SURPASS-4

CompletedPhase 3Results posted

A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk

Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Lead sponsor

Eli Lilly and Company

Asset

Tirzepatide

Subcutaneous · GLP-1 / GIP dual

Listed sites

216

Recruiting sites

—

Enrollment

2,002

actual

Study population

Cardiovascular disease, Type 2 diabetes

Key I/E criteria

•BMI ≥25•HbA1c 7.5-10.5%

Primary endpoint

•HbA1c, change

Footprint

Where this trial recruits

Site locations as reported to ClinicalTrials.gov. Site count is not enrollment count; per-site enrollment is not available from source.

Identifiers

Registered as

NCT IDNCT03730662

Org study ID17072

Secondary ID2018-002618-11

Secondary IDI8F-MC-GPGMEli Lilly and Company

Timeline

Milestones

Study first posted2018-11-05actual

Study start2018-11-20actual

Primary completion2021-01-22actual

Study completion2021-04-22actual

Last update posted2022-02-14actual

Results first posted2022-02-14actual

Assets

Investigational agents

Tirzepatide

Study populations

Who this study enrolls

Cardiovascular diseaseType 2 diabetes

Eligibility

Who can enroll

Minimum age18 Years

SexAll

Healthy volunteersNot accepted

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

Endpoints (16)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Glycemic / diabetes

Safety / tolerability / PK

Weight & body composition

2 endpoints

Secondary/registry result

Change From Baseline in Body Weight

Time frame:Baseline, Week 52

Body weight, absolute change (kg)

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), Kilograms (kg)	95% CI
5 mg Tirzepatide	-7.1	—
10 mg Tirzepatide	-9.5	—
15 mg Tirzepatide	-11.7	—
Insulin Glargine	1.9	—

Mean Difference (Net)-9.095% CI-9.8 – -8.3p<0.001Mixed Models Analysis

Mean Difference (Net)-11.495% CI-12.1 – -10.6p<0.001Mixed Models Analysis

Mean Difference (Net)-13.595% CI-14.3 – -12.8p<0.001Mixed Models Analysis

Secondary/protocol endpoint

Change From Baseline in Body Weight

Time frame:Baseline, Week 52

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

10 endpoints

Primary/registry result

Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Time frame:Baseline, Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

Group	Value (least_squares_mean), Percentage of HbA1c	95% CI
10 mg Tirzepatide	-2.43	—
15 mg Tirzepatide	-2.58	—
Insulin Glargine	-1.44	—

Mean Difference (Net)-0.9997.5% CI-1.13 – -0.86p<0.001Mixed Models Analysis

Mean Difference (Net)-1.1497.5% CI-1.28 – -1.00p<0.001Mixed Models Analysis

Primary/protocol endpoint

Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)

Time frame:Baseline, Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Secondary/registry result

Change From Baseline in HbA1c (5 mg)

Time frame:Baseline, Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

Group	Value (least_squares_mean), Percentage of HbA1c	95% CI
5 mg Tirzepatide	-2.24	—
Insulin Glargine	-1.44	—

Mean Difference (Net)-0.8097.5% CI-0.93 – -0.66p<0.001Mixed Models Analysis

Secondary/registry result

Percentage of Participants With HbA1c of <7.0%

Time frame:Week 52

HbA1c <7.0% achievement

threshold achievement, improvement

LOINC 4548-4

Posted result

Group	Value (number), percentage of participants	95% CI
5 mg Tirzepatide	80.98	—
10 mg Tirzepatide	88.16	—
15 mg Tirzepatide	90.72	—
Insulin Glargine	50.72	—

Odds Ratio (OR)4.7895% CI3.47 – 6.58p<0.001Regression, Logistic

Odds Ratio (OR)9.2395% CI6.31 – 13.49p<0.001Regression, Logistic

Odds Ratio (OR)11.8795% CI7.88 – 17.89p<0.001Regression, Logistic

Secondary/registry result

Change From Baseline in Fasting Serum Glucose

Time frame:Baseline, Week 52

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Posted result

Group	Value (least_squares_mean), milligram per Deciliter (mg/dL)	95% CI
5 mg Tirzepatide	-50.4	—
10 mg Tirzepatide	-54.9	—
15 mg Tirzepatide	-59.3	—
Insulin Glargine	-51.4	—

Mean Difference (Net)1.095% CI-3.7 – 5.7p0.672Mixed Models Analysis

Mean Difference (Net)-3.695% CI-8.2 – 1.1p0.134Mixed Models Analysis

Mean Difference (Net)-8.095% CI-12.6 – -3.4p<0.001Mixed Models Analysis

Secondary/registry result

Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Time frame:Baseline, Week 52

change from baseline, improvement

Posted result

Group	Value (least_squares_mean), mg/dL	95% CI
5 mg Tirzepatide	-58.4	—
10 mg Tirzepatide	-61.1	—
15 mg Tirzepatide	-66.1	—
Insulin Glargine	-46.1	—

