This single-center observational study of a prospective PCI registry database involving consecutive Japanese diabetic patients primarily demonstrated that the use of DPP4i at the time of PCI procedure was associated with avoiding subsequent CV death and 3P-MACE. The merit of DPP4i was considerably augmented in patients with a lower BMI. Moreover, the ratio of IGF-1 to IGFBP-3, one of the enzymatic substrates of DPP4 to its main transport protein indicating the bioavailability of IGF-1, was significantly higher in patients with DPP4i. Kaplan-Meier analyses, as well as unadjusted and adjusted Cox proportional hazard analyses showed that a high IGF-1/IGFBP-3 ratio was associated with a significantly lower risk of CV death and 3P-MACE after PCI. Moreover, very similar to analyses with and without DPP4i, the prognostic impact of the IGF-1/IGFBP-3 ratio was enhanced in patients with a lower BMI.
DPP4, a multifunctional circulating or cell surface protein, is present on a wide range of cell types and exerts a variety of biological activities, such as protease activity, interaction with the extracellular matrix, and regulation of intracellular signaling [17, 19]. Inhibition of DPP4 lowers blood glucose by inhibiting the catalytic degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which promote insulin secretion from pancreatic beta-cells, and inhibit glucagon secretion and glucose production in the liver [20, 21]. Other than incretins, there are physiological substrates of DPP4 that are bioactive molecules cleaved by DPP4, such as BNP, neuropeptide Y, stromal cell-derived factor-1α (SDF-1α) and IGF-1 [17, 22]. Multiple lines of previous experimental evidence have demonstrated the cardioprotective and anti-atherogenic effects of DPP4i [7–9]. However, landmark large-scale randomized CVOTs of DPP4i which mainly involved patients with a history of CV disease (secondary prevention) did not show any clear benefit for reducing the risk of the composite of cardiovascular events [10–13]. Although these studies had been primarily designed to identify the non-inferiority, and not the superiority, of DPP4i compared to conventional diabetic medications, the study results and their clinical impacts were considerably different to those of SGLT-2 inhibitors [23, 24] and GLP-1 receptor agonists [25, 26]. However, observational studies have indicated that the effects of DPP4i might not be uniform among ethnicities or those with different BMI [14, 15]. The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (the DECODE) and in Asia (the DECODA) studies from the World Health Organization (WHO) demonstrated that both insulin resistance and secretion capacity are higher in Caucasians than Asians [27–29]. In Western countries, insulin resistance, which frequently occurs in conjunction with obesity, is the predominant pathophysiological issue, while impaired insulin secretion is a major issue in Asians  and a genetic difference in relation to diabetes between Asians and non-Asians has been also reported . In addition to ethnicity, it has been reported BMI might alter the effects of DPP4i . DPP4 enzymatic activity was suggested to be upregulated in proinflammatory situations, including obesity, and it was reported to be significantly positively correlated with BMI [19, 32].
Consistent with these previous findings regarding the possible superiority in the effects of DPP4i in Asians and individuals with low BMI, DPP4i in the present study was found to be beneficial at reducing the risk of CV death and 3P-MACE after PCI in the entire study population. Moreover, the merit of DPP4i was substantially enhanced in patients with a lower BMI (≤ 25) and attenuated in those who were overweight (BMI > 25). The present findings indicate that there might be subpopulations, such as Asians and those without overweight, who specifically benefit from DPP4i, although large scale CVOTs involving a limited number of Asians (9–20%) [10–13] and patients with low BMI failed to show any significant merit.
Among substrates which are catalytically deactivated by DPP4, there is a large body of evidence suggesting the cardioprotective effects are mediated through the IGF-1 axis, which leads to the improvement of endothelial function, plaque stability, and the inhibition of vascular inflammation [33–35]. It has been suggested that low circulating IGF-1 levels and high IGFBP-3 levels significantly increase the risk of developing ischemic heart disease in a primary prevention population . In this study, serum IGF-1 levels were similar in both patients with and without DPP4i, but IGFBP-3 levels were significantly reduced and the IGF-1/IGFBP-3 ratio was significantly increased in patients with DPP4i. Since the IGF-1/IGFBP-3 ratio has been considered to be an indicator of IGF-1 bioavailability , these findings suggest that administration of DPP4i might increase its bioavailability in this population, which in turn may lead to better outcomes. Consistently, prognostic analyses of the IGF-1/IGFBP-3 ratio by Kaplan-Meier and Cox proportional analyses have indicated its elevation was significantly associated with a reduced risk of adverse outcomes after PCI. Moreover, similar to that for DPP4i, the favorable prognostic impact of the IGF-1/IGFBP-3 ratio was substantially augmented in the population that was not overweight. Taking these findings together, the beneficial prognostic effects of DPP4i in this population may be exerted through the DPP4-IGF-1 axis.