14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

The effectiveness of MOUNJARO as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus was established in five trials. In these trials, MOUNJARO was studied as monotherapy (SURPASS-1); as an add-on to metformin, sulfonylureas, and/or sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) (SURPASS-2, -3, and -4); and in combination with basal insulin with or without metformin (SURPASS-5). In these trials, MOUNJARO (5 mg, 10 mg, and 15 mg given subcutaneously once weekly) was compared with placebo, semaglutide 1 mg, insulin degludec, and/or insulin glargine.

In adult patients with type 2 diabetes mellitus, treatment with MOUNJARO produced a statistically significant reduction from baseline in HbA1c compared to placebo. The effectiveness of MOUNJARO was not impacted by age, gender, race, ethnicity, region, or by baseline BMI, HbA1c, diabetes duration, or renal function.

14.2 Monotherapy Use of MOUNJARO in Adult Patients with Type 2 Diabetes Mellitus

SURPASS-1 (NCT03954834) was a 40-week double-blind trial that randomized 478 adult patients with type 2 diabetes mellitus with inadequate glycemic control with diet and exercise to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg, or placebo once weekly.

Patients had a mean age of 54 years, and 52% were men. The mean duration of type 2 diabetes mellitus was 4.7 years, and the mean BMI was 32 kg/m2. Overall, 36% were White, 35% were Asian, 25% were American Indians/Alaska Natives, and 5% were Black or African American; 43% identified as Hispanic or Latino ethnicity.

Monotherapy with MOUNJARO 5 mg, 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3).

Table 3: Results at Week 40 in a Trial of MOUNJARO as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control with Diet and Exercise
a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 25%, 2%, 3%, and 2% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c data were missing for 12%, 6%, 7%, and 14% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using placebo-based multiple imputation.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. placebo, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Placebo	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	113	121	121	120
HbA1c (%)
Baseline (mean)	8.1	8.0	7.9	7.9
Change at Week 40b	-0.1	-1.8	-1.7	-1.7
Difference from placebob (95% CI)	--	-1.7c (-2.0, -1.4)	-1.6c (-1.9, -1.3)	-1.6c (-1.9, -1.3)
Patients (%) achieving HbA1c <7%d	23	82c	85c	78c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	155	154	153	154
Change at Week 40b	4	-40	-40	-39
Difference from placebob (95% CI)	--	-43c (-55, -32)	-43c (-55, -32)	-42c (-54, -30)
Body Weight (kg)
Baseline (mean)	84.5	87.0	86.2	85.5
Change at Week 40b	-1.0	-6.3	-7.0	-7.8
Difference from placebob (95% CI)	--	-5.3c (-6.8, -3.9)	-6.0c (-7.4, -4.6)	-6.8c (-8.3, -5.4)

14.3 MOUNJARO Use in Combination with Metformin, Sulfonylureas, and/or SGLT2 Inhibitors in Adult Patients with Type 2 Diabetes Mellitus

Add-on to metformin

SURPASS-2 (NCT03987919) was a 40-week open-label trial (double-blind with respect to MOUNJARO dose assignment) that randomized 1879 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin alone to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, or MOUNJARO 15 mg once weekly or subcutaneous semaglutide 1 mg once weekly.

Patients had a mean age of 57 years and 47% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 34 kg/m2. Overall, 83% were White, 4% were Black or African American, and 1% were Asian; 70% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with semaglutide 1 mg once weekly (see Table 4 and Figure 2).

Table 4: Results at Week 40 in a Trial of MOUNJARO versus Semaglutide 1 mg in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin
a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 3%, 2%, 1%, and 1% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c endpoint was missing for 5%, 4%, 5%, and 5% of patients randomized to semaglutide 1 mg, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.05 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
d p<0.001 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
e Analyzed using logistic regression adjusted for baseline value and other stratification factors.
f p<0.01 (two-sided) for superiority vs. semaglutide, adjusted for multiplicity.
	Semaglutide 1 mg	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	468	470	469	469
HbA1c (%)
Baseline (mean)	8.3	8.3	8.3	8.3
Change at Week 40b	-1.9	-2.0	-2.2	-2.3
Difference from semaglutideb (95% CI)	--	-0.2c (-0.3, -0.0)	-0.4d (-0.5, -0.3)	-0.5d (-0.6, -0.3)
Patients (%) achieving HbA1c <7%e	79	82	86f	86f
Fasting Serum Glucose (mg/dL)
Baseline (mean)	171	174	174	172
Change at Week 40b	-49	-55	-59	-60
Body Weight (kg)
Baseline (mean)	93.7	92.5	94.8	93.8
Change at Week 40b	-5.7	-7.6	-9.3	-11.2
Difference from semaglutideb (95% CI)	--	-1.9c (-2.8, -1.0)	-3.6d (-4.5, -2.7)	-5.5d (-6.4, -4.6)

