Abstract Body (Do not enter title and authors here): Background: In SURMOUNT-4, participants with obesity demonstrated a mean weight reduction of 21% during the 36-week lead-in with the maximum tolerated dose (MTD) of tirzepatide (TZP). During the 52-week double-blind period, participants who switched to placebo (PBO) experienced a 14% weight regain, while those who continued TZP achieved an additional 6% weight reduction. This post hoc analysis assessed whether participants who shifted to a lower BMI category had improved cardiometabolic factors.

Methods: Shift in BMI category (<25 kg/m², 25 to <30 kg/m², 30 to <35 kg/m², 35 to <40 kg/m², and ≥40 kg/m²) from baseline (week 0) during the lead-in period (week 36) and at the primary endpoint (week 88) and from week 36 to week 88 was assessed in participants from SURMOUNT-4 randomized to TZP MTD (N=332) or PBO (N=329). BMI shifts were grouped into “improved” (shift to ≥1 lower category) or “not improved” (stable/attenuated [no change/shift to a higher category]). Changes from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, vitals and lipid profile were assessed.

Results: From weeks 0 to 36, 296 (89%) participants improved in BMI category with TZP, and none had attenuated (Table). From weeks 36 to 88, 130 (39%) participants improved in BMI category with TZP, while the majority (99%) randomized to PBO did not. Overall, from weeks 0 to 88, 304 (92%) vs 189 (57%) participants improved in BMI category with TZP vs PBO, respectively, where the improvements observed in the PBO group originated from the 36-week lead-in period. In general, participants who improved in BMI category at week 88 were noted to have greater improvements in cardiometabolic parameters with TZP vs PBO, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, triglycerides, and cholesterol (total, non-HDL-c, LDL-c, and VLDL-c).

Conclusions: In this post hoc analysis of SURMOUNT-4, the majority of TZP-treated participants shifted to lower “improved” BMI categories. Shift to an improved BMI category was accompanied by improved cardiometabolic risk factors, suggesting that TZP treatment may lower further cardiovascular outcomes. Relevant outcomes trials are ongoing.