPASS-5 and SURPASS-6), where the insulin dose, not the tirzepatide, was the primary driver of low blood sugar events.
Discontinuation rates due to adverse events ranged from 3% to 7% across tirzepatide doses in the SURPASS program, comparable to or lower than rates seen with GLP-1 agonists alone.
For a detailed breakdown of GLP-1 side effects and what to expect during dose titration, see our dedicated article. For readers comparing GLP-1 agonists to insulin or GLP-1 to metformin, the SURPASS data provides the most rigorous comparison framework available.
What the SURPASS program does not answer
Durability. The longest SURPASS trial was 52 weeks. Whether tirzepatide's HbA1c-lowering effect persists beyond 1-2 years, or whether tachyphylaxis occurs, is not established by the phase 3 program. Open-label extensions are ongoing.
What happens when you stop. Data on HbA1c and weight rebound after tirzepatide discontinuation is limited. Early data suggests both blood sugar and weight return toward baseline after stopping, consistent with GLP-1 agonist class behavior. Whether the beta-cell improvements persist after discontinuation is unknown.
Comparison to semaglutide 2.4 mg. SURPASS-2 compared to semaglutide 1 mg (diabetes dose). A head-to-head against semaglutide 2.4 mg (the weight-loss dose) has not been conducted. This limits the ability to compare the two drugs at their maximum potencies.
Long-term safety. The SURPASS program provides 40-52 weeks of randomized safety data. Post-marketing surveillance and real-world studies are adding to this, but the long-term safety profile (5+ years) is not yet established.
Cost-effectiveness. Tirzepatide is priced as a premium biologic. Whether the incremental HbA1c benefit over semaglutide or insulin justifies the incremental cost depends on payer perspective, patient outcomes, and health system context.
The Bottom Line
The SURPASS clinical program demonstrated that tirzepatide produces the largest HbA1c reductions reported for any injectable diabetes therapy, up to 2.59% at the 15 mg dose when added to insulin glargine. It proved superior to semaglutide 1 mg in SURPASS-2 and superior to insulin in multiple comparator trials. Weight loss (5-13 kg), lipid improvements, and beta-cell function enhancement were consistent secondary findings. Gastrointestinal side effects were the primary tolerability concern. The 40-52 week trial durations leave questions about long-term durability and what happens after discontinuation.