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Mounjaro ® (tirzepatide) injection
2.5 mg/5 mg/7.5 mg/10 mg/12.5 mg/15 mg
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
What were the results of the SURPASS-5 study comparing Mounjaro® (tirzepatide) with placebo with background use of insulin glargine?
In patients with type 2 diabetes with titrated insulin, tirzepatide resulted in superior reduction in HbA1c, fasting glucose, and also weight; more participants reached an HbA1c <7.0% compared with placebo at 40 weeks.
See important safety information, including boxed warning, in the attached prescribing information.
SURPASS-5 Overview
Mounjaro (tirzepatide) is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2D) for once-weekly, subcutaneous administration.1
SURPASS-5 was a 40-week, phase 3, double-blind, randomized study of tirzepatide 5, 10, and 15 mg once weekly compared with placebo in 475 adults with T2D, as add-on to titrated insulin glargine with or without metformin.2
Key Inclusion and Exclusion Criteria
Inclusion criteria for this study were
- T2D
- glycated hemoglobin (HbA1c) ≥7.0% to ≤10.5% at screening
- body mass index (BMI) ≥23 kg/m2 with stable weight
- stable dose of once-daily insulin glargine (>0.25 IU/kg/day or >20 IU/day) with or without metformin in the 3 months prior to screening, and
- requirement for increased insulin glargine dose at randomization.2
Exclusion criteria for this study were
- type 1 diabetes (T1D)
- history of pancreatitis
- estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 (<45 mL/min/1.73m2 if on metformin), and
- history of proliferative diabetic retinopathy or maculopathy (or nonproliferative diabetic retinopathy requiring acute treatment).2
Study Design
The study randomized 475 study participants across the Czech Republic, Germany, Japan, Poland, Puerto Rico, Slovakia, Spain, and the United States in 1:1:1:1 ratio to receive either tirzepatide 5, 10, or 15 mg, or placebo as add-on to insulin glargine with or without metformin.2
The primary objective of this study was to demonstrate that tirzepatide 10 and/or 15 mg when added to titrated insulin glargine are superior compared with placebo for mean change from baseline in HbA1c to 40 weeks.2
The SURPASS-5 study design included a 40-week study period. The starting dose of tirzepatide was 2.5 mg once weekly for 4 weeks, escalated in 2.5 mg increments every 4 weeks until the assigned dose of 5, 10, or 15 mg was achieved, which took up to 20 weeks (SURPASS-5 Study Design). Insulin glargine was titrated in all arms during the insulin titration period from weeks 5 to 40 following a treat-to-target algorithm with the goal of fasting serum glucose (FSG) <100 mg/dL.2
Figure description: Study Period I: 1 week of screening and 2-week lead-in period. Study Period II: 40-week treatment period. The starting dose of tirzepatide was 2.5 mg once weekly for 4 weeks, escalated in 2.5 mg increments every 4 weeks until the assigned dose of 5, 10, or 15 mg was achieved. Placebo was given once weekly. Tirzepatide and placebo were given with once-daily insulin glargine ± metformin. Study Period III: 4-week safety follow-up period.
Abbreviation: QW = once weekly.
a Stabilization period = first 4 weeks after randomization, with restricted insulin dose adjustments. Insulin glargine titration period weeks 4 to 40 (end of treatment/end of study), with unrestricted insulin dose adjustments. Maintenance period = weeks 24 to 40 (end of treatment/end of study), the period when insulin glargine dose is expected to be stable.
Baseline Characteristics
Baseline demographics and clinical characteristics of randomized patients are presented in SURPASS-5: Baseline Demographics and Clinical Characteristics.2
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Placebo |
Age (y) |
62±10 |
60±10 |
61±10 |
60±10 |
Women, n (%) |
55 (47) |
47 (39) |
55 (46) |
54 (45) |
Men, n (%) |
61 (53) |
72 (61) |
65 (54) |
66 (55) |
Race, n (%) |
||||
American Indian or Alaska Native |
0 (0.0) |
1 (0.8) |
1 (0.8) |
0 (0.0) |
White |
95 (81.9) |
94 (79.7) |
94 (78.3) |
97 (81.5) |
Asian |
20 (17.2) |
21 (17.8) |
22 (18.3) |
22 (18.5) |
Black or African American |
1 (0.9) |
2 (1.7) |
3 (2.5) |
0 (0.0) |
Duration of diabetes (y) |
14.1±8.1 |
12.6±6.2 |
13.7±7.5 |
12.9±7.4 |
HbA1c (%) |
8.30±0.88 |
8.36±0.83 |
8.23±0.86 |
8.37±0.84 |
≤8.0%, n (%) |
52 (44.8) |
49 (41.5) |
52 (43.3) |
48 (40.0) |
>8.0%, n (%) |
64 (55.2) |
69 (58.5) |
68 (56.7) |
72 (60.0) |
FSG, mg/dL |
162.9±53.9 |
162.3±52.0 |
160.3±54.2 |
164.1±45.0 |
Using metformin, n (%) |
99 (85.3) |
99 (83.2) |
97 (80.8) |
99 (82.5) |
Insulin glargine dose, median (IQR) |
||||
IU |
30.0 (24.0-45.0) |
29.0 (22.0-43.0) |
32.0 (22.0-47.0) |
30.0 (23.0-44.5) |
IU/kg/day |
0.34 (0.28-0.46) |
0.32 (0.25-0.51) |
0.34 (0.26-0.49) |
0.36 (0.26-0.46) |
Weight (kg) |
95.8±19.8 |
94.5±22.2 |
96.3±22.8 |
94.1±21.8 |
BMI (kg/m2) |
33.6±5.9 |
33.4±6.2 |
33.4±5.9 |
33.2±6.3 |
Abbreviations: BMI = body mass index; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; IQR = interquartile range; mITT = modified intention-to-treat.
