NCT03861052: SURPASS J-mono

A Study of Tirzepatide (LY3298176) Compared to Dulaglutide in Participants With Type 2 Diabetes

Completed Phase 3 Results posted Last updated 14 April 2022

What this trial tests

Phase 3 trial testing Tirzepatide in Type 2 Diabetes in 636 participants. Completed in 31 March 2021.

Timeline

7 May 2019

Primary endpoint
10 March 2021

31 March 2021

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	636
Start date	7 May 2019
Primary completion	10 March 2021
Estimated completion	31 March 2021
Sites	46 locations across Japan

Drugs / interventions tested

• Tirzepatide (TIRZEPATIDE) — full drug profile →
• Dulaglutide (DULAGLUTIDE) — full drug profile →

Conditions studied

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

Sponsor

Eli Lilly and Company — full company profile →

Who can join

20 and older, any sex, with Type 2 Diabetes. 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 52

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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-2.37	± 0.066
10 mg Tirzepatide	-2.55	± 0.067
15 mg Tirzepatide	-2.82	± 0.066
0.75 mg Dulaglutide	-1.29	± 0.065

Percentage of Participants With HbA1c of <7.0% Secondary · Week 52

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	93.67
10 mg Tirzepatide	96.79
15 mg Tirzepatide	99.37
0.75 mg Dulaglutide	67.30

Change From Baseline in Fasting Serum Glucose Secondary · Baseline, Week 52

Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-57.9	± 1.73
10 mg Tirzepatide	-64.6	± 1.76
15 mg Tirzepatide	-67.6	± 1.75
0.75 mg Dulaglutide	-31.9	± 1.73

Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values Secondary · Baseline, Week 52

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. LS mean was determined by analysis of covariance (ANCOVA) model for with Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment (Type III sum of squares) as variables.

Group	Value	95% CI
5 mg Tirzepatide	-59.5	± 1.46
10 mg Tirzepatide	-64.2	± 1.50
15 mg Tirzepatide	-68.6	± 1.50
0.75 mg Dulaglutide	-42.2	± 1.48

Change From Baseline in Body Weight Secondary · Baseline, Week 52

Change from baseline in body weight. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-5.8	± 0.41
10 mg Tirzepatide	-8.5	± 0.42
15 mg Tirzepatide	-10.7	± 0.41
0.75 mg Dulaglutide	-0.5	± 0.41

Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline Secondary · Week 52

Percentage of participants who achieve weight loss ≥5% from baseline.

Group	Value	95% CI
5 mg Tirzepatide	60.76
10 mg Tirzepatide	82.05
15 mg Tirzepatide	89.31
0.75 mg Dulaglutide	10.69

Change From Baseline in Fasting Insulin Secondary · Baseline, Week 52

Fasting Insulin is a test used to measure the amount of insulin in the body. LS mean was determined by MMRM model for post-baseline measures with log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.

Group	Value	95% CI
5 mg Tirzepatide	-1.07	± 0.374
10 mg Tirzepatide	-1.87	± 0.344
15 mg Tirzepatide	-2.00	± 0.335
0.75 mg Dulaglutide	1.40	± 0.482

Change From Baseline in Fasting C-Peptide Secondary · Baseline, Week 52

Fasting C-peptide is a test used to measure the amount of C-peptide in the body. A high level of C-peptide can mean that body is making too much insulin. LS mean was determined by MMRM model for post-baseline measures: log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	-0.25	± 0.045
10 mg Tirzepatide	-0.39	± 0.042
15 mg Tirzepatide	-0.37	± 0.042
0.75 mg Dulaglutide	0.01	± 0.052

Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) Secondary · Baseline, Week 52

HOMA-2B is an estimated steady state beta cell function based on updated HOMA2 model. The HOMA2 model estimates steady state pancreatic beta cell function (%B) as a percentage of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement/Baseline) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	38.5	± 2.15
10 mg Tirzepatide	43.0	± 2.38
15 mg Tirzepatide	46.3	± 2.44
0.75 mg Dulaglutide	22.4	± 1.66

Change From Baseline in HOMA-2S (Insluin) Secondary · Baseline, Week 52

HOMA2-S is an estimated insulin sensitivity based on updated HOMA2 model. The HOMA2 model is a computer model that estimates insulin sensitivity (%S) as percentages of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).

