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

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. 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/m 2 ), or overweight (BMI ≥ 27 kg/m 2 ) with ≥1 obesity-related complication (ORC), without type 2 diabetes (T2D). 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/m 2 [−2.43,−1.31], −2.37 kg/m 2 [−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. 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.