What was the primary endpoint of SURPASS-3?

The primary endpoint was change from baseline HbA1c at 52 weeks. All three tirzepatide doses (5, 10, and 15 mg) were tested for superiority against insulin degludec.

How much weight did patients lose on tirzepatide compared to insulin?

Tirzepatide patients lost between 7.0 and 12.4 kg depending on dose. Insulin degludec patients gained 2.3 kg. The net separation ranged from about 9 to 15 kg across the three tirzepatide doses.

Was the insulin dose in SURPASS-3 high enough to be a fair comparison?

Yes. Insulin degludec was titrated to a fasting glucose target below 90 mg/dL, and the mean dose reached approximately 49 units/day by week 52. This aggressive titration made it a genuine best-effort comparison rather than a straw-man comparator.

How common were gastrointestinal side effects with tirzepatide?

Nausea affected 12% to 24% of tirzepatide patients in a dose-dependent pattern. Diarrhea occurred in 15% to 17%, and vomiting in 3% to 9%. Most episodes were mild to moderate and peaked during the dose-escalation phase.

Did SURPASS-3 measure cardiovascular outcomes?

No. SURPASS-3 was designed to measure glycemic and metabolic endpoints over 52 weeks. Cardiovascular outcome data for tirzepatide is being evaluated in the separate SURPASS-CVOT trial.

Were patients allowed to take other diabetes medications during the trial?

All participants were on metformin at baseline. About 32% were also on an SGLT2 inhibitor. Sulfonylureas were allowed in some cases but were associated with higher hypoglycemia rates in the tirzepatide arms.

Is tirzepatide a GLP-1 receptor agonist?

Tirzepatide is a dual GIP and GLP-1 receptor agonist, meaning it activates two incretin pathways rather than one. This dual mechanism may explain the larger A1C and weight effects compared to GLP-1-only agents, though head-to-head data comparing it to semaglutide comes from the SURPASS-2 trial, not SURPASS-3.

Who should still use basal insulin instead of tirzepatide?

Patients with very high A1C and catabolic symptoms (severe hyperglycemia with weight loss), those who cannot afford tirzepatide, and anyone with a contraindication to GLP-1 receptor agonists may be better served by basal insulin. The choice is individualized.

How does the injection schedule compare?

Tirzepatide is given once weekly. Insulin degludec is given once daily. Over a year, that is roughly 52 injections vs. 365 injections, a difference that matters for patient adherence and quality of life.

Has SURPASS-3 influenced treatment guidelines?

Yes. Data from SURPASS-3 and related trials contributed to the 2022 ADA/EASD consensus update, which now positions GLP-1 receptor agonists (and dual agonists like tirzepatide) ahead of basal insulin for most patients after metformin.

SURPASS-3 Trial: A Plain-English Overview of What It Established

By HealthRX Medical Team

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

At a glance

| Detail | Value | |---|---| | Trial name | SURPASS-3 | | N | 1,444 | | Population | Adults with T2D inadequately controlled on metformin (with or without an SGLT2 inhibitor) | | Intervention | Tirzepatide 5 mg, 10 mg, or 15 mg subcutaneous once weekly | | Comparator | Insulin degludec (titrated to fasting glucose <90 mg/dL) once daily | | Duration | 52 weeks | | Primary endpoint | Change from baseline in HbA1c at week 52 | | Key result | All tirzepatide doses were superior to insulin degludec for A1C reduction and produced weight loss vs. weight gain |

The Question SURPASS-3 Set Out to Answer

Before tirzepatide entered the picture, the standard step after metformin failure for many patients with type 2 diabetes was basal insulin. Insulin degludec (brand name Tresiba) is a long-acting insulin analog with a well-established safety record and consistent glucose-lowering effect. The question was straightforward: could a once-weekly injection of tirzepatide, a first-in-class dual GIP and GLP-1 receptor agonist, outperform a best-in-class basal insulin that was titrated aggressively to target?

This mattered because the comparison was not soft. Insulin degludec was not given at a fixed low dose. Investigators titrated it every week aiming for a fasting plasma glucose below 90 mg/dL, a strict target that pushed the insulin arm toward its ceiling of glycemic benefit.

