Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • Further indirect evidence supporting an important

    2021-02-23

    Further indirect evidence supporting an important role of DPP-4 in the modulating the actions of both incretins comes from the observations that analogues of GLP-1 and GIP, modified to be resistant to DPP-4 cleavage, were subsequently shown to have greater metabolic stability in vivo which was associated with more potent and longer-lasting effects [23], [24], [25], [26], [27]. This line of research culminated in the clinical development of stable, long-lasting GLP-1 receptor agonists for the treatment of T2DM.
    Harnessing the therapeutic potential of DPP-4 inhibition By the late-1990s, the significance of DPP-4 for the initial degradation of the incretin hormones was becoming more apparent. This had led to the idea that blocking this route of metabolism may elevate levels of the intact biologically active peptides, which should therefore enhance their insulinotropic and hence, glucose-lowering effects, giving the rationale for using DPP-4 inhibition as a means of controlling hyperglycaemia in patients with T2DM [1]. While, theoretically, this was expected to be the case, it was unknown whether, once DPP-4 action was blocked, the half-life of the intact peptide would be prolonged in vivo and actually result in greater insulinotropic and glucose-lowering effects or whether any other routes of metabolism would be uncovered, meaning that in vivo efficacy would not be not improved. That DPP-4 was the major, if not the only route of metabolism of GLP-1 in vivo, at least acutely, was confirmed when it was shown that a DPP-4 inhibitor (valine-pyrrolidide) could not only completely prevent the degradation of exogenous GLP-1 in anaesthetised pigs, but was also associated with potentiated insulinotropic and antihyperglycaemic effects following an intravenous Berberine hydrochloride load [28]. Similar results were subsequently shown for GIP [29]. In rats, administration of a single dose of another DPP-4 inhibitor (ile-thiazolidide) improved insulin secretion and reduced glucose excursions after an oral glucose tolerance test, which was thought to be due to increased circulating levels of intact endogenous incretins [30]. This speculation was subsequently shown to be correct by the demonstration that valine-pyrrolidide fully protected endogenous GLP-1, released from the perfused porcine intestine, from degradation [21], while acute DPP-4 inhibition in vivo in rodent models of glucose intolerance using ile-thiazolodide [31], NVP-DPP728 [32] or valine-pyrrolidide [33] inhibited plasma DPP-4 activity and was associated with enhanced glucose-stimulated intact GLP-1 levels and improved glucose tolerance. Together, these studies established pre-clinical proof-of hypothesis that inhibiting DPP-4 activity could potentiate circulating levels of intact GLP-1 to enhance its effects on the endocrine pancreas and improve glucose homeostasis, and were soon followed by studies showing that these beneficial effects were still evident with chronic dosing. Thus, improvements in glucose tolerance were sustained over 12 weeks dosing with ile-thiazolidide in diabetic rats [34], while similar results were obtained in glucose-intolerant insulin-resistant mice treated with NVP-DPP728 for 8 weeks [35]. The final step, demonstrating clinical proof-of-concept, was achieved in 2002, just 7 years after the initial hypothesis [1] was published, when Ahrén and colleagues reported a 4 week clinical study using NVP-DPP728 in drug-naïve patients with T2DM, showing that the anti-hyperglycaemic effects of DPP-4 inhibition were also evident in humans. Fasting and postprandial glucose excursions were reduced and, despite the short treatment period, HbA1c levels were also modestly, but significantly, improved [36]. In another, analogous, 4 week study, this time with LAF237 (a.k.a. vildagliptin), similar results were obtained, but in this study, GLP-1 levels were also measured, showing that, as in the preclinical studies, the improved glycaemic control resulting from DPP-4 inhibition was associated with elevations in intact GLP-1 levels [37]. Finally, in 2004, the results of a 1-year study were published, convincingly showing that the antidiabetic effects of sustained DPP-4 inhibition were maintained. In this study, the addition of vildagliptin in patients with inadequate glycaemic control with metformin monotherapy not only prevented the deterioration in glycaemic control seen in the placebo group, but also improved fasting and postprandial glucose levels, resulting in a significant reduction in HbA1c levels [38]. Importantly, and indeed, as anticipated, given that it was already well-known that the insulinotropic and glucagonostatic effects of GLP-1 were dependent on the prevailing glucose levels (ie. glucose-dependent) [12], [39], the improvements in glucose homeostasis in these clinical studies were not accompanied by any increase in hypoglycaemia [36], [37], [38]. These early results were soon followed by numerous studies with a variety of different DPP-4 inhibitors, uniformly showing that DPP-4 inhibition effectively improves glycaemic control with low risk of hypoglycaemia, no weight gain and low incidence of adverse events when used as monotherapy or in combination with other anti-diabetic drugs, even in patients with long-standing diabetes and poor β-cell function (because they act to suppress glucagon secretion) [40], [41]. DPP-4 inhibitors soon after received regulatory approval for use as anti-hyperglycaemic agents, and the first compound was launched in 2006. As testament to the success of a drug design strategy based on a prior understanding of the endocrinology and degradation of GLP-1, DPP-4 inhibitors are now a successful and widely used therapy of T2DM, with at least 11 different drugs approved in various parts of the world [42].