Figure 2. Mean HbA1c (%) Over Time - Baseline to Week 40

Number of patients
MOUNJARO 5mg	470	451	470
MOUNJARO 10mg	469	445	469
MOUNJARO 15mg	469	447	469
Semaglutide 1mg	468	443	468

Note: Displayed results are from modified Intent-to-Treat Full Analysis Set. (1) Observed mean value from Week 0 to Week 40, and (2) least-squares mean ± standard error at Week 40 multiple imputation (MI).

Add-on to metformin with or without SGLT2 inhibitor

SURPASS-3 (NCT03882970) was a 52-week open-label trial that randomized 1444 adult patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin with or without SGLT2 inhibitor to the addition of MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin degludec 100 units/mL once daily. In this trial, 32% of patients were on SGLT2 inhibitor. Insulin degludec was initiated at 10 units once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 26% of patients randomized to insulin degludec achieved the fasting serum glucose target of <90 mg/dL, and the mean daily insulin degludec dose was 49 U (0.5 U per kilogram).

Patients had a mean age of 57 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 8.4 years, and the mean baseline BMI was 34 kg/m2. Overall, 91% were White, 3% were Black or African American, and 5% were Asian; 29% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with daily insulin degludec (see Table 5).

Table 5: Results at Week 52 in a Trial of MOUNJARO versus Insulin Degludec in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin with or without SGLT2 Inhibitor
a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%,1%, 1%, and 2% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 6%, 10%, and 5% of patients randomized to insulin degludec, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. insulin degludec, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Insulin Degludec	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT)a Population (N)	359	358	360	358
HbA1c (%)
Baseline (mean)	8.1	8.2	8.2	8.2
Change at Week 52b	-1.3	-1.9	-2.0	-2.1
Difference from insulin degludecb (95% CI)	--	-0.6c (-0.7, -0.5)	-0.8c (-0.9, -0.6)	-0.9c (-1.0, -0.7)
Patients (%) achieving HbA1c <7%d	58	79c	82c	83c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	167	172	170	168
Change at Week 52b	-51	-47	-50	-54
Body Weight (kg)
Baseline (mean)	94.0	94.4	93.8	94.9
Change at Week 52b	1.9	-7.0	-9.6	-11.3
Difference from insulin degludecb (95% CI)	--	-8.9c (-10.0, -7.8)	-11.5c (-12.6, -10.4)	-13.2c (-14.3, -12.1)

Add-on to 1-3 oral anti-hyperglycemic agents (metformin, sulfonylurea or SGLT-2 inhibitor)

SURPASS-4 (NCT03730662) was a 104-week open-label trial (52-week primary endpoint) that randomized 2002 adult patients with type 2 diabetes mellitus with increased cardiovascular risk to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or insulin glargine 100 units/mL once daily (1:1:1:3 ratio) on a background of metformin (95%) and/or sulfonylureas (54%) and/or SGLT2 inhibitors (25%).

Patients had a mean age of 64 years, and 63% were men. The mean duration of type 2 diabetes mellitus was 11.8 years, and the mean baseline BMI was 33 kg/m2. Overall, 82% were White, 4% were Black or African American, and 4% were Asian; 48% identified as Hispanic or Latino ethnicity. Across all treatment groups, 87% had a history of cardiovascular disease. At baseline, eGFR was ≥90 mL/min/1.73 m2 in 43%, 60 to 90 mL/min/1.73 m2 in 40%, 45 to 60 mL/min/1.73 m2 in 10%, and 30 to 45 mL/min/1.73 m2 in 6% of patients.

Insulin glargine was initiated at 10 U once daily and adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values. At Week 52, 30% of patients randomized to insulin glargine achieved the fasting serum glucose target of <100 mg/dL, and the mean daily insulin glargine dose was 44 U (0.5 U per kilogram).