Who Got Into the Trial

Eligible participants were 18 years or older with type 2 diabetes, an A1C between 7.0% and 10.5%, and a BMI of 25 kg/m² or higher. All were already taking metformin (at least 1 to 500 mg/day). Roughly 32% were also on an SGLT2 inhibitor at baseline, which is notable because it means a meaningful subset was on dual background therapy, reflecting real-world prescribing patterns.

Key exclusion criteria removed anyone with type 1 diabetes, a history of pancreatitis, or eGFR below 45 mL/min. Patients with a personal or family history of medullary thyroid carcinoma or MEN2 syndrome were also excluded, consistent with the class labeling for GLP-1 receptor agonists.

The enrolled population averaged about 57 years old with a mean baseline A1C of 8.17% and mean BMI of 33.5 kg/m². Roughly 56% were male. Mean diabetes duration was about 8.4 years. These numbers describe a population with established but not extreme disease, the kind of patients who commonly face the metformin-to-injectable decision in clinic.

What Each Group Received

Participants were randomized 1:1:1:1 into four arms:

Tirzepatide 5 mg once weekly (n = 358)
Tirzepatide 10 mg once weekly (n = 360)
Tirzepatide 15 mg once weekly (n = 359)
Insulin degludec once daily, titrated to target (n = 360)

All tirzepatide arms started at 2.5 mg weekly and escalated by 2.5 mg every four weeks until they reached their assigned dose. This slow ramp was designed to reduce gastrointestinal side effects. The insulin degludec arm started at 10 units/day with weekly titration guided by a treat-to-target algorithm. By week 52, the mean insulin dose reached approximately 49 units/day, confirming the titration was genuinely aggressive and not sandbagged.

The trial was open-label for practical reasons: tirzepatide is a weekly subcutaneous injection and insulin degludec is a daily one, making blinding impractical without sham injections. However, endpoint adjudication was blinded.

What Was Measured and How

The primary efficacy endpoint was change from baseline in HbA1c at 52 weeks. Secondary endpoints included body weight change, proportion of participants reaching A1C targets (<7% and <6.5%), fasting serum glucose, and seven-point self-monitored blood glucose profiles.

The HealthRX Efficacy-vs-Tradeoff Framework for SURPASS-3

To make sense of the results, it helps to evaluate them along two axes that matter to clinicians deciding between these agents: glycemic potency and metabolic cost. "Metabolic cost" here means unintended effects on weight, hypoglycemia risk, and injection burden. A drug that wins on both axes changes the clinical calculus differently than one that wins on only one.

| Axis | Tirzepatide (all doses) | Insulin Degludec | |---|---|---| | A1C reduction | 1.93% to 2.37% from baseline | 1.34% from baseline | | Weight trajectory | Lost 7.0 to 12.4 kg | Gained 2.3 kg | | Hypoglycemia rate (clinically significant, <54 mg/dL) | 0.4% to 1.1% | 7.5% | | Injection frequency | Once weekly | Once daily |

When a treatment wins on every row, the conversation shifts from "is the new drug better?" to "who still needs the old one?" That framing structures the clinical implications section below.

The Core Results

A1C Reductions

All three tirzepatide doses produced statistically superior A1C reductions compared to insulin degludec at 52 weeks (Ludvik et al., 2021):

| Arm | Baseline A1C | A1C Change | Estimated Treatment Difference vs. Degludec (95% CI) | |---|---|---|---| | Tirzepatide 5 mg | 8.17% | −1.93% | −0.59% (−0.73 to −0.45) | | Tirzepatide 10 mg | 8.19% | −2.20% | −0.86% (−1.00 to −0.72) | | Tirzepatide 15 mg | 8.21% | −2.37% | −1.04% (−1.17 to −0.90) | | Insulin degludec | 8.13% | −1.34% |, |

All p-values were <0.001 for superiority. The 15 mg dose delivered a full percentage point more A1C reduction than aggressively titrated basal insulin. That gap is clinically substantial.

The proportion reaching A1C <7% was 82% to 93% across tirzepatide arms compared to 61% in the insulin arm. For the stricter <6.5% target, the numbers were 71% to 86% with tirzepatide vs. 44% with degludec.