aData are mean±SD, unless otherwise specified; mITT population (all randomly assigned participants who took at least 1 dose of the study drug).
Discontinuation
Treatment discontinuation in SURPASS-5 is summarized in Summary of Treatment Discontinuation in SURPASS-5 . In all treatment groups, the most common reasons for study drug discontinuation were adverse events (AEs).2
Efficacy Results
Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data from the phase 3 clinical trials of tirzepatide. Efficacy estimand evaluates the treatment effect prior to discontinuation of the study drug without confounding effects of antihyperglycemic rescue therapy. Treatment-regimen estimand evaluates the treatment effect irrespective of adherence to the study drug or initiation of rescue antidiabetic drugs. Differences in reported data may reflect the application of these estimands. This response presents data reflecting the efficacy estimand. For treatment-regimen estimand results, please refer to the manuscript cited and/or the US prescribing information, where applicable.2
In the SURPASS-5 study at week 40, tirzepatide 5, 10, and 15 mg were superior compared with placebo in
- mean change in HbA1c
- mean change in FSG
- mean change in weight, and
- proportion of participants achieving HbA1c <7.0% (Key Efficacy Endpoints at Baseline and Week 40 in SURPASS-5).2
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Placebo |
HbA1c, % |
||||
Baseline |
8.29±0.08 |
8.34±0.08 |
8.22±0.08 |
8.39±0.08 |
Change from baseline |
-2.23±0.08 |
-2.59±0.08 |
-2.59±0.08 |
-0.93±0.08 |
Difference vs placebob |
-1.30 (-1.52, -1.07)** |
-1.66 (-1.88, -1.43)** |
-1.65 (-1.88, -1.43)** |
-- |
Proportion of participants achieving HbA1c goals, n (%) |
||||
<7.0%b |
107 (93.04)** |
110 (97.35)** |
110 (94.02)** |
40 (33.90) |
≤6.5%c |
92 (80.00)** |
107 (94.69)** |
108 (92.31)** |
20 (16.95) |
<5.7%d |
30 (26.09)** |
54 (47.79)** |
73 (62.39)** |
3 (2.54) |
FSG, mg/dL |
||||
Baseline |
162.2±4.81 |
162.9±4.79 |
160.4±4.75 |
164.4±4.75 |
Change from baseline |
-61.4±2.55 |
-67.9±2.55 |
-67.7±2.64 |
-38.9±2.49 |
Difference vs placebob |
-22.5 (-29.5, -15.4)** |
-29.0 (-36.0, -22.0)** |
-28.8 (-35.9, -21.6)** |
-- |
Body weight, kg |
||||
Baseline |
95.5±2.02 |
95.4±2.03 |
96.2±2.00 |
94.1±1.99 |
Change from baseline |
-6.2±0.58 |
-8.2±0.58 |
-10.9±0.59 |
1.7±0.57 |
Difference vs placebob |
-7.8 (-9.4, -6.3)** |
-9.9 (-11.5, -8.3)** |
-12.6 (-14.2, -11.0)** |
-- |
Proportion of participants achieving body weight loss, n (%) |
||||
≥5%c |
62 (53.91)** |
73 (64.60)** |
99 (84.62)** |
7 (5.93) |
≥10%c |
26 (22.61)** |
53 (46.90)** |
60 (51.28)** |
1 (0.85) |
≥15%c |
8 (6.96)* |
30 (26.55)* |
37 (31.62)** |
0 (0.00) |
Insulin glargineedose (IU/day) |
||||
Baseline |
34.3±1.45 |
32.0±1.34 |
35.0±1.46 |
32.9±1.36 |
Percent change from baseline |
13.0±7.34 |
8.1±7.03 |
-11.4±5.85 |
75.0±11.1 |
Difference vs placeboc |
-35.4 (-46.0, -22.8)** |
-38.2 (-48.3, -26.1)** |
-49.3 (-57.7, -39.4)** |
-- |
Abbreviations: FSG = fasting serum glucose; HbA1c = glycated hemoglobin; LSM = least squares mean; mITT = modified intention-to-treat; MMRM = mixed-effects model for repeated measures; TTT = treat-to-target.
