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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.
How did Mounjaro® (tirzepatide) compare with insulin glargine as add-on therapy in SURPASS-4 in adults with T2D and high cardiovascular risk?
In SURPASS-4, tirzepatide was superior to insulin glargine in reduction in HbA1c and weight at week 52. Mounjaro is not approved to reduce the risk of MACE. Mounjaro is not a weight loss drug, and individual results may vary.
See important safety information, including boxed warning, in the attached prescribing information.
Content Overview
SURPASS-4 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-4 was a 52-week, phase 3, open-label, parallel-group, randomized study comparing tirzepatide 5, 10, and 15 mg once weekly with titrated insulin glargine once daily added to at least 1 and up to 3 oral antihyperglycemic medications (OAMs) [metformin, sulfonylureas, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors] in 2002 adults with type 2 diabetes (T2D) and increased cardiovascular risk.2
Key Inclusion and Exclusion Criteria in SURPASS-4
Key inclusion and exclusion criteria for the SURPASS-4 study are provided in Key Inclusion and Exclusion Criteria in the SURPASS-4 Clinical Study .
Key Inclusion Criteria |
Key Exclusion Criteria |
|
|
Abbreviations: BMI = body mass index; HbA1c = glycated hemoglobin; MI = myocardial infarction OAM = oral antihyperglycemic medication; SGLT-2 = sodium-glucose cotransporter-2; T1D = type 1 diabetes; T2D = type 2 diabetes.
Study Design in SURPASS-4
The study randomized 2002 study participants across the European Union, Canada, United States, Australia, Israel, Taiwan, Brazil, Argentina, and Mexico in 1:1:1:3 ratio to receive tirzepatide 5, 10, or 15 mg, or insulin glargine with at least 1 and up to 3 OAMs (metformin, sulfonylureas, or SGLT-2 inhibitors).2
The primary objective of the study was to demonstrate that tirzepatide 10 mg and/or 15 mg are noninferior to insulin glargine daily for mean change from baseline in glycated hemoglobin (HbA1c) at 52 weeks in people with T2D and increased cardiovascular risk.2
SURPASS-4 Study Design presents an overview of the SURPASS-4 study design.
Figure 1 description: SURPASS-4 was a phase 3, 52-week, active-controlled, open-label study in adults with type 2 diabetes and high cardiovascular risk inadequately controlled with oral glucose-lowering medications. Participants were randomized in a 1:1:1:3 ratio to receive tirzepatide (5 mg, 10 mg, or 15 mg) once weekly or insulin degludec once daily subcutaneously. Tirzepatide-treated participants started at a 2.5 mg dose and followed a dose escalation regimen (escalated in 2.5 mg increments every 4 weeks) until the assigned dose was reached, which took up to 20 weeks. The starting dose of insulin degludec was 10 IU/day at bedtime and titrated to a fasting serum glucose <100 mg/dL. Tirzepatide and insulin degludec were used in combination with or without metformin ± sulfonylurea ± sodium-glucose cotransporter-2 inhibitor
Abbreviations: FBG = fasting blood glucose; QD = once daily; QW = once weekly; SGLT-2i = sodium-glucose cotransporter-2 inhibitor; SU = sulfonylurea; TTT = treat-to-target.
a Participants will be on the study drug for at least 12 months and will receive no more than 24 months of treatment.
b All participants will perform a visit 801, an off-medication safety follow-up, 4 weeks after their last treatment visit.
c The starting dose of insulin glargine will be 10 IU/day at bedtime, titrated to an FBG <100 mg/dL, following a TTT algorithm (Riddle et al. 2003).
d Patients will titrate insulin glargine dose in a weekly manner and will make the dose decision with the investigator for the first 8 weeks (phone or clinic visit). From week 8 to week 16, patients will continue the titration by a phone consultation or clinic visit every other week, with 3 weeks between visits 13 and 14.
Baseline Characteristics of Participants in SURPASS-4
Demographics and clinical characteristics were similar across treatment groups (SURPASS-4: Baseline Demographics and Clinical Characteristics). Overall, participants had a mean
- duration of diabetes of 11.8 years
- HbA1c of 8.52%, and
- bodyweight of 90.3 kg.2
The study included 1738 (87%) participants who had a history of cardiovascular disease. The most frequently reported cardiovascular conditions were
- coronary artery disease (N=880 [44%])
- myocardial infarction (N=646 [32%]), and
- coronary revascularization procedure (N=644 [32%]).2
The efficacy and safety of tirzepatide have not been specifically evaluated in subgroups of participants based on cardiovascular disease at baseline.
