Weight Regain During Continued Incretin Therapy Is Associated With an Inflammatory Signature at Weight Nadir and Higher Cardiovascular Event Rates

Weight regain during semaglutide or tirzepatide treatment is linked to increased inflammation and higher cardiovascular event rates, highlighting the need for careful monitoring.

Summary and findings

This study analyzed weight trajectories in adults treated with semaglutide or tirzepatide, focusing on weight regain after initial loss. Among 58,618 patients, 8,389 (14.3%) regained ≥5 percentage points from their lowest body weight. The study also examined inflammatory markers and cardiovascular event rates associated with weight regain.

Abstract

For patients treated with semaglutide or tirzepatide, weight-loss plateau followed by regain is a major concern, yet rebound occurring while treatment continues to be documented remains underappreciated and its biological correlates are poorly understood. Using a federated de-identified electronic health record (EHR) system across over 29 million de-identified U.S. patients, we analyzed adults initiating semaglutide or tirzepatide between 2021 and 2024. Among 58,618 patients who achieved ≥5% weight loss with evaluable 1-year weight trajectories, 8,389 (14.3%) regained ≥5 percentage points from their lowest observed bodyweight ("nadir"). Post-nadir treatment was ascertained from structured prescription orders together with positive mentions of medication received from clinical notes via AI-augmented curation. Among patients with at least of 90 days follow-up post-nadir, 45.8% of weight-regain patients were documented on treatment for at least half of their follow-up at a dose maintained at or above their pre-nadir maximum dose, compared with 51.6% of sustained responders (P < 0.001). Measured at the nadir relative to treatment initiation, weight-regain patients had a greater increase in neutrophil-to-lymphocyte ratio (+0.73 vs. +0.29) and neutrophils (+0.48 vs. +0.12 ×10⁹/L), with corresponding changes in albumin (−0.12 vs. −0.03 g/dL) and HDL (−0.65 vs. +1.03 mg/dL) (all P<0.001). These differences remained significant for the 45.8% of weight-regain patients with documented evidence of maintained treatment throughout their follow-up, indicating that the nadir-centred inflammatory, acute-phase, and lipoprotein changes may not be confined to patients whose treatment documentation lapsed. Gastrointestinal diagnoses and infections also peaked in weight-regain patients during the 3 months preceding the nadir (3.23% vs. 1.26% and 2.84% vs. 1.43%, both P<0.001). When weight status was reassessed longitudinally, event rates during regained time exceeded those during maintained-loss time (all q<0.001), including nonfatal MACE (12.9 vs. 9.6 per 1,000 person-years; adjusted RR: 1.43, 95% CI 1.22–1.67), heart failure (20.1 vs. 13.6; RR: 1.66, 1.45–1.89), and cardiac arrest (1.8 vs. 0.9; RR: 2.11, 1.37–3.26). Our findings identify the weight nadir as an underappreciated transition point that may help recognize patients entering rebound while treatment continues, motivating prospective study of whether weight-loss durability can be preserved and whether doing so alters cardiovascular risk.

Limitations

Not reported in abstract.

Elsewhere in the Semaglutide corpus