SURMOUNT 2: Tirzepatide Once Weekly for the Treatment of Obesity in People with T2DM

27 May, 26

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Introduction

Weight management has a pivotal role in the treatment of type-2 diabetes mellitus (T2DM). Attaining weight reduction thresholds of more than 5% to more than 15% results in health benefits that go beyond glycemic control. Tirzepatide, a once-weekly injectable, subcutaneous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist has been approved for the treatment of T2DM and chronic weight management in people with obesity. In SURMOUNT 1 trial, that recruited people with obesity without T2DM, tirzepatide reduced bodyweight by up to 22.5% after 72 weeks of treatment. The treatment was also associated with improvements in cardiometabolic risk factors and patient-reported outcomes. Nevertheless, people with obesity and T2DM often have lesser weight reduction, as compared to those without T2DM, when treated with anti-obesity medications. It is therefore necessary to evaluate the efficacy and safety of tirzepatide in people with obesity and T2DM.

Aim

To determine the efficacy and safety of tirzepatide, versus placebo, for weight management in people with obesity and T2DM.

Patient Profile

Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m² or higher and diagnosed with T2DM [glycated hemoglobin (HbA1c) of 7–10%] on stable therapy, either diet and exercise alone or oral antihyperglycemic medication, for at least 3 months before screening.

Methods

Study Design

A phase 3, double-blind, randomised, parallel group, placebo-controlled, multicentre trial conducted across 77 sites in seven countries (Argentina, Brazil, India, Japan, Russia, Taiwan, and the USA).

Treatment Strategy

After a 3-week screening period, participants were randomized 1:1:1 to receive either once-weekly, subcutaneous tirzepatide 10 mg or 15 mg, or placebo, along with a lifestyle intervention, for 72 weeks. This was followed by a 4-week safety follow-up period without treatment.
Tirzepatide (or matching placebo) was initiated at 2·5 mg once weekly, the dosage was increased by 2·5 mg every 4 weeks until the target dose was reached (i.e., 10 mg or 15 mg at 12 weeks or 20 weeks, respectively).
The lifestyle intervention included regular lifestyle counselling sessions focusing on healthy, balanced meals with a recommended caloric deficit of 500 calories per day relative to the estimated total daily energy expenditure and at least 150 minutes of physical activity per week.

Outcomes

Coprimary Outcomes

The percent change in bodyweight from baseline to week 72.
Proportion of participants achieving bodyweight reduction of ≥5% from baseline to week 72.

Key Secondary Outcomes

Proportion of participants achieving bodyweight reductions of at least 10%, 15%, and 20% at week 72.
The change from baseline in HbA1c at week 72.
Proportion of participants achieving HbA1c <7%, ≤6·5%, and <5·7% at week 72.
The change from baseline in fasting glucose, waist circumference (WC), systolic blood pressure (SBP), and fasting lipid levels [triglycerides, high-density lipoprotein-cholesterol (HDL-C), and non-HDL cholesterol] at week 72.

Additional Secondary Outcomes

The change from baseline in bodyweight, BMI, diastolic blood pressure (DBP), seven-point self-monitoring blood glucose (SMBG) profile, fasting insulin, fasting lipids [total cholesterol, low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C), and free fatty acids]
The change in the Short Form-36 Version 2 Health Survey acute form (SF-36v2) physical functioning score, and the Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL-Lite- CT) physical function composite score.

Safety Outcomes

Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and level 2 hypoglycemia (blood glucose <54 mg/dL), or level 3 (severe) hypoglycemia (an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions).

Results

A total of 938 participants (mean age 54·2 years, females; 51%,) were randomized and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315).
Baseline mean bodyweight was 100·7 kg, mean BMI was 36·1 kg/m², and mean HbA1c was 8·02%. Duration of obesity and diabetes was 17·7 years and 8·5 years, respectively.
Both the doses of tirzepatide were superior to placebo in terms of least-squares mean (LSM) change in bodyweight at week 72 (Tirzepatide10 mg: -13.4%, Tirzepatide 15 mg: -15.7%, placebo: -3.3%, mean diff: -10.1% and -12.4%, respectively, all p<0·0001) (Fig. 1).

Fig. 1: Effect of tirzepatide vs placebo on body weight at week 72 (efficacy estimand)

Higher proportion of participants treated with both doses of tirzepatide vs. placebo achieved bodyweight reduction thresholds of ≥5% (81.6%, 86.4% vs. 30.6%). Similarly, a higher proportion of participants treated with both doses of tirzepatide achieved reductions in bodyweight of ≥10%, ≥15%, ≥20%, and ≥25% from baseline, as compared to those treated with placebo (Fig. 2).

Fig. 2: Percentage of participants reaching weight reduction thresholds (efficacy estimand)

Participants treated with both doses of tirzepatide showed greater improvements in the HbA1c levels at 72 weeks, as compared to placebo (Fig. 3).