Discontinuations During the SURPASS-4 Study
Treatment discontinuation in SURPASS-4 is summarized in Summary of Treatment Discontinuation Through End of Safety Follow-up in SURPASS-4. In patients treated with tirzepatide, the most common reason for study drug discontinuation was gastrointestinal-related adverse events (AEs).2
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
Overall treatment discontinuation |
51 (15.5) |
44 (13.3) |
55 (16.3) |
139 (13.8) |
aData are n (%) in all randomized population.
Efficacy Results From SURPASS-4
Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data from the phase 3 clinical trials of tirzepatide. In the SURPASS studies, the
- efficacy estimand evaluates the treatment effect prior to discontinuation of the study drug without confounding effects of antihyperglycemic rescue therapy, and
- treatment-regimen estimand evaluates the treatment effect irrespective of adherence to the study drug or initiation of rescue antidiabetic drugs.2
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 SURPASS-4, at week 52, tirzepatide 5, 10, and 15 mg were superior compared with titrated insulin glargine in
- mean change in HbA1c from baseline
- proportion of participants at HbA1c threshold <7.0%, and
- mean change in weight from baseline (SURPASS-4: Primary and Secondary Endpoints at 52 Weeks).2
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
HbA1c, % |
||||
Baseline |
8.52±0.05 |
8.60±0.05 |
8.52±0.05 |
8.51±0.03 |
HbA1c change from baseline |
-2.24±0.05 |
-2.43±0.05 |
-2.58±0.05 |
-1.44±0.03 |
-0.80 (-0.92, -0.68)** |
-0.99 (-1.11, -0.87)** |
-1.14 (-1.26, -1.02)** |
-- |
|
Proportion of participants at HbA1c thresholds, n (%) |
||||
<7.0%c |
264 (81)** |
283 (88)** |
303 (91)** |
496 (51) |
≤6.5% |
215 (66)** |
244 (76)** |
271 (81)** |
310 (32) |
<5.7% |
75 (23)** |
105 (33)** |
144 (43)** |
33 (3) |
FSG, mg/dL |
||||
Baseline |
172.3±2.81 |
175.7±2.84 |
174.2±2.78 |
168.7±1.62 |
Change from baseline at 52 weeks |
-50.4±2.07 |
-54.9±2.06 |
-59.3±2.04 |
-51.4±1.17 |
Difference vs insulin glargine |
1.0 (-3.7, 5.7) |
-3.6 (-8.2, 1.1) |
-8.0 (-12.6, -3.4)* |
-- |
Body Weight, kg |
||||
Baseline |
90.3±1.03 |
90.7±1.04 |
90.0±1.02 |
90.3±0.60 |
Change from baseline at 52 weeks |
-7.1±0.34 |
-9.5±0.34 |
-11.7±0.33 |
1.9±0.19 |
Difference vs insulin glarginec |
-9.0 (-9.8, -8.3)** |
-11.4 (-12.1, -10.6)** |
-13.5 (-14.3, -12.8)** |
-- |
Proportion of participants at weight reduction thresholds, n (%) |
||||
≥5% |
205 (63)** |
249 (78)** |
285 (85)** |
78 (8) |
≥10% |
117 (36)** |
170 (53)** |
219 (66)** |
15 (2) |
≥15% |
45 (14)** |
77 (24)** |
122 (37)** |
5 (<1) |
Abbreviations: FSG = fasting serum glucose; HbA1c = glycated hemoglobin; LSM = least squares mean; mITT = modified intention-to-treat.
Note: Data presented are from the efficacy estimand that evaluates the treatment effect prior to discontinuation of the study drug without confounding effects of antihyperglycemic rescue therapy. Missing values were handled by MMRM using the mITT population (efficacy analysis set).
*p<.001 and **p<.0001 vs insulin glargine.
aData are LSM±SE, n (%), or LSM (95%CI) treatment difference vs insulin glargine at 52 weeks.
bTested for noninferiority, controlled for type I error.
cTested for superiority, controlled for type I error.
