Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Are Associated With Reduced Early but Increased Chronic Postoperative...

Background Diabetes mellitus increases the risk of postoperative complications following orthopedic shoulder surgery. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for glycemic control in type 2 diabetes mellitus, yet their influence on perioperative and long-term postoperative outcomes remains unclear.  Methods A retrospective cohort study was conducted using the TriNetX Research Network to identify adults (≥18 years) with type 2 diabetes who underwent orthopedic shoulder procedures and were either prescribed or not prescribed a DPP-4 inhibitor. After 1:1 propensity score matching for demographics, comorbidities, and procedure type, 834 patients were included in each cohort. Outcomes included 30-day emergency department (ED) visits, one- and two-year reoperation rates, and postoperative opioid use.  Results ED visits and reoperation rates at one and two years were similar between cohorts. DPP-4 inhibitor users demonstrated significantly lower rates of early postoperative opioid use compared with non-users (33.6% vs. 45.3%; RR: 0.741; 95% CI: 0.656-0.836; p < 0.001). No significant difference was observed in prolonged opioid use (21.5% vs. 21.2%; RR: 1.011; 95% CI: 0.841-1.216; p = 0.952). However, DPP-4 users had significantly higher rates of chronic postoperative opioid use (21.2% vs. 13.7%; RR: 1.553; 95% CI: 1.252-1.925; p < 0.001). Conclusion DPP-4 inhibitor exposure within six months prior to shoulder surgery was not associated with differences in long-term surgical outcomes or early emergency medical utilization among patients with type 2 diabetes. However, DPP-4 users demonstrated lower early but higher chronic postoperative opioid use, suggesting that incretin pathway modulation may have time-dependent effects on postoperative pain physiology. These findings suggest a potential link between metabolic therapy and postoperative pain adaptation and warrant further investigation into the underlying mechanisms.