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  • DPP is show two relevant

    2020-03-21

    DPP-4is show two relevant benefits in the clinical management of type 2 diabetic patients: negligible risk of severe hypoglycemia, particularly when compared with sulphonylureas [[33], [34]], and weight neutrality, in contrast with the weight gain generally observed with insulin therapy, sulfonylureas, glinides, and thiazolidinediones [[11], [33]]. Indeed, since the insulinotropic effects of DPP-4is are glucose-dependent, these agents do not affect the glucagon compensatory response to hypoglycemia, leading to low incidence of hypoglycemic episodes [24]. Currently, five DPP-4is are available for use in clinical practice: sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin [24]. The main pharmacokinetic and pharmacodynamic features of DPP-4is available on the European market are summarized in Table 1. All these agents are rapidly absorbed orally, irrespective of concomitant administration with food, and their peak plasma concentrations (tmax) occur between 1 and 3 h after administration [35]. Their bioavailability is ≥63% except for linagliptin (∼30%) [36], whose gastrointestinal Kif15-IN-1 mg is inhibited by P-glycoprotein [37]. Both lipophilicity and protein binding strongly affect the distribution of DPP-4is. Compared to other gliptins, linagliptin exhibits higher volume distribution (Vd) (more than 1000 l) and protein binding (≥75%), showing extensive distribution into tissues [[35], [38]]. Metabolism of DPP-4is is widely variable. Both vildagliptin and saxagliptin are largely metabolized in the liver: vildagliptin produces several inactive metabolites through pathways that are not mediated by the cytochrome P450 (CYP) system, while saxagliptin is mainly metabolized by CYP 3A4/5 isoforms to 5-hydroxy saxagliptin, a major metabolite that is two-fold less potent than its parent molecule [39]. On the other hand, metabolism represents a minor elimination pathway for sitagliptin [40]. No DPP-4 inhibitor has been shown to induce or inhibit CYP isoforms: hence, a low risk of clinically significant drug–drug interactions is associated with these agents. However, a potential higher risk of drug–drug interactions with saxagliptin exists when this agent is co-administered with drugs that are strong inhibitors (e.g. ketoconazole) or inducers (e.g. rifampicin) of CYP3A4/5 isoforms. Dose adjustment is required in these cases [[35], [39]]. All gliptins are predominantly excreted in the urine, with 60–85% of each dose eliminated as unchanged parent compound. In contrast, linagliptin undergoes enterohepatic cycling and it is mainly excreted in the feces (∼90%). Accordingly, the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidelines advocate dosing-adjustment for sitagliptin, vildagliptin, saxagliptin, and alogliptin in patients with moderate or severe renal impairment whereas no restrictions have been posed for linagliptin [[18], [42]].
    Pleiotropic effects of DPP-4 inhibitors beyond glycemic control Beyond the pancreas, GLP-1R and DPP-4 are expressed in a wide variety of organs and tissues, such as the central and peripheral nervous system, heart, lung, gastrointestinal tract, eye and kidney, thereby explaining the pleiotropic effects of the incretin system [[43], [44], [45]]. Some of these extra-pancreatic effects might be exploited to prevent or treat diabetes-related complications, independently of the achievement of glycemic control. Accordingly, GLP-1 has been shown to prevent atherosclerosis-related diseases (i.e., cerebrovascular, coronary artery and peripheral artery disease), through direct actions on the brain [[46], [47], [48], [49]], heart [[50], [51], [52], [53]] and vascular endothelial cells (ECs) [[54], [55], [56], [57], [58], [59]]. Particularly, GLP-1 has been reported to inhibit macrophage-driven atherosclerosis in healthy and diabetic apolipoprotein E-deficient mice [[60], [61]]. Furthermore, GLP-1-mediated suppression of inflammatory cytokines has been shown in diabetic patients, resulting in improved endothelial dysfunction [[62], [63], [64]]. In addition, in vitro studies showed that GLP-1 was able to increase endothelial nitric oxide (NO) production and promote both proliferation and differentiation of cultured endothelial progenitor cells by upregulating vascular endothelial growth factor [[56], [57]]. These effects respectively translated into increased microvascular blood flow and improved endothelial dysfunction in preclinical models [[56], [58]]. Inhibition of both nuclear factor (NF)-kB pathway and apoptosis of human umbilical vein ECs appear to be other GLP-1-mediated anti-atherogenic mechanisms [[59], [65]]. Consistent with the above anti-atherosclerotic effects, sitagliptin [66], alogliptin [[66], [67]], and vildagliptin [[68], [69]] inhibited the production of inflammatory cytokines and the NF-kB pathway while increasing endothelial NO production in experimental animal models. Interestingly, such vasoprotective effects were also observed in type 2 diabetic patients treated with sitagliptin [[70], [71]]. It is noteworthy that the increase in NO production might explain the ability of GLP-1 to counteract hypertension by exerting an arteriolar vasodilatory action, as consistently shown in several clinical trials [[72], [73]]. Moreover, it has been reported that sitagliptin attenuates blood pressure in both hypertensive rats [[74], [75]] and humans [[76], [77]].