Safety Results From SURPASS-4
The most frequently reported AEs for patients treated with tirzepatide were gastrointestinal in nature. Most events
- were mild to moderate in severity, and
- usually occurred during the dose escalation period and decreased with continued use.2
Overview of AEs and treatment-emergent adverse events (TEAEs) with ≥5% frequency in any treatment group is provided in SURPASS-4: Summary of Adverse Events Through End of Safety Follow-up and Treatment-Emergent Adverse Events With ≥5% Frequency Through End of Safety Follow-up in SURPASS-4 , respectively.2
Parameter |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
Patients with ≥1 TEAE |
232 (71) |
241 (74) |
259 (77) |
679 (68) |
SAE |
48 (15) |
54 (17) |
41 (12) |
193 (19) |
Deatha |
15 (5) |
2 (<1) |
8 (2) |
35 (4) |
AEs leading to treatment discontinuation |
37 (11) |
28 (9) |
36 (11) |
54 (5) |
Abbreviations: AE = adverse event; mITT = modified intention-to-treat; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Note: Data are n (%) and from mITT population (safety analysis set). Participants may be counted in more than 1 category.
aDeaths are also included as SAEs as well as discontinuations due to AEs.
Parameter |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
Diarrhea |
41 (13) |
65 (20) |
74 (22) |
44 (4) |
Nausea |
39 (12) |
53 (16) |
76 (23) |
23 (2) |
COVID-19 |
15 (5) |
14 (4) |
19 (6) |
59 (6) |
Nasopharyngitis |
10 (3) |
16 (5) |
16 (5) |
65 (7) |
Decreased appetite |
29 (9) |
36 (11) |
35 (10) |
5 (<1) |
Vomiting |
16 (5) |
27 (8) |
29 (9) |
16 (2) |
Dyspepsia |
18 (6) |
27 (8) |
26 (8) |
13 (1) |
Lipase increased |
10 (3) |
13 (4) |
21 (6) |
18 (2) |
Constipation |
17 (5) |
14 (4) |
14 (4) |
5 (<1) |
Abbreviations: COVID-19 = coronavirus disease 2019; mITT = modified intention-to-treat.
Note: Data are n (%). mITT population (safety analysis set). Participants may be counted in more than 1 category.
Episodes of hypoglycemia were seen more often in participants who had a background therapy of a sulfonylurea. Overall hypoglycemia frequency is provided in SURPASS-4: Incidence of Hypoglycemia Postbaseline .2
Parameter |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
Hypoglycemia (BG ≤70 mg/dL or severe) |
112 (34) |
107 (33) |
127 (38) |
641 (64) |
Hypoglycemia (BG <54 mg/dL or severe) |
29 (9) |
20 (6) |
27 (8) |
191 (19) |
Severe hypoglycemia |
1 (<1) |
0 |
3 (1) |
11 (1) |
Abbreviations: BG = blood glucose; mITT = modified intention-to-treat.
Note: Data are n (%). In mITT population (safety analysis set). Post baseline including safety follow-up. Excludes hypoglycemic events occurring after initiation of a new glucose-lowering therapy. Severe hypoglycemia defined as events requiring external assistance to administer therapy.
SURPASS-4 was conducted in participants at high risk for major adverse cardiovascular events (MACE-4), the incidence of first MACE-4 endpoint, including cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina, was also investigated. The trial was not powered to evaluate differences in MACE-4 incidence between tirzepatide treatment groups and glargine.2
The hazard ratio for MACE-4 comparing the pooled tirzepatide arms versus insulin glargine was 0.74 (95% CI 0.51 to 1.08). A hazard ratio less than 1 indicates a lower risk in the treatment group compared with the control group.2
Parameter |
Tirzepatide 5 mg N=329 |
Tirzepatide 10 mg N=328 |
Tirzepatide 15 mg N=338 |
Pooled Tirzepatide Arms N=995 |
Insulin Glargine N=1000 |
Hazard Ratio |
MACE-4, n (%) |
19 (6) |
17 (5) |
11 (3) |
47 (5) |
62 (6) |
0.74 (0.51, 1.08)a |
Cardiovascular death |
10 (3) |
1 (<1) |
5 (2) |
16 (2) |
21 (2) |
-- |
Myocardial infarction |
7 (2) |
9 (3) |
3 (<1) |
19 (2) |
26 (3) |
-- |
Hospitalization for unstable angina |
0 |
2 (<1) |
2 (<1) |
4 (<1) |
8 (<1) |
-- |
Stroke |
5 (2) |
5 (2) |
1 (<1) |
11 (1) |
13 (1) |
-- |
Abbreviations: MACE-4 = major adverse cardiovascular event; mITT = modified intent-to-treat; mITT population = all randomly assigned participants who took at least 1 dose of the study drug.
mITT population (safety analysis set). All events confirmed by the Clinical Endpoint Committee.
aPoint estimate and 95% CI of hazard ratio comparing pooled tirzepatide arms versus insulin glargine obtained from time-to-first event analysis using Cox proportional hazards model.
