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  • TCS 5861528 and The possibility of harm with DPP inhibitors

    2019-10-16

    The possibility of harm with DPP-4 inhibitors in patients with clinically overt heart failure has been recently highlighted by the results of the VIVIDD (Vildagliptin in Ventricular Dysfunction Diabetes) trial (68), the only trial to date that has been designed to evaluate the effects of a DPP-4 inhibitor in patients with established left ventricular dysfunction. In the trial, 254 patients with diabetes with chronic heart failure and left ventricular ejection fractions <40% were randomly assigned (double-blind) to placebo and vildagliptin for 1 year. The background use of metformin was low (≤35%). Left ventricular chamber size increased significantly in the patients treated with the DPP-4 inhibitor compared with placebo. Furthermore, 14.8% of the vildagliptin group and 11.1% of the placebo group experienced cardiovascular hospitalizations; 8.6% of the vildagliptin group, but only 3.2% of the placebo group, died. The number of clinical events was too small to interpret reliably. Nevertheless, these results are not reassuring, and they heighten concerns that physicians know little about the use of DPP-4 inhibitors in patients with clinically important left ventricular dysfunction. Interestingly, a review of studies registered at ClinicalTrials.gov does not identify any planned or ongoing randomized controlled clinical trials of DPP-4 inhibitors in patients with established heart failure.
    Summary and Conclusions
    Introduction Dipeptidyl peptidase 4 (DPP-4) is an exopeptidase expressed on a variety of different organs and also on the surface of inflammatory TCS 5861528 and and cells from the kidney, it also occurs in a soluble form in the plasma [1]. DPP-4 is an important target to improve glucose homeostasis in patients with diabetes mellitus since it inactivates incretins like glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) that stimulate secretion of insulin [2]. The proteolytic activity of DPP-4 is not restricted to incretins, it also influences the activity of several different bioactive compounds including chemokines like Rantes or CCL2 and growth factors like SDF-1 [3]. The activity of DPP-4 in the kidney is compared to other organs one of the highest [4]. Interestingly, data from clinical studies and experimental studies investigating animal models of renal injury suggest that DPP-4 inhibitor therapy may be renoprotective [5], [6], [7], [8], [9]. Currently, several different DPP-4 inhibitors are available for the treatment of patients with type 2 diabetes mellitus. The various inhibitors are known to express different binding and pharmacokinetic characteristics [10]. However, meta-analysis for linagliptin and sitagliptin in patients with type 2 diabetes mellitus revealed comparable efficacy on changes in HbA1c and and safety [11], but data on their impact on renal DPP-4 activity are lacking.
    Methods
    Results In non-treated control rats, kidney-specific DPP-4 activity ranged between 4 and 5.8µU/mg total protein at all investigated time points (Fig. 1A). Inhibition of kidney-specific DPP-4 activity in sitagliptin-treated rats decrease rapidly below 40% at 10 h after last dosing and was lost after 24 h (Fig. 1B, triangles). In contrast, in linagliptin-treated rats kidney-specific DPP-4 activity was significantly lower 6–24 h after last dosing compared to the sitagliptin group (Fig. 1A). Of note, within the first 24 h in linagliptin-treated rats, renal DPP-4 inhibition remained relatively high, always being above 85% (Fig. 1B). Inhibition of renal DPP-4 activity was confirmed by in situ activity assay using kidney cryosections. In the control animals, high DPP-4 activity was detected in glomeruli and proximal tubules, whereas DPP-4 activity in linagliptin-treated rats was almost lacking during first the 24 h after last dosing and still visible after 48 h (Fig. 2). In contrast, renal DPP-4 inhibition in the sitagliptin group was hardly detectable by the in situ assay, even at early time points (Fig. 2). In addition, inhibition of plasma DPP-4 activity was again significantly higher 10–48 h after last dosing in linagliptin-treated compared to sitagliptin-treated rats (Fig. 1C). Although inhibition of plasma DPP-4 activity was 44.7 ± 6.2% at the 24-hour time point in the linagliptin group, we detected only 10.6 ± 5.6% inhibition in the sitagliptin group (Fig. 1C). Plasma levels of incretins, the natural DPP-4 substrates GLP-1 and GIP, were markedly increased transiently, showing peak levels 6 h after last dosing and highest concentrations in linagliptin-treated rats (Fig. 1D, E). Fed plasma glucose at the beginning ranged between 7.2 and 8.6 mM in the different groups, showing the glucose levels following food intake during the night phase. At later time points plasma glucose decreased to around 6 mM without significant differences between treatment and control groups (Fig. 1F).