Secondary/protocol endpoint

Change From Baseline in HbA1c (5 mg)

Time frame:Baseline, Week 52

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Secondary/protocol endpoint

Percentage of Participants With HbA1c of <7.0%

Time frame:Week 52

HbA1c <7.0% achievement

threshold achievement, improvement

LOINC 4548-4

Secondary/protocol endpoint

Change From Baseline in Fasting Serum Glucose

Time frame:Baseline, Week 52

Fasting glucose, change

change from baseline, improvement

LOINC 1558-6

Secondary/protocol endpoint

Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values

Time frame:Baseline, Week 52

change from baseline, improvement

Safety / tolerability / PK

4 endpoints

Secondary/registry result

Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide

Time frame:1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35

AUC₀–∞

concentration, descriptive

Posted result

Group	Value (geometric_mean), Nanograms per millilitre per hour	95% CI
5 mg Tirzepatide	81800	—
10 mg Tirzepatide	165000	—
15 mg Tirzepatide	246000	—

Secondary/registry result

Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia

Time frame:Baseline through Week 52

Documented hypoglycemia

event count, event

componentsDocumented hypoglycemia, Severe hypoglycemia

Posted result

Group	Value (mean), Episodes/participant/365.25 days	95% CI
5 mg Tirzepatide	0.10	—
10 mg Tirzepatide	0.09	—
15 mg Tirzepatide	0.11	—
Insulin Glargine	0.35	—

Secondary/protocol endpoint

Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide

Time frame:1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35

AUC₀–∞

concentration, descriptive

Secondary/protocol endpoint

Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia

Time frame:Baseline through Week 52

Documented hypoglycemia

event count, event

componentsDocumented hypoglycemia, Severe hypoglycemia

Publications (9)

Bibliography

Records linked to this trial through ClinicalTrials.gov references, PubMed NCT search, and curated study seeds. 'Canonical' marks design/result papers; others are registry references or candidates.

Registry references + supporting bibliography

Long-term efficacy and safety of tirzepatide in participants with type 2 diabetes with inadequate glycaemic control on metformin and/or sulfonylurea: Post-hoc analysis of SURPASS-4.
Diabetes, obesity & metabolism2025 Nov (month)PMID40926359doi:10.1111/dom.70047via pubmed nct search
Tirzepatide for Older Adults with Type 2 Diabetes and Without Obesity: A Post Hoc Analysis of the SURPASS Clinical Trials.
Diabetes therapy : research, treatment and education of diabetes and related disorders2025 Apr (month)PMID40016573doi:10.1007/s13300-025-01711-0via pubmed nct search
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 therapy : research, treatment and education of diabetes and related disorders2025 Jan (month)PMID39531161doi:10.1007/s13300-024-01660-0via clinicaltrials gov reference derived + pubmed nct search
Patient-Reported Outcomes in People with Type 2 Diabetes Receiving Tirzepatide in the SURPASS Clinical Trial Programme.
Diabetes therapy : research, treatment and education of diabetes and related disorders2023 Nov (month)PMID37526908doi:10.1007/s13300-023-01451-zvia clinicaltrials gov reference derived + pubmed nct search
Improved Glycaemic and Weight Management Are Associated with Better Quality of Life in People with Type 2 Diabetes Treated with Tirzepatide.
Diabetes therapy : research, treatment and education of diabetes and related disorders2023 Nov (month)PMID37668888doi:10.1007/s13300-023-01457-7via clinicaltrials gov reference derived + pubmed nct search
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.
The lancet. Diabetes & endocrinology2022 Nov (month)PMID36152639doi:10.1016/S2213-8587(22)00243-1via clinicaltrials gov reference derived + pubmed nct search
Tirzepatide-Friend or Foe in Diabetic Cancer Patients?
Biomolecules2022 Oct 28PMID36358930doi:10.3390/biom12111580via pubmed nct search
Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis.
Nature medicine2022 Mar (month)PMID35210595doi:10.1038/s41591-022-01707-4via clinicaltrials gov reference derived + pubmed nct search
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 (London, England)2021 Nov 13PMID34672967doi:10.1016/S0140-6736(21)02188-7via clinicaltrials gov reference derived + pubmed nct search

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 1, 2026

Endpoint classificationDelfa endpoint taxonomy v2 (May 13, 2026)

Results tableClinicalTrials.gov results section

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 1, 2026 snapshot.