DPP-4 Inhibition and the Path to Clinical Proof

Abstract

In the 1990s it was discovered that the enzyme dipeptidyl peptidase-4 (DPP-4) inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibition results in raised levels of the two incretin hormones which in turn result in lowering of circulating glucose through stimulation of insulin secretion and inhibition of glucagon secretion. Since then, several small orally available molecules have been developed with DPP-4 inhibitory action. Early studies in the 1990s showed that the DPP-4 inhibitors improve glycemia in animals. Subsequent clinical studies during the 2000s showed a glucose-lowering action of DPP-4 inhibitors also in human subjects with type 2 diabetes. This action was seen when DPP-4 inhibitors were used both as monotherapy and as add-on to other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. The DPP-4 inhibitors were also found to have a low risk of adverse events, including hypoglycemia. Five of the DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities and entered the market between 2006 and 2013. DPP-4 inhibitors have thereafter undergone long-term cardiovascular outcome trials, showing non-inferiority for risk of major acute cardiovascular endpoints. Also the risk of other potential adverse events is low in these long-term studies. DPP-4 inhibitors are at present included in guidelines as a glucose-lowering concept both as monotherapy and in combination therapies. This article summarizes the development of the DPP-4 inhibition concept from its early stages in the 1990s. The article underscores that the development has its basis in scientific studies on pathophysiology of type 2 diabetes and the importance of targeting the islet dysfunction, that the development has been made possible through academic science in collaboration with the research-oriented pharmaceutical industry, and that the development of a novel concept takes time and requires focused efforts, persistence and long-term perserverance.

Repurposing anti-diabetic drug “Sitagliptin” as a novel virulence attenuating agent in Serratia marcescens

“…Heterocyclic nitrogenous compounds were tested broadly as anti-QS inhibitors [18][19][20], particularly pyrazine derivatives that were successfully used to modulate QS in Vibrio cholerae [18] and triazole derivatives that showed efficient anti-QS activity [21][22][23]. Sitagliptin, a pyrazine derivative with triazole moiety, is a hypoglycaemic agent for type II diabetes patients via inhibition of dipeptidyl-peptidase IV [35]. In this study, augmented resistance of S. marcescens isolated from endotracheal aspiration of diabetic patient admitted to intensive care unit was found.…”

Sitagliptin as an Initial Therapy and Differential Regulations of Metabolic Parameters Depending on its Glycemic Response in Subjects with Type 2 Diabetes

“…DPP-4 inhibitors are known to augment beta-cell function [2,3], however, their effects on insulin resistance (sensitivity) remain elu-▶table 2 Link between the A1c index and glyemic and non-glycemic parameters. Simple regression analysis was performed between the A1c index and the baseline levels or changes of the indicated parameters (overall subjects).…”

Immune interaction map of human SARS-CoV-2 target proteins: implications for therapeutic avenues

“…Subsequent clinical studies during the 2000s showed a glucose-lowering authority of DPP4 inhibitors in humans with type 2 diabetes as monotherapy or as combination with other therapies, i.e., metformin, sulfonylureas, tiazolidinediones or exogenous insulin. Five DPP-4 inhibitors (sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin) were approved by regulatory authorities for treatment of type 2 diabetes and entered the market between 2006 and 2013 (22).…”

“…Interestingly, a correlation between DPP4 and ACE2 was found suggesting that both membrane proteins are relevant for the virus entry (21). DPP4 inhibitors are small molecules, which enter the catalytic pocket of the dimeric structure of DPP4 and bind to the catalytic site, thereby preventing the proteolytic activity (22). The coexpression of ACE2 and DPP4 as receptors of spike glycoproteins postulates that different human CoVs target similar cell types across different human tissues and explain the presence of comparable clinical features in patients infected with different CoVs.…”