Fasting GLP-1 and GIP levels predict differential weight loss response to semaglutide and tirzepatide

Despite the significant efficacy of semaglutide and tirzepatide in obesity treatment, individual patient responses vary considerably. The incretin system, comprising glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is frequently dysregulated in obesity. However, it remains unclear whether baseline fasting incretin levels can predict a patient's differential pharmacological response to these potent anti-obesity medications. Understanding this could lead to more personalized and effective treatment strategies.

This prospective, parallel-group, open-label pilot study enrolled 90 treatment-naïve patients with BMI > 40 kg/m2 (mean 42.5 ± 3.5 kg/m2) in Italy. Fasting serum GLP-1 and GIP levels were measured using chemiluminescence immunoassay and categorized into tertiles, creating nine combinatorial profiles (P1-P9; n = 10 per profile). Within each profile, five patients were randomized to receive semaglutide (escalated to 2.4 mg/week) or tirzepatide (escalated to 15 mg/week). The primary outcome was pharmacological response category (low, intermediate, or optimal) at six months.

Baseline characteristics were balanced across all nine incretin profiles (p > 0.05). The study found that tirzepatide achieved an optimal weight loss response (defined as >15% body weight reduction) primarily in profiles characterized by a low GIP tertile, irrespective of the GLP-1 level (profiles P1, P6, P8). Conversely, semaglutide achieved optimal response when GLP-1 was low and GIP was intermediate-to-high (profiles P4, P5). Both medications demonstrated a low response (<5% body weight reduction) in the high GLP-1/high GIP profile (P3).