Background Modest body weight reduction can greatly improve many health-related outcomes. In the SURMOUNT clinical trial program, once-weekly tirzepatide resulted in substantial body weight reductions in people with obesity, without and with type 2 diabetes. Objective This post-hoc analysis assessed the proportion of participants achieving body weight reduction thresholds (≥5%, ≥10%, ≥15%), systolic blood pressure reduction ≥5 mmHg, and non-high-density lipoprotein cholesterol (non-HDL-C) <130 mg/dL with tirzepatide. Methods Participants from SURMOUNT 1–4 randomized to tirzepatide or placebo with valid baseline and ≥1 non-missing post-baseline body weight, systolic blood pressure and non-HDL-C measurements were included in this analysis. The proportion of participants achieving the triple endpoints was assessed at the primary endpoint of each study (Week 72 for SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3 and Week 88 for SURMOUNT-4). Results Across the trials, 32–38% vs 2–8% of tirzepatide-treated vs placebo-treated participants achieved ≥5% body weight reduction, systolic blood pressure reduction ≥5 mmHg, and non-HDL-C <130 mg/dL, 28–37% vs 1–5%, respectively, achieved the triple endpoint with the ≥10% body weight reduction threshold, and 22–34% vs 1–3%, respectively, achieved the triple endpoint with the ≥15% body weight reduction threshold. The between-treatment odds ratios for these proportions across the trials, were statistically significant (all p<0.001). Conclusion In this post hoc analysis of SURMOUNT, more participants achieved the triple endpoint of body weight reduction thresholds, systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL with tirzepatide vs placebo. Studies evaluating the potential cardiovascular benefits of tirzepatide are ongoing.