Dipeptidyl Peptidase-4 Inhibitors Reduced Long-term Cardiovascular Risk in Japanese Diabetic Patients After Percutaneous Coronary Intervention via Insulin-like Growth Factor-1 Axis: A 10-year Follow-up Study

Abstract Background: Dipeptidyl-peptidase-4 inhibitors (DPP4i) have become one of the most used antidiabetic medications worldwide due to their good safety profiles and tolerability with a low risk of hypoglycemia, however, no large cardiovascular outcome trials (CVOTs) have shown any significant superiority with respect to reducing cardiovascular risk. On the contrary, since observational studies have suggested the effects of DPP4i are enhanced some populations, such as Asians and those who without overweight, their prognostic benefit is still under debate. Therefore, the aim of this study was to assess the prognostic impact of DPP4i in patients with both diabetes and coronary artery disease (CAD) through the insulin-like growth factor-1 (IGF-1) axis, a substrate of DPP4 and it is relevant for the cardiovascular system.Methods: This single-center analysis involved consecutive Japanese diabetic patients who underwent percutaneous coronary intervention (PCI) for the first time between 2008 and 2018 (n=885). Primary and secondary endpoints were set as cardiovascular (CV)-death and the composite of CV-death, non-fatal myocardial infarction and ischemic stroke (3P-MACE). Serum levels of IGF-1 and its main binding protein (IGF- binding protein 3: IGFBP-3) were measured by ELISA.Results: Unadjusted Kaplan-Meier analyses revealed reduced incidences of CV-death and 3P-MACE by DPP4i, which was particularly enhanced in patients who were not overweight (BMI ≤25). Multivariate Cox hazard analyses consistently indicated reduced risks of CV-death by DPP4i at PCI (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.16–0.82, p=0.01) and 3P-MACE (HR: 0.47, 95% CI: 0.25–0.84, p=0.01), respectively. Moreover, elevated IGF-1 activity indicated by the IGF-1/IGFBP-3 ratio was associated with decreased risks of both endpoints and it was significantly higher in patients with DPP4i (p<0.0001).Conclusion: The findings of the present study indicate that DPP4i improved outcomes in Japanese diabetic patients following PCI, in which the beneficial effects might be mediated by DPP4-IGF-1 axis. Trial registration: This study reports the retrospective analysis of a prospective registry database of patients who underwent PCI at Juntendo University Hospital, Tokyo, Japan (Juntendo Physicians’ Alliance for Clinical Trials, J-PACT), which is publicly registered (University Medical Information Network Japan - Clinical Trials Registry, UMIN-CTR 000035587).