Primary outcome
What SURPASS-4 measured first
| 10 mg Tirzepatiden=289 | 15 mg Tirzepatiden=291 | Insulin Glarginen=887 |
|---|---|---|
| -2.43(0.053) | -2.58(0.053) | -1.44(0.030) |
Phase 3 · Tirzepatide
SURPASS-4 trial results
Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)
Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) (Percentage of HbA1c), Baseline, Week 52. 10 mg Tirzepatide: -2.43; 15 mg Tirzepatide: -2.58; Insulin Glargine: -1.44.
- Participants
- 2,002
- Status
- completed
- Completed
- 2021-04-22
- Sponsor
- Eli Lilly and Company
As posted on ClinicalTrials.gov (NCT03730662), updated at source Feb 14, 2022. Read again whenever the registry updates it. Registry figures can differ from a published paper, which may use another analysis.
Side effects by arm
Side effects in SURPASS-4
Percent of participants affected, Baseline Up To 2 Years. The most common events the registry lists.
| Event | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Any serious event | 14.6% | 16.5% | 12.1% | 19.3% |
| Nausea | 11.9% | 16.2% | 22.5% | 2.3% |
| Diarrhoea | 12.5% | 19.8% | 21.9% | 4.4% |
| Decreased appetite | 8.8% | 11% | 10.4% | 0.5% |
| Vomiting | 4.9% | 8.2% | 8.6% | 1.5% |
| Dyspepsia | 5.5% | 8.2% | 7.7% | 1.3% |
| Nasopharyngitis | 3% | 4.9% | 4.7% | 6.5% |
| Lipase increased | 3% | 4% | 6.2% | 1.8% |
| Constipation | 5.2% | 4.3% | 4.1% | 0.5% |
| Covid-19 | 4% | 3.7% | 5% | 4.9% |
Secondary outcomes
What else it measured
| 5 mg Tirzepatiden=283 | Insulin Glarginen=887 |
|---|---|
| -2.24(0.053) | -1.44(0.030) |
| 5 mg Tirzepatiden=285 | 10 mg Tirzepatiden=288 | 15 mg Tirzepatiden=291 | Insulin Glarginen=891 |
|---|---|---|---|
| -7.1(0.34) | -9.5(0.34) | -11.7(0.33) | 1.9(0.19) |
| 5 mg Tirzepatiden=326 | 10 mg Tirzepatiden=321 | 15 mg Tirzepatiden=334 | Insulin Glarginen=978 |
|---|---|---|---|
| 80.98 | 88.16 | 90.72 | 50.72 |
| 5 mg Tirzepatiden=281 | 10 mg Tirzepatiden=283 | 15 mg Tirzepatiden=288 | Insulin Glarginen=880 |
|---|---|---|---|
| -50.4(2.07) | -54.9(2.06) | -59.3(2.04) | -51.4(1.17) |
| 5 mg Tirzepatiden=265 | 10 mg Tirzepatiden=261 | 15 mg Tirzepatiden=265 | Insulin Glarginen=784 |
|---|---|---|---|
| -58.4(1.65) | -61.1(1.66) | -66.1(1.66) | -46.1(0.96) |
| 5 mg Tirzepatiden=326 | 10 mg Tirzepatiden=324 | 15 mg Tirzepatiden=334 |
|---|---|---|
| 81800(23.9) | 165000(20.3) | 246000(20.6) |
| 5 mg Tirzepatiden=329 | 10 mg Tirzepatiden=328 | 15 mg Tirzepatiden=338 | Insulin Glarginen=1,000 |
|---|---|---|---|
| 0.10(0.023) | 0.09(0.025) | 0.11(0.030) | 0.35(0.044) |
The trial
How SURPASS-4 was run
The purpose of the trial is to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in participants with type 2 diabetes and increased cardiovascular risk. The study will last about 108 weeks and may include up to 30 visits.
- 5 mg Tirzepatide: 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.
- 10 mg Tirzepatide: 10 mg tirzepatide administered SC once a week.
- 15 mg Tirzepatide: 15 mg tirzepatide administered SC once a week.
- Insulin Glargine: Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG \<100 mg/dL, following a treat-to-target (TTT) algorithm.
Who could join the trial
Inclusion Criteria: Participants must: * Have been diagnosed with type 2 diabetes mellitus (T2DM) * Have HbA1c between ≥7.5% and ≤10.5% * Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening * Have increased risk for cardiovascular (CV) events * Be of stable weight (± 5%) * Have a BMI ≥25 kilograms per meter squared (kg/m2) at screening Exclusion Criteria Participants must not: * Have type 1 diabetes mellitus * Have had chronic or acute pancreatitis any time prior to study entry * Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment * Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss * Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level \>3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is ≤3.0 the ULN for the reference range * Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months * Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 * Have been taking any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months * Have been taking weight loss drugs, including over-the-counter medications during the last 3 months
Published papers
Papers from SURPASS-4
- De Block C, Peleshok J, Wilding JPH, Kwan AYM, Rasouli N, Maldonado JM, Wysham C, Liu M, Aleppo G, Benneyworth BD. Post Hoc Analysis of SURPASS-1 to -5: Efficacy and Safety of Tirzepatide in Adults with Type 2 Diabetes are Independent of Baseline Characteristics. Diabetes Ther. 2025 Jan;16(1):43-71. doi: 10.1007/s13300-024-01660-0. Epub 2024 Nov 12.
- Boye KS, Sapin H, Dong W, Williamson S, Lee CJ, Thieu VT. Improved Glycaemic and Weight Management Are Associated with Better Quality of Life in People with Type 2 Diabetes Treated with Tirzepatide. Diabetes Ther. 2023 Nov;14(11):1867-1887. doi: 10.1007/s13300-023-01457-7. Epub 2023 Sep 5.
- Boye KS, Thieu VT, Sapin H, Lee CJ, Lando LF, Brown K, Bray R, Wiese RJ, Patel H, Rodriguez A, Yu M. Patient-Reported Outcomes in People with Type 2 Diabetes Receiving Tirzepatide in the SURPASS Clinical Trial Programme. Diabetes Ther. 2023 Nov;14(11):1833-1852. doi: 10.1007/s13300-023-01451-z. Epub 2023 Aug 1.
- Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, Wiese RJ, Tuttle KR, Cherney DZI. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Nov;10(11):774-785. doi: 10.1016/S2213-8587(22)00243-1. Epub 2022 Sep 21.
- Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24.
- Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, Aizenberg D, Wynne AG, Riesmeyer JS, Heine RJ, Wiese RJ; SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021 Nov 13;398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7. Epub 2021 Oct 18.
Trial averages do not predict what one person will experience. Results are shown as the registry posts them, without interpretation.
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