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

Background : Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonist tirzepatide provide significant glycemic control and weight loss, along with other benefits such as cardiovascular (CV) advantages. Despite these advancements, widespread use is mainly limited by gastrointestinal side effects, cost, and frequent shortages. The oral antidiabetic class dipeptidyl peptidase-4 inhibitors (DPP-4i), though less effective, are well-tolerated and more affordable. Current guidelines recommend against combining GLP-1RAs with DPP-4i, citing redundancy and limited clinical benefit. Methods : A narrative synthesis of the pharmacology, physiology, and clinical data related to incretin receptor agonists and DPP-4i was conducted to critically assess whether and when their combination can be safely and effectively used. Results and discussion : The standard guidelines recommendations against combining a DPP-4i with a GLP-1RA or tirzepatide are based on 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. Conclusion : 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.