Fig 3: Change in HbA1c levels at week 72 (efficacy estimand)

A higher proportion of participants in each group reaching HbA1c levels of < 7·0%, ≤ 6·5%, or < 5·7% at week 72 was significantly higher in tirzepatide 10 mg and tirzepatide 15 mg groups, as compared to the placebo group (Fig. 4).

Fig 4: Percentage of participants reaching target HbA1c thresholds (efficacy estimand)

Participants treated with both doses of tirzepatide showed greater improvements in fasting serum glucose, fasting insulin, and seven-point SMBG profiles, as compared with placebo (Table 1).
Patients treated with both the doses of tirzepatide achieved a significantly greater reduction in waist circumference, as compared to placebo (Table 1).
Patients treated with both doses of tirzepatide had a greater improvement in SBP and DBP, as compared to those treated with placebo. Improvements in BMI, fasting insulin and lipid profile, and SF-36v2 Physical Function score and IWQOL-Lite-CT Physical Function score were also significantly greater with tirzepatide treatment vs. placebo (Table 1).

Table 1: Changes in the additional efficacy outcomes at week 72 (efficacy estimand)

	Tirzepatide 10 mg (LSM)	Tirzepatide 15 mg (LSM)	Placebo (LSM)	Treatment comparison vs. placebo (95% CI); p value
	Tirzepatide 10 mg (LSM)	Tirzepatide 15 mg (LSM)	Placebo (LSM)	Tirzepatide 10 mg	Tirzepatide 15 mg
Key secondary outcomes at week 72
Waist circumference (cm)	-11.2	-13.8	-3.4	ETD -7.8(-9.2, -6.4); p<0.0001	ETD -10.4 (-11.8, -8.9); p<0.0001
Fasting glucose (mg/dL)	-49.2	-51.7	-2.4	ETD -46.8 (-52.7, -40.9); p<0.0001	ETD -49.3 (-55.2, -43.3); p<0.0001
Additional secondary outcomes at week 72
BMI (kg/m²)	-4.9	-5.7	-1.2	ETD -3.7 (-4.2, -3.2); p<0.0001	ETD -4.5 (-5.0, -4.0); p<0.0001
Percent change in fasting insulin	-29.6	-40.3	-14.5	ETD -17.6 (-25.5, -8.9); p=0.0002	ETD -30.2 (-37.0, -22.7); p<0.0001
Triglycerides	-26.8	-30.6	-5.8	ETD -22.2 (-27.3, -16.8); p<0.0001	ETD -26.3 (-31.1, -21.0); p<0.0001
Non-HDL cholesterol	-6.6	-6.7	2.3	ETD -8.7 (-12.5, -4.8); p<0.0001	ETD -8.8 (-12.6, -4.8); p<0.0001
HDL cholesterol	6.9	9.6	1.1	ETD 5.7 (2.7, 8.7); p=0.0001	ETD 8.4 (5.3, 11.6); p<0.0001
Total cholesterol	-3.0	-2.2	2.1	ETD -5.0 (-7.8, -2.0); p=0.0010	ETD -4.2 (-7.1, -1.2); p=0.0065
LDL cholesterol	2.3	3.2	6.3	ETD -3.7 (-8.3, 1.0); p=0.12	ETD -3.0 (-7.6, 1.9); p=0.23
VLDL cholesterol	-26.3	-29.5	-6.0	ETD -21.6 (-26.4, -16.5); p<0.0001	ETD -25.0 (-29.7, -20.1); p<0.0001
Free fatty acids	-22.9	-24.3	0.04	ETD -22.9 (-28.7, -16.7); p<0.0001	ETD -24.3 (-30.1, -18.2); p<0.0001
Change in SF-36v2 Physical Function score*	3.4	3.8	1.6	ETD 1.8 (0.7, 2.9); p=0.0013	ETD 2.3 (1.1, 3.4); p<0.0001
Change in IWQOL-Lite-CT Physical* Function score	14.3	15.2	7.4	ETD 6.9 (4.1, 9.7); p<0.0001	ETD 7.8 (5.0, 10.7); p<0.0001

ETD: estimated treatment difference, OR: Odds ratio; *Data shown are last observation carried forward.

Gastrointestinal events such as nausea, diarrhea, vomiting—were the most common TEAEs observed with tirzepatide. Most of these events occurred during dose escalation, were mild to moderate in severity, and decreased over time.

Conclusions

The SURMOUNT 2 trial demonstrated that once-weekly treatment with tirzepatide resulted in clinically meaningful bodyweight reductions in adults with a BMI of 27 kg/m² or higher and T2DM.
Tirzepatide resulted in bodyweight reductions of up to 15%, nearly one-third of tirzepatide-treated participants achieved weight reductions of 20% or higher.
Additionally, tirzepatide improved cardiometabolic risk factors and glycemic control, with almost half of tirzepatide-treated participants achieving an HbA1c target of less than 5·7%.

Lancet 2023; 402: 613–26.

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