Rationale for DPP-4 Inhibitors as Bridge or Dose-Sparing Therapy in Patients Using GLP-1 Receptor Agonists or Tirzepatide

Guidelines recommend against combining a DPP-4i (e.g., sitagliptin) with a GLP-1RA (e.g., semaglutide) or tirzepatide due to limited evidence. However, analyzing agents’ different pharmacodynamics suggests potential complementarity rather than complete redundancy: incretin receptor agonists provide continuous, supraphysiological receptor activation, while DPP-4i extend endogenous GLP-1 and GIP activity, maintaining meal-related pulsatility. Additionally, DPP-4 cleaves multiple peptides beyond incretins, raising the possibility of other effects. Thus, DPP-4i could offer supportive benefits to incretin receptor agonist therapy: bridging during treatment gaps, dose-sparing when higher doses aren’t tolerated, stabilizing weight control in obesity without diabetes, and maintaining incretin tone in resource-limited settings. Physiological reasoning and real-world needs support re-evaluating the potential of using an incretin receptor agonist with a DPP-4i. Rigorous crossover studies, randomized trials, and pharmacoeconomic analyses are urgently needed to determine if the theoretical synergy leads to clinically meaningful outcomes.