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with insulin glargine once daily (see Table 6).

Table 6: Results at Week 52 in a Trial of MOUNJARO versus Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus Added to Metformin and/or Sulfonylurea and/or SGLT2 Inhibitor
a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%, 0%, 0%, and 1% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 52 the HbA1c endpoint was missing for 9%, 9%, 6%, and 4% of patients randomized to insulin glargine, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. insulin glargine, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Insulin Glargine	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	998	328	326	337
HbA1c (%)
Baseline (mean)	8.5	8.5	8.6	8.5
Change at Week 52b	-1.4	-2.1	-2.3	-2.4
Difference from insulin glargineb (95% CI)	--	-0.7c (-0.9, -0.6)	-0.9c (-1.1, -0.8)	-1.0c (-1.2, -0.9)
Patients (%) achieving HbA1c <7%d	49	75c	83c	85c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	168	172	176	174
Change at Week 52b	-49	-44	-50	-55
Body Weight (kg)
Baseline (mean)	90.2	90.3	90.6	90.0
Change at Week 52b	1.7	-6.4	-8.9	-10.6
Difference from insulin glargineb (95% CI)	--	-8.1c (-8.9, -7.3)	-10.6c (-11.4, -9.8)	-12.2c (-13.0, -11.5)

14.4 MOUNJARO Use in Combination with Basal Insulin with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus

SURPASS-5 (NCT04039503) was a 40-week double-blind trial that randomized 475 patients with type 2 diabetes mellitus with inadequate glycemic control on insulin glargine 100 units/mL, with or without metformin, to MOUNJARO 5 mg, MOUNJARO 10 mg, MOUNJARO 15 mg once weekly, or placebo. The dose of background insulin glargine was adjusted using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <100 mg/dL.

Patients had a mean age of 61 years, and 56% were men. The mean duration of type 2 diabetes mellitus was 13.3 years, and the mean baseline BMI was 33 kg/m2. Overall, 80% were White, 1% were Black or African American, and 18% were Asian; 5% identified as Hispanic or Latino ethnicity.

The mean dose of insulin glargine at baseline was 34, 32, 35, and 33 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. At randomization, the initial insulin glargine dose in patients with HbA1c ≤8.0% was reduced by 20%. At week 40, mean dose of insulin glargine was 38, 36, 29, and 59 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively.

Treatment with MOUNJARO 5 mg once weekly, 10 mg once weekly and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 7).

Table 7: Results at Week 40 in a Trial of MOUNJARO Added to Basal Insulin with or without Metformin in Adult Patients with Type 2 Diabetes Mellitus
a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment because they did not meet study enrollment criteria were excluded. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 4%, 1%, 0%, and 1% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. At Week 40 the HbA1c endpoint was missing for 2%, 6%, 3%, and 7% of patients randomized to placebo, MOUNJARO 5 mg, 10 mg, and 15 mg, respectively. Missing Week 40 data were imputed using placebo-based multiple imputation.
b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
c p<0.001 (two-sided) for superiority vs. placebo, adjusted for multiplicity.
d Analyzed using logistic regression adjusted for baseline value and other stratification factors.
	Placebo	MOUNJARO 5 mg	MOUNJARO 10 mg	MOUNJARO 15 mg
Modified Intent-to-Treat (mITT) Population (N)a	119	116	118	118
HbA1c (%)
Baseline (mean)	8.4	8.3	8.4	8.2
Change at Week 40b	-0.9	-2.1	-2.4	-2.3
Difference from placebob (95% CI)	--	-1.2c (-1.5, -1.0)	-1.5c (-1.8, -1.3)	-1.5c (-1.7, -1.2)
Patients (%) achieving HbA1c <7%d	35	87c	90c	85c
Fasting Serum Glucose (mg/dL)
Baseline (mean)	164	163	163	160
Change at Week 40b	-39	-58	-64	-63
Difference from placebob (95% CI)	--	-19c (-27, -11)	-25c (-32, -17)	-23c (-31, -16)
Body Weight (kg)
Baseline (mean)	94.2	95.8	94.6	96.0
Change at Week 40b	1.6	-5.4	-7.5	-8.8
Difference from placebob (95% CI)	--	-7.1c (-8.7, -5.4)	-9.1c (-10.7, -7.5)	-10.5c (-12.1, -8.8)