Group	Value	95% CI
5 mg Tirzepatide	14.5	± 3.38
10 mg Tirzepatide	21.6	± 3.83
15 mg Tirzepatide	25.7	± 3.95
0.75 mg Dulaglutide	-5.4	± 2.52

Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia Secondary · Baseline through Week 52

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 for post-baseline comparisons between treatment and control group: number of episodes = bas

Group	Value	95% CI
5 mg Tirzepatide	0
10 mg Tirzepatide	0
15 mg Tirzepatide	0.012
0.75 mg Dulaglutide	0

Number of Participants With Anti-Tirzepatide Antibodies Secondary · Baseline through Week 52

Number of participants with anti-tirzepatide antibodies. A participant is treatment emergent (TE) anti-drug antibody (ADA) evaluable if there is at least one non-missing test result for tirzepatide ADA for each of the baseline period and the postbaseline period. All percentages are relative to the total number of TE ADA evaluable participants in each treatment group. A TE ADA evaluable participant is considered to be TE ADA+ if the participant has at least one postbaseline titer that is a 4-fold or greater increase in titer from baseline measurement.

Group	Value	95% CI
5 mg Tirzepatide	97
10 mg Tirzepatide	102
15 mg Tirzepatide	123
0.75 mg Dulaglutide	8

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline through Week 52. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

5 mg Tirzepatide

Serious: 8/159 (5%)

Deaths: 0/159

10 mg Tirzepatide

Serious: 10/158 (6%)

Deaths: 0/158

15 mg Tirzepatide

Serious: 7/160 (4%)

Deaths: 0/160

0.75 mg Dulaglutide

Serious: 14/159 (9%)

Deaths: 0/159

Serious adverse events (43 terms)

Reaction	System	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	0.75 mg Dulaglutide
Covid-19 pneumonia	Infections and infestations	—	—	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—
Angina unstable	Cardiac disorders	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—
Cataract	Eye disorders	—	—	—	—
Duodenal ulcer	Gastrointestinal disorders	—	—	—	—
Gastric ulcer	Gastrointestinal disorders	—	—	—	—
Gastric ulcer haemorrhage	Gastrointestinal disorders	—	—	—	—
Inguinal hernia	Gastrointestinal disorders	—	—	—	—
Large intestine polyp	Gastrointestinal disorders	—	—	—	—
Rectal polyp	Gastrointestinal disorders	—	—	—	—
Cholangitis	Hepatobiliary disorders	—	—	—	—
Cholangitis acute	Hepatobiliary disorders	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—
Appendicitis	Infections and infestations	—	—	—	—
Atypical pneumonia	Infections and infestations	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—
Infectious pleural effusion	Infections and infestations	—	—	—	—
Periodontitis	Infections and infestations	—	—	—	—
Pyelitis	Infections and infestations	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—
Acetabulum fracture	Injury, poisoning and procedural complications	—	—	—	—
Clavicle fracture	Injury, poisoning and procedural complications	—	—	—	—

Other adverse events (349 terms — click to expand)

Reaction	System	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	0.75 mg Dulaglutide
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—	—
Injection site reaction	General disorders	—	—	—	—
Lipase increased	Investigations	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Amylase increased	Investigations	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—	—
Cystitis	Infections and infestations	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Malaise	General disorders	—	—	—	—
Gallbladder polyp	Hepatobiliary disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—
Pancreatic enzymes increased	Investigations	—	—	—	—
Weight decreased	Investigations	—	—	—	—
Eczema	Skin and subcutaneous tissue disorders	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—
Urticaria	Skin and subcutaneous tissue disorders	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—
Dry eye	Eye disorders	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—
Dental caries	Gastrointestinal disorders	—	—	—	—
Gingivitis	Infections and infestations	—	—	—	—
Herpes zoster	Infections and infestations	—	—	—	—
Influenza	Infections and infestations	—	—	—	—
Periarthritis	Musculoskeletal and connective tissue disorders	—	—	—	—
Dermatitis contact	Skin and subcutaneous tissue disorders	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—

Most-reported serious reactions: Covid-19 pneumonia, Prostate cancer, Acute myocardial infarction, Angina unstable, Cardiac failure, Myocardial infarction, Cataract, Duodenal ulcer.

Data from ClinicalTrials.gov NCT03861052 adverse events section.

Sponsor's own description

The reason for this study is to see if the study drug tirzepatide (LY3298176) is effective and safe compared to dulaglutide in participants with type 2 diabetes in Japan.

Publications & conference data

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

1. 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
2. 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
3. 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
4. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial.
   Inagaki N, Takeuchi M, Oura T, Imaoka T, et al · · 2022 · cited 147× · PMID 35914543 · DOI 10.1016/s2213-8587(22)00188-7
5. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy.
   Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, et al · · 2022 · cited 83× · PMID 35552683 · DOI 10.1210/endrev/bnab034
6. 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
7. 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
8. 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