Background/Objectives: Semaglutide and tirzepatide demonstrate substantial efficacy in obesity treatment, yet individual responses vary markedly. The incretin system-comprising glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-is frequently dysregulated in obesity, but whether fasting incretin levels predict differential pharmacological responses remains unexplored. We investigated whether combinatorial fasting GLP-1/GIP tertile profiles predict the initial weight-loss response to semaglutide versus tirzepatide in patients with severe obesity. Methods: 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) at the University of Catania, Italy. Fasting serum GLP-1 (0.8-50 pg/mL) and GIP (1-16 ng/mL) were measured by chemiluminescence immunoassay and distributed into tertiles, generating nine combinatorial profiles (P1-P9; n = 10 per profile). Within each profile, five patients were randomly assigned to semaglutide (escalated to 2.4 mg/week) or tirzepatide (escalated to 15 mg/week). Primary outcome was pharmacological response category at six months: low (<5% body weight reduction), intermediate (5-15%), or optimal (>15%). Results: Baseline characteristics were balanced across profiles (age 48 ± 8 years, BMI 42.5 ± 3.5 kg/m2, waist circumference 134 ± 12 cm, HOMA-IR 8.5 ± 3.0; all p > 0.05). Tirzepatide achieved optimal response in profiles with low GIP tertile regardless of GLP-1 level (P1, P6, P8), while semaglutide achieved optimal response when GLP-1 was low and GIP was intermediate-to-high (P4, P5). Both drugs showed low response in the high GLP-1/high GIP profile (P3). Mean weight loss in optimal-response groups was 18.2 ± 2.1% for tirzepatide and 16.8 ± 1.9% for semaglutide. Waist circumference reductions paralleled weight loss patterns. HOMA-IR decreased significantly in all optimal-response groups (mean reduction 4.2 ± 1.1 units). Conclusions: In this hypothesis-generating pilot study, fasting GLP-1/GIP combinatorial profiling, obtained from a single fasting blood sample, was associated with differential pharmacological responses to semaglutide and tirzepatide in severe obesity. Low GIP levels were tentatively associated with optimal tirzepatide response; low GLP-1 with intermediate-to-high GIP was tentatively associated with optimal semaglutide response. These preliminary findings provide proof-of-concept for incretin-guided personalised obesity pharmacotherapy but require confirmation in larger, adequately powered randomised trials before any clinical recommendations can be made. The inability to discriminate incretin secretory deficiency from receptor resistance using fasting measurements alone, the absence of a placebo control, and the six-month follow-up (shorter than the 12-18 months at which maximal efficacy is typically observed) remain critical limitations.
