Clinical effectiveness

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Tirzepatide has been studied in weight management in 2 large, phase 3 studies: SURMOUNT‑1 (n=2,539) in people who did not have diabetes and SURMOUNT‑2 (n=938) in people with type 2 diabetes. Both trials had a similar design and the same co-primary endpoints: the percentage change in body weight from baseline to week 72 and a weight reduction of 5% or more at week 72. The 72‑week treatment period included a dose-escalation phase. Tirzepatide was started at a dose of 2.5 mg once weekly (or matching placebo) and the dose was increased by 2.5 mg every 4 weeks until the target dose was reached. In both trials, people in all the study arms had lifestyle counselling sessions, delivered by a dietitian or other qualified healthcare professional. These were to help them adhere to healthy, balanced meals with a deficit of 500 calories per day, and at least 150 minutes of physical activity per week.

People without diabetes

SURMOUNT‑1 included people with a BMI of 30 kg/m² or more, or 27 kg/m² or more and at least 1 weight-related complication (excluding diabetes). The mean baseline BMI was 38.0 kg/m² (35% of people in the trial had a BMI 30 to 34 kg/m², 28% had a BMI 35 to 39 kg/m² and 32% had a BMI 40 kg/m² or more). People were randomised in equal numbers to tirzepatide 5 mg weekly, 10 mg weekly or 15 mg weekly, or placebo.

Evidence on tirzepatide's treatment effect compared with placebo in the population covered by the technology appraisal recommendation (BMI of at least 35 kg/m² and at least 1 weight-related comorbidity) was provided to NICE in confidence. Published results from the whole trial intention-to-treat population (treatment estimand) are shown in table 1. This treatment estimand represents the average treatment effect of tirzepatide relative to placebo for everyone who was randomised, regardless of treatment discontinuation.

**Table 1 Effects of tirzepatide on body weight and BMI at 72 weeks in SURMOUNT-1 (means and 95% confidence intervals)**
Outcome	Tirzepatide 5 mg	Tirzepatide 10 mg	Tirzepatide 15 mg	Placebo
Percentage reduction in body weight	15.0% (14.2% to 15.9%)	19.5% (18.5% to 20.4%)	20.9% (19.9% to 21.8%)	3.1% (1.9% to 4.3%)
Weight reduction of 5% or more	85.1% (81.6% to 88.6%)	88.9% (85.9% to 91.9%)	90.9% (88.0% to 93.8%)	34.5% (29.8% to 39.2%)
Weight reduction of 10% or more	68.5% (64.5% to 72.5%)	78.1% (74.4% to 81.7%)	83.5% (80.0% to 86.9%)	18.8% (14.9% to 22.7%)
Weight reduction of 15% or more	48.0% (43.9% to 52.1%)	66.6% (62.6% to 70.6%)	70.6% (66.7% to 74.5%)	8.8% (5.9% to 11.7%)
Weight reduction of 20% or more	30.0% (26.4% to 33.6%)	50.1% (46.0% to 54.2%	56.7% (52.6% to 60.8%)	3.1% (1.1% to 5.1%)

People with diabetes

SURMOUNT‑2 included people with a BMI of 27 kg/m² or more and type 2 diabetes (HbA1c 53 to 86 mmol/mol on stable therapy, excluding DPP‑4 inhibitors, GLP‑1 agonists or any other injectable treatment for diabetes). The mean baseline BMI was 36.1 kg/m²; 17% had a BMI less than 30 kg/m², 33% had a BMI between 30 and less than 35 kg/m², and roughly equal proportions of the remaining half had a BMI between 35 to less than 40 kg/m² and 40 kg/m² or more. People were randomised in equal numbers to tirzepatide 10 mg weekly or 15 mg weekly, or placebo.

Published results from the whole trial intention-to-treat population (treatment estimand) are shown in table 2.

**Table 2 Effects of tirzepatide on body weight and BMI at 72 weeks in SURMOUNT-2 (95% confidence intervals not stated in study report)**
Outcome	Tirzepatide 10 mg	Tirzepatide 15 mg	Placebo
Percentage reduction in body weight	12.8%	14.7%	3.2%
Weight reduction of 5% or more	79%	83%	32%
Weight reduction of 10% or more	61%	65%	9%
Weight reduction of 15% or more	40%	48%	3%
Weight reduction of 20% or more	22%	31%	1%