NCT03954834: SURPASS-1

A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone

Completed Phase 3 Results posted Last updated 20 October 2021

What this trial tests

Phase 3 trial testing Tirzepatide in Type 2 Diabetes Mellitus in 478 participants. Completed in 28 October 2020.

Timeline

3 June 2019

Primary endpoint
5 October 2020

28 October 2020

Quick facts

Lead sponsor	Eli Lilly and Company
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	478
Start date	3 June 2019
Primary completion	5 October 2020
Estimated completion	28 October 2020
Sites	53 locations across Japan, Mexico, Puerto Rico, United States, India

Drugs / interventions tested

• Tirzepatide (TIRZEPATIDE) — full drug profile →
• Placebo

Conditions studied

• Type 2 Diabetes Mellitus — all drugs for Type 2 Diabetes Mellitus →

Sponsor

Eli Lilly and Company — full company profile →

Who can join

18 and older, any sex, with Type 2 Diabetes Mellitus. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Hemoglobin A1c (HbA1c) Primary · Baseline, Week 40

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Prior Use of oral antihyperglycemic medication (OAM) (Yes, No) + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-1.87	± 0.094
10 mg Tirzepatide	-1.89	± 0.096
15 mg Tirzepatide	-2.07	± 0.098
Placebo	0.04	± 0.105

Change From Baseline in Body Weight Secondary · Baseline, Week 40

Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-7.0	± 0.52
10 mg Tirzepatide	-7.8	± 0.53
15 mg Tirzepatide	-9.5	± 0.54
Placebo	-0.7	± 0.57

Percentage of Participants With HbA1c Target Value of <7% Secondary · Week 40

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

Group	Value	95% CI
5 mg Tirzepatide	86.78
10 mg Tirzepatide	91.53
15 mg Tirzepatide	87.93
Placebo	19.64

Change From Baseline in Fasting Serum Glucose Secondary · Baseline, Week 40

Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-43.6	± 3.40
10 mg Tirzepatide	-45.9	± 3.45
15 mg Tirzepatide	-49.3	± 3.62
Placebo	12.9	± 4.00

Percentage of Participants With HbA1c Target Value of <5.7% Secondary · Week 40

Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

Group	Value	95% CI
5 mg Tirzepatide	33.88
10 mg Tirzepatide	30.51
15 mg Tirzepatide	51.72
Placebo	0.89

Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values Secondary · Baseline, Week 40

The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment\*Time (Type III sum of squares).

Morning Premeal - Fasting

Group	Value	95% CI
5 mg Tirzepatide	-46.9	± 2.09
10 mg Tirzepatide	-47.9	± 2.11
15 mg Tirzepatide	-45.7	± 2.23
Placebo	-9.2	± 2.53

Morning 2-hour Postmeal

Group	Value	95% CI
5 mg Tirzepatide	-69.5	± 3.41
10 mg Tirzepatide	-61.4	± 3.44
15 mg Tirzepatide	-68.9	± 3.66
Placebo	-11.6	± 4.12

Midday Premeal

Group	Value	95% CI
5 mg Tirzepatide	-43.5	± 2.80
10 mg Tirzepatide	-42.5	± 2.82
15 mg Tirzepatide	-42.7	± 3.00
Placebo	-2.6	± 3.42

Midday 2-hour Postmeal

Group	Value	95% CI
5 mg Tirzepatide	-64.2	± 3.60
10 mg Tirzepatide	-60.0	± 3.63
15 mg Tirzepatide	-63.4	± 3.84
Placebo	-12.7	± 4.33

Evening Premeal

Group	Value	95% CI
5 mg Tirzepatide	-44.8	± 2.80
10 mg Tirzepatide	-45.1	± 2.82
15 mg Tirzepatide	-42.3	± 3.02
Placebo	-5.8	± 3.38

Evening 2-hour Postmeal

Group	Value	95% CI
5 mg Tirzepatide	-61.9	± 3.76
10 mg Tirzepatide	-62.8	± 3.81
15 mg Tirzepatide	-63.5	± 4.03
Placebo	-10.3	± 4.52

Bedtime

Group	Value	95% CI
5 mg Tirzepatide	-57.0	± 3.49
10 mg Tirzepatide	-59.8	± 3.52
15 mg Tirzepatide	-60.8	± 3.66
Placebo	-9.1	± 4.10

Percentage of Participants Who Achieved Weight Loss ≥5% Secondary · Week 40

Percentage of Participants who Achieved Weight Loss ≥5%.