Note: Efficacy estimand is efficacy prior to discontinuation of study drug without confounding effects of antihyperglycemic rescue therapy. Missing values were implicitly handled by MMRM using the mITT population, efficacy analysis set.
*p<0.05 and **p<0.001 vs placebo.
aData are LSM±SE, n (%), or LSM (95% CI) treatment difference vs placebo at 40 weeks.
bTested for superiority, controlled for type 1 error.
cTested for superiority, not controlled for type 1 error.
dTested for superiority; tirzepatide 10 mg and 15 mg versus placebo was controlled for type 1 error, while tirzepatide 5 mg was not controlled for type 1 error.
eInsulin glargine was titrated from week 5 through 40 using a TTT algorithm to reach target FSG <100 mg/dL.
Safety Results
The most frequently reported AEs for tirzepatide were gastrointestinal in nature. Most gastrointestinal events were mild to moderate in severity, usually occurred during the dose escalation period, and decreased overtime.2
Overview of AEs and treatment-emergent adverse events (TEAEs) with ≥5% frequency are provided in Overview of Adverse Events Through 40 Weeks in SURPASS-5 and Treatment-Emergent Adverse Events With ≥5% Frequency Through 40 Weeks in SURPASS-5.2
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Placebo |
Patients with ≥1 TEAE |
85 (73.3) |
81 (68.1) |
94 (78.3) |
81 (67.5) |
SAEb |
9 (7.8) |
13 (10.9) |
9 (7.5) |
10 (8.3) |
Death |
0 |
0 |
0 |
0 |
AEs leading to study drug discontinuation |
7 (6.0) |
10 (8.4) |
13 (10.8) |
3 (2.5) |
Abbreviations: AE = adverse event; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
aData are n (%); all randomly assigned patients exposed to at least 1 dose of the study drug with all data from the start of study treatment to the end of safety follow-up (safety analysis set). Patients may be counted in more than 1 category.
bSerious adverse event was defined as any adverse event that resulted in death, initial or prolonged inpatient hospitalization, a life-threatening experience, persistent or significant disability or incapacity, congenital anomaly or birth defect, or medical events that may not be immediately life-threatening or result in death or hospitalization but jeopardized the patient’s health or required intervention to prevent the previously listed events
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Placebo |
Diarrhea |
14 (12.1) |
15 (12.6) |
25 (20.8) |
12 (10.0) |
Nasopharyngitis |
18 (15.5) |
8 (6.7) |
15 (12.5) |
23 (19.2) |
Nausea |
15 (12.9) |
21 (17.6) |
22 (18.3) |
3 (2.5) |
Decreased appetite |
8 (6.9) |
15 (12.6) |
17 (14.2) |
2 (1.7) |
Vomiting |
8 (6.9) |
9 (7.6) |
15 (12.5) |
3 (2.5) |
Dyspepsia |
8 (6.9) |
10 (8.4) |
6 (5.0) |
2 (1.7) |
Constipation |
7 (6.0) |
8 (6.7) |
8 (6.7) |
2 (1.7) |
Back pain |
6 (5.2) |
6 (5.0) |
4 (3.3) |
7 (5.8) |
Hyperglycemia |
2 (1.7) |
0 (0.0) |
1 (0.8) |
16 (13.3) |
Eructation |
6 (5.2) |
4 (3.4) |
7 (5.8) |
1 (0.8) |
Lipase increased |
4 (3.4) |
2 (1.7) |
10 (8.3) |
2 (1.7) |
Flatulence |
3 (2.6) |
6 (5.0) |
7 (5.8) |
0 (0.0) |
Arthralgia |
6 (5.2) |
4 (3.4) |
3 (2.5) |
2 (1.7) |
Hypertension |
3 (2.6) |
3 (2.5) |
1 (0.8) |
7 (5.8) |
Abbreviation: TEAE = treatment-emergent adverse event.
aData are n (%) of TEAE with ≥5% frequency in any arm; safety analysis set. Patients may be counted in more than 1 category.
Hypoglycemia frequency is provided in Hypoglycemia Frequency Through 40 Weeks in SURPASS-5.
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Placebo |
Hypoglycemia (BG ≤70 mg/dL) |
70 (60.3) |
75 (63.0) |
72 (60.0) |
73 (60.8) |
Hypoglycemia (BG <54 mg/dL) |
18 (15.5) |
23 (19.3) |
17 (14.2) |
15 (12.5) |
Severe hypoglycemiab |
0 |
2 (1.6) |
1 (0.8) |
0 |
Abbreviation: BG = blood glucose.
aData are n (%); safety analysis set. Patients may be counted in more than 1 category. Data after initiation of new glucose-lowering therapy not included.
bEpisodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Enclosed Prescribing Information
References
The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).
1Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2023.
2Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-545. https://doi.org/10.1001/jama.2022.0078
3Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Date of Last Review: September 06, 2022