Evaluation of clinical relevance of weight nadirs and weight regain during 3 years of treatment with tirzepatide in participants with obesity or overweight and prediabetes

Objective For adults with obesity, fluctuations in body weight are expected to occur during weight management. Weight nadirs, which can become a point of focus for people living with obesity, are often hard to maintain. This study aimed to investigate the not well-defined clinical relevance of weight nadir, especially during long-term treatment with an obesity medication. Methods This was a post hoc analysis of the phase 3, double-blind, randomized, placebo-controlled SURMOUNT-1 3-year clinical trial in participants with obesity or overweight and at least one weight-related complication. The analysis included participants who were tirzepatide-adherent (≥75% of doses received) with obesity, or overweight, and prediabetes at randomization and had ≥5% weight reduction from baseline at time of weight nadir. Weight regain analyses from weight nadir to Week 176 included mean percent change, and participants were grouped as having <5%, 5% to <10%, and ≥10% weight regain. Results In this post hoc analysis, the mean weight regain from nadir weight to Week 176 was 3.8kg, 4.4kg, and 3.7kg for those treated with tirzepatide 5mg, 10mg, and 15mg, respectively. For the pooled tirzepatide doses, 70% of participants had <5% weight regain, 22% of participants had 5 to <10% weight regain, and 8% of participants had ≥10% weight regain. The median percent of weight reduction maintenance from time of weight nadir to Week 176 was 94.8%, 69.9%, and 44.3%, for <5%, 5-<10%, and ≥10%, respectively. While at baseline 94% of tirzepatide-treated participants had high waist-to-height ratio (WHtR) (>0.59), at week 176 this had reduced to 45%, 59%, and 68% in the <5%, 5% to <10%, and ≥10% weight regain groups, respectively. At Week 176, conversion from prediabetes to normoglycemia occurred in over 90% of tirzepatide-treated participants regardless of weight regain. Conclusion These findings suggest that most tirzepatide-treated participants with baseline prediabetes in the SURMOUNT-1 3-year study had limited weight regain after reaching weight nadir and sustained improvements in glycemia. (SURMOUNT-1 ClinicalTrials.gov identifier: NCT04184622.) Clinical Relevance In the current study, 92% of prediabetes participants treated with tirzepatide in the SURMOUNT-1 3-year study had a stable weight journey. Their limited weight regain from weight nadir appears not to be clinically meaningful, as improvements in cardiometabolic risk parameters were largely maintained.