br Discussion Several DPP inhibitors

Discussion Several DPP-4 inhibitors are currently available for use in the treatment of type 2 diabetes mellitus. Due to the different chemical structures there are marked differences both in the binding kinetics on the target enzyme [10] and also different pathways of elimination [13] exist. In this study we investigated renal DPP-4 inhibition by comparing the actions of sitagliptin and linagliptin. Although earlier studies indicated that functional capacity, measured in terms of glucose-lowering ability and increase of active GLP-1 levels, was comparable across all available DPP-4 inhibitors, there are clear differences in metabolism, half-life and elimination [14]. These differences could well be responsible for apparent differences in their ability to inhibit tissue DPP-4 activity. In these experiments, inhibition of renal DPP-4 was low for sitagliptin whereas, linagliptin effectively inhibited DPP-4 activity for over 24 h. The kidney is the organ with the most prominent DPP-4 GSK1838705A in rodents but also in humans. Linagliptin is the DPP-4 inhibitor, which shows the slowest dissociation from DPP-4 protein than all other DPP-4 inhibitors. This is reflected by a Koff which is around 1000x lower than for sitagliptin [10]. As a consequence, sitagliptin dissociates much faster from DPP-4 protein in the kidney and is further eliminated. Linagliptin binds much longer and therefore has the potential to inhibit renal DPP-4 more sustainable. The doses for sitagliptin used in this study were 3 times higher compared to other rat studies [12], [15], therefore it is unlikely that the observed sitagliptin effects are underestimated. In addition, active GIP and GLP-1 were similarly increased by sitagliptin and linagliptin in the current study, indicating correct dosing of both drugs. Therefore, it is possible that differences in kidney-specific DPP-4 inhibition profiles could differentiate DPP-4 inhibitors in terms of their known renoprotective effects [5], [7], [8], [9], [16]. Potential renoprotection due to DPP-4 inhibition include anti-fibrotic effects as demonstrated in mouse models e.g. for unilateral ureter obstruction [6], diabetes mellitus [10] and a model for chronic kidney disease in the rat [11] and anti-inflammatory effects as observed in different renal disease models [12], [13], [14]. In addition, DPP-4 inhibitor mediated renoprotection is may be also due to improved endothelial function, as reported in a recent study in patients with type 2 diabetes treated with linagliptin [17]. The ultimate clarification of the potential clinical renal benefits of linagliptin will be shown by the final results of the ongoing Carmelina trial, a randomized, double-blind, clinical trial conduced in 27 countries in type 2 diabetes patients at high cardiovascular and/or kidney events [18], investigating renal outcomes including occurrence of end-stage kidney disease, changes in glomerular filtration rate and renal death.
Introduction The pharmacological and therapeutic implications [1] as well as the cardiovascular (CV) benefits and safety [2], [3] of glucose-lowering medications used in the treatment of type 2 diabetes mellitus (T2DM) have been recently examined in extensive reviews. Sulphonylureas (SUs) have been the only insulin secretagogues available for the treatment of T2DM for many decades. In a number of countries, they are still the only option to combine with metformin and, in other places, they remain the preferred compounds instead of the other, more recent options because of their more widespread clinical experience and economic factors [4]. Indeed, they are considerably cheaper than the newly developed glucose-lowering agents. However, SUs are associated with undesirable effects such as the risk of hypoglycaemia and of weight gain [5]. Furthermore, their CV safety has been a matter of debate for>40 years despite their extensive use worldwide [4], [6]. Consequently, opinion varies widely in the international literature, with some authors arguing that now is the time to abandon the use of SUs [7], whereas others believe that SUs still have a place in clinical practice [8], [9].