Improvements in Cardiometabolic Risk Factors by Weight Reduction: A Post Hoc Analysis of Adults With Obesity Randomly Assigned to Tirzepatide

Abstract

Background: Tirzepatide reduced weight and improved cardiometabolic risk factors for participants in the SURMOUNT-1 trial. The changes in cardiometabolic risk factors by degree of tirzepatide-induced weight reduction across a wide spectrum of weight loss have not been reported. Objective: To determine changes in cardiometabolic risk factors by weight reduction. Design: Post hoc analysis of the phase 3, randomized, double-blind, SURMOUNT-1 trial (ClinicalTrials.gov: NCT04184622). Setting: 119 sites in 9 countries. Participants: Adults (n ¼ 1605) with obesity, or overweight with weight-related complications (excluding diabetes), randomly assigned to tirzepatide treatment groups. Intervention: Once-weekly tirzepatide, 5, 10, or 15 mg. Measurements: Changes from baseline to week 72 in cardiometabolic risk factors by weight reduction. Results: Participants had a mean age of 45.4 years (SD, 12.2) and mean body mass index of 37.9 kg/m2 (SD, 6.7), and 68% were female. The greater weight reduction categories had higher percentages of female and White participants. Participants who lost at least 35% of their body weight from baseline to week 72 had mean changes of up to -14.2 mm Hg (95% CI, -16.1 to -12.3 mm Hg) for systolic blood pressure, -9.2 mm Hg (CI, -10.6 to -7.8 mm Hg) for diastolic blood pressure, -32.4 cm (CI, -33.5 to -31.3 cm) for waist circumference, -59.7% (CI, -63.6% to -55.3%) for the homeostatic model assessment of insulin resistance (HOMA-IR), and -0.65 percentage point (CI, -0.70 to -0.61 percentage point) for hemoglobin A1c. The relationship between percentage weight reduction and changes in cardiometabolic risk factors seemed mostly linear for waist circumference and blood pressure, with a steeper slope for systolic than diastolic blood pressure. Decreases in HOMA-IR and hemoglobin A1c were observed even with modest weight reduction, with the steepest effect occurring between less than 5% and less than 20% weight reduction. Improvements in levels of triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and non-HDL cholesterol were primarily observed only after weight reductions greater than 10%. Results were consistent after adjustment for baseline differences. Limitations: The analysis was post hoc and should be regarded as hypothesis-generating. Duration and sample size precluded evaluation of cardiovascular outcomes. Conclusion: In SURMOUNT-1, tirzepatide-associated improvements in cardiometabolic risk factors positively related to the degree of weight reduction, but the pattern varied depending on outcome measure.