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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, treatment with tirzepatide led to superior HbA1c and weight reductions compared with insulin glargine in people with T2D.
See important safety information, including boxed warning, in the attached prescribing information.
SURPASS-4 Overview
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.1
Key Inclusion and Exclusion Criteria
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
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).1
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.1
The SURPASS-4 study design included a 52-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-4 Study Design). The starting dose of insulin glargine was 10 IU/day and titrated following a treat-to-target algorithm to reach a fasting serum glucose (FSG) <100 mg/dL.1
Figure description: Study Period I: 1 week of screening and 2-week lead-in period. Study Period II: 52-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. The starting dose of insulin glargine was 10 IU/day at bedtime, and titrated to a fasting blood glucose <100 mg/dL. Tirzepatide and insulin glargine were used with or without metformin ± sulfonylurea ± sodium-glucose cotransporter-2 inhibitor. Study Period III: Treatment continued for a maximum 104 weeks. Study Period IV: 4-week safety follow-up period.
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
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.1
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%]).1
The efficacy and safety of tirzepatide have not been specifically evaluated in subgroups of participants based on cardiovascular disease at baseline.
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).
Discontinuation
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).1
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
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.1
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 achieving HbA1c <7.0%, and
- mean change in weight from baseline (SURPASS-4: Primary and Secondary Endpoints at 52 Weeks).1
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 achieving HbA1c goals |
||||
<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 achieving weight loss |
||||
≥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
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. 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.1
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 .1
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.
In a population with long-standing diabetes and increased cardiovascular risk, tirzepatide demonstrated no increased risk for major adverse cardiovascular events (MACE-4) compared with insulin glargine (SURPASS-4: Summary of MACE-4 Events Through End of Safety Follow-up ).1
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).
1Del 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
Date of Last Review: October 29, 2024