Enclosed Prescribing Information
Reference
The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).
1Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2025.
2Del Prato S, Kahn SE, Pavo I, et al; 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;398(10313):1811-1824. https://doi.org/10.1016/S0140-6736(21)02188-7
Appendix
Baseline Demographics and Clinical Characteristics of Participants in SURPASS-4
Parametera |
Tirzepatide 5 mg |
Tirzepatide 10 mg |
Tirzepatide 15 mg |
Insulin Glargine |
Total |
Age (y) |
62.9±8.6 |
63.7±8.7 |
63.7±8.6 |
63.8±8.5 |
63.6±8.6 |
Female, n (%) |
131 (40) |
119 (36) |
135 (40) |
364 (36) |
749 (38) |
Male, n (%) |
198 (60) |
209 (64) |
203 (60) |
636 (64) |
1246 (62) |
Race, n (%) |
|||||
Asian |
15 (5) |
16 (5) |
8 (2) |
31 (3) |
70 (4) |
Black or African American |
13 (4) |
17 (5) |
11 (3) |
32 (3) |
73 (4) |
White |
260 (79) |
259 (79) |
285 (85) |
825 (83) |
1629 (82) |
Duration of diabetes, years |
9.8 (6.2-15.3) |
10.6 (6.5-16.2) |
10.4 (5.5-15.7) |
10.7 (6.3-16.5) |
10.5 (6.2-15.9) |
HbA1c (%) |
8.52±0.84 |
8.59±0.91 |
8.52±0.98 |
8.50±0.85 |
8.52±0.88 |
FSG, mg/dL |
172.3±49.11 |
175.5±51.93 |
174.1±53.84 |
168.4±49.72 |
171.2±50.75 |
Weight (kg) |
90.3±20.32 |
90.6±18.21 |
90.0±16.34 |
90.2±19.00 |
90.3±18.66 |
BMI (kg/m2) |
32.6±6.06 |
32.8±5.51 |
32.5±5.02 |
32.5±5.55 |
32.6±5.54 |
History of CVD, n (%) |
275 (84) |
296 (90) |
293 (87) |
874 (87) |
1738 (87) |
Documented coronary artery disease |
133 (40) |
146 (44) |
146 (43) |
455 (45) |
880 (44) |
Myocardial infarction |
109 (33) |
87 (26) |
106 (31) |
344 (34) |
646 (32) |
Coronary revascularization procedure |
109 (33) |
104 (32) |
102 (30) |
329 (33) |
644 (32) |
Hospitalization for unstable angina |
21 (6) |
30 (9) |
22 (7) |
91 (9) |
164 (8) |
Hospitalization for heart failure |
22 (7) |
31 (9) |
19 (6) |
68 (7) |
140 (7) |
Stroke |
37 (11) |
36 (11) |
43 (13) |
125 (12) |
241 (12) |
Transient ischemic attack |
16 (5) |
12 (4) |
17 (5) |
53 (5) |
98 (5) |
Peripheral artery disease |
89 (27) |
109 (33) |
106 (31) |
302 (30) |
606 (30) |
eGFR (mL/min/1.73 m2) |
80.3±22.66 |
81.4±20.44 |
81.6±21.22 |
81.5±20.78 |
81.3±21.11 |
On SGLT-2i, n (%) |
78 (24) |
81 (25) |
86 (25) |
256 (26) |
501 (25) |
On sulfonylurea, n (%) |
189 (57) |
181 (55) |
179 (53) |
537 (54) |
1086 (54) |
On metformin |
306 (93) |
316 (96) |
317 (94) |
954 (95) |
1893 (95) |
Abbreviations: BMI = body mass index; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; mITT = modified intention-to-treat; SGLT-2i = sodium-glucose cotransporter-2 inhibitor.
aData are mean (SD) unless otherwise specified. Data include all randomly assigned participants who took at least 1 dose of the study drug (mITT population).
Date of Last Review: July 21, 2025