Group	Value	95% CI
5 mg Tirzepatide	66.94
10 mg Tirzepatide	77.97
15 mg Tirzepatide	76.72
Placebo	14.29

Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia Secondary · Baseline through end of safety follow-up (up to week 44)

The hypoglycemia events were defined by participant reported events with blood glucose \<54mg/dL) (\<3.0 mmol/L\] or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Prior Use o

Group	Value	95% CI
5 mg Tirzepatide	0.02	± 0.002
10 mg Tirzepatide	0.02	± 0.002
15 mg Tirzepatide	0.02	± 0.002
Placebo	0.04	± 0.028

Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide Secondary · Week 7, 15 and 23

Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide. AUC is a combined measure obtained from Week 7, 15 and 23, and a single averaged measure of AUC was reported.

Group	Value	95% CI
5 mg Tirzepatide	86900	± 25.4
10 mg Tirzepatide	171000	± 26.2
15 mg Tirzepatide	252000	± 23.3

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline to end of Safety follow-up (up to 44 weeks). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

5 mg Tirzepatide

Serious: 5/121 (4%)

Deaths: 0/121

10 mg Tirzepatide

Serious: 2/121 (2%)

Deaths: 0/121

15 mg Tirzepatide

Serious: 1/121 (1%)

Deaths: 0/121

Placebo

Serious: 3/115 (3%)

Deaths: 1/115

Serious adverse events (13 terms)

Reaction	System	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Acute myocardial infarction	Cardiac disorders	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—
Colitis ischaemic	Gastrointestinal disorders	—	—	—	—
Clostridium difficile infection	Infections and infestations	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Cholangiocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—
Nephrolithiasis	Renal and urinary disorders	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—	—	—

Other adverse events (10 terms — click to expand)

Reaction	System	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Influenza	Infections and infestations	—	—	—	—

Most-reported serious reactions: Acute myocardial infarction, Cardiac failure, Supraventricular tachycardia, Colitis ischaemic, Clostridium difficile infection, Pneumonia, Musculoskeletal chest pain, Adenocarcinoma.

Data from ClinicalTrials.gov NCT03954834 adverse events section.

Sponsor's own description

The goal for this study is to evaluate the efficacy and safety of tirzepatide versus placebo in participants with type 2 diabetes not under control with diet and exercise alone. The study will last approximately 47 weeks and may include about 15 visits.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.
   Rosenstock J, Wysham C, Frías JP, Kaneko S, et al · · 2021 · cited 675× · PMID 34186022 · DOI 10.1016/s0140-6736(21)01324-6
2. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis.
   Sattar N, McGuire DK, Pavo I, Weerakkody GJ, et al · · 2022 · cited 239× · PMID 35210595 · DOI 10.1038/s41591-022-01707-4
3. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis.
   Karagiannis T, Avgerinos I, Liakos A, Del Prato S, et al · · 2022 · cited 179× · PMID 35579691 · DOI 10.1007/s00125-022-05715-4
4. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials.
   Min T, Bain SC. · · 2021 · cited 176× · PMID 33325008 · DOI 10.1007/s13300-020-00981-0
5. Transforming obesity: The advancement of multi-receptor drugs.
   Kusminski CM, Perez-Tilve D, Müller TD, DiMarchi RD, et al · · 2024 · cited 77× · PMID 39059360 · DOI 10.1016/j.cell.2024.06.003
6. Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.
   Karagiannis T, Malandris K, Avgerinos I, Stamati A, et al · · 2024 · cited 64× · PMID 38613667 · DOI 10.1007/s00125-024-06144-1
7. Tirzepatide and prevention of chronic kidney disease.
   Bosch C, Carriazo S, Soler MJ, Ortiz A, et al · · 2023 · cited 46× · PMID 37151412 · DOI 10.1093/ckj/sfac274
8. Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Phase II/III Trials.
   Bhagavathula AS, Vidyasagar K, Tesfaye W. · · 2021 · cited 41× · PMID 34681215 · DOI 10.3390/ph14100991