Indirect comparative efficacy and safety of tirzepatide vs semaglutide for the treatment of obesity or overweight in patients without type 2 diabetes

Background/objectives: Tirzepatide is a once-weekly, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) for obesity treatment. This indirect treatment comparison (ITC) assessed the relative efficacy and safety of tirzepatide versus the GLP-1 RA semaglutide. Subjects/methods: Adjusted (for sex, and sex and ethnicity) and unadjusted ITCs compared tirzepatide 5, 10, and 15 mg/week and semaglutide 2.4 mg/week via placebo, all adjunct to reduced-calorie diet and increased physical activity, at primary trial endpoints (Week 68, STEP 1; Week 72, SURMOUNT-1) for adults with obesity (BMI ≥ 30 kg/m2), or overweight (BMI ≥ 27 kg/m2) with ≥1 obesity-related complication (ORC), without type 2 diabetes (T2D). Results: For efficacy estimand unadjusted ITCs, tirzepatide 10 and 15 mg demonstrated statistically significant improvements versus semaglutide in weight reduction (−5.10 kg [−6.63, − 3.57], −6.50 kg [−8.03,−4.97]), participants achieving ≥10/15/20% weight reduction, BMI (−1.87 kg/m2 [−2.43,−1.31], −2.37 kg/m2 [−2.93,−1.81]), waist circumference (−5.25 cm [−6.69,−3.81], −5.75 cm [−7.19,−4.31]), HbA1c(−0.08% [−0.13,−0.03], −0.10% [−0.15, −0.05]) and fasting plasma glucose (−1.69 mg/dL [−3.36,−0.02], −2.52 mg/dL [−4.19,−0.85]). Tirzepatide 5 mg showed non-significant trends of greater improvements in these outcomes versus semaglutide. All tirzepatide doses showed statistically significantly greater decreases in diastolic blood pressure (−1.90 mmHg [−3.19,−0.61], −2.40 mmHg [−3.69,−1.11], −1.30 mmHg [−2.59,−0.01]) and increases in HDL (3.80% [1.23,6.37], 5.40% [2.83,7.97], 5.00% [2.43,7.57]). In participants reporting on body composition, tirzepatide 15 mg demonstrated statistically significant improvements in body composition versus semaglutide, with a reduction of percentage body fat mass (−3.50% [−6.66, −0.34]) and an increase of percentage body lean mass (3.40% [0.40, 6.40]). Results were broadly consistent across adjusted and unadjusted comparisons. Safety profiles of tirzepatide and semaglutide were generally similar. Conclusions: In this ITC for obesity treatment in adults without T2D, with obesity, or overweight with ≥1 ORC, compared with semaglutide, tirzepatide 10 or 15 mg was associated with improvements in weight reduction, body composition and several cardiometabolic risk factors and generally similar safety profiles. (Figure presented.)