Body Weight

This is where the divergence was most striking. Tirzepatide produced dose-dependent weight loss:

5 mg: −7.0 kg
10 mg: −9.6 kg
15 mg: −12.4 kg

The insulin degludec group gained 2.3 kg, creating a net separation of roughly 9 to 15 kg between the two treatments. For patients with type 2 diabetes who commonly carry excess weight, this difference is not academic. It affects cardiovascular risk factors, joint health, sleep apnea severity, and medication burden.

Hypoglycemia

Clinically significant hypoglycemia (blood glucose <54 mg/dL) occurred in 0.4% to 1.1% of tirzepatide patients versus 7.5% of insulin degludec patients. The overall incidence of any hypoglycemia was roughly five to six times higher with insulin. Rates were higher in the subgroup of patients also taking sulfonylureas, a pattern seen across the entire SURPASS clinical development program.

Side Effects Worth Knowing About

Gastrointestinal events were the dominant adverse effect in the tirzepatide arms. Nausea occurred in 12% to 24% of tirzepatide patients (dose-dependent) vs. 2% with insulin. Diarrhea affected 15% to 17% in the tirzepatide groups vs. 4% with degludec. Vomiting occurred in 3% to 9% of tirzepatide patients.

Most GI events were mild to moderate and occurred during the dose-escalation phase. They generally subsided after 4 to 8 weeks at a stable dose. However, the discontinuation rate due to adverse events was higher with tirzepatide (4% to 7% across doses) compared to insulin degludec (2%), and GI complaints were the primary driver.

Injection site reactions were infrequent in both groups. There were no confirmed cases of pancreatitis in any arm. Amylase and lipase levels rose modestly with tirzepatide but without clinical sequelae, consistent with GLP-1 receptor agonist class effects reported in prior semaglutide trials.

Limitations the Authors Acknowledged

The open-label design is the most obvious limitation. Patients and investigators knew which treatment was being administered, which could influence reporting of subjective endpoints like nausea or treatment satisfaction. However, A1C and body weight are objective, laboratory-measured endpoints, reducing the risk of meaningful bias on the primary outcomes.

The 52-week duration, while substantial, does not answer questions about durability over multiple years. Basal insulin can be titrated indefinitely upward, while tirzepatide has a dose ceiling at 15 mg. Whether the glycemic advantage persists at year three or year five remains unclear.

The population was predominantly White (approximately 63%) with enrollment weighted toward Europe and North America. Representation of Black and Hispanic patients, who bear a disproportionate burden of type 2 diabetes in the United States, was limited.

Finally, this trial measured glycemic and metabolic surrogates. It was not powered for cardiovascular outcomes, which is why the ongoing SURPASS-CVOT trial (expected to read out in 2024-2026) exists.

What This Means for Clinical Practice

SURPASS-3 provided evidence that tirzepatide can replace the "after metformin, add basal insulin" reflex for many patients. The 2022 ADA/EASD consensus report already moved GLP-1 receptor agonists ahead of insulin in the treatment algorithm for most patients with type 2 diabetes, and SURPASS-3 data contributed to that shift.

Patients who stand to benefit most from choosing tirzepatide over basal insulin include those with obesity as a co-morbidity, those at high hypoglycemia risk (older adults, those living alone, people with variable meal schedules), and those who prefer weekly over daily injections.

Basal insulin remains the better choice when cost is prohibitive (insulin biosimilars are dramatically cheaper), when patients have very high A1C values (above 10%) with catabolic symptoms and may need the rapid glucose-lowering that only insulin provides, or when a patient has a contraindication to GLP-1 receptor agonists such as a personal or family history of medullary thyroid carcinoma.

The FDA approved tirzepatide (Mounjaro) for type 2 diabetes in May 2022, and SURPASS-3 was one of the key trials supporting that approval.

Frequently asked questions

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References

Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. PubMed
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503-515. PubMed
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375(19):1834-1844. PubMed
Tirzepatide (Mounjaro) prescribing information. U.S. Food and Drug Administration. 2022. FDA Label
Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the ADA and EASD. Diabetologia. 2022;65(12):1925-1966. PubMed
Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022;28(3):591-598. PubMed