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  • br Future perspectives Understanding how

    2020-05-15


    Future perspectives Understanding how peptides are degraded, particularly those which may be therapeutically useful, such as GLP-1, has proved to be invaluable in providing a rationale for the development of a novel class of therapeutic agents. However, while DPP-4 plays an important role in the initial degradation of GLP-1, it is not the only enzyme involved in its metabolism. GLP-1 is also a substrate for neutral endopeptidase (NEP)-24.11 (a.k.a. neprilysin), which cleaves the molecule at several sites in the mid-region and C-terminal end [96]. Indeed, studies in anaesthetised pigs using a selective NEP 24.11 inhibitor raised immunoreactive GLP-1 levels (measured using C-terminal immunoassays) by around 50%, indicating substantial degradation by NEP 24.11 [97], a finding corroborated by measurement of GLP-1 in animals lacking NEP 24.11 activity (neprilysin knock-out mice) [98]. These results also suggest that immunoassays based around epitopes in the C-terminal portion of GLP-1 (often referred to as “total” GLP-1 assays because they measure both intact GLP-1 and the primary DPP-4 metabolite) may be under-estimating true concentrations. Such findings raise the possibility of further stabilising GLP-1 by targeting additional routes of metabolism in order to gain greater therapeutic efficacy. In itself, NEP 24.11 inhibition did not enhance the insulinotropic action of GLP-1 in anaesthetised pigs (because the peptide was still degraded by DPP-4), but, when combined with DPP-4 inhibition, Nitecapone synthesis secretion was enhanced [97]. In diabetic rats, however, there was no additional glycaemic benefit of combining NEP 24.11 and DPP-4 inhibition beyond that obtained by DPP-4 inhibition alone [99]. Whether this was because maximal efficacy had already been reached with the GLP-1 levels attained with DPP-4 inhibition alone or whether alterations in levels of other metabolites of GLP-1 (or other substrates) played a role is currently unknown. In this context, cleavage by NEP 24.11 is responsible for the generation of a C-terminal metabolite, GLP-1 28–36 amide in vitro [96] and in vivo [100]. This peptide has been shown to suppress glucose production in isolated hepatocytes [101] and to have β-cell protective and antidiabetic effects in mice [102], [103]. Although whether endogenous levels of this metabolite are affected by NEP 24.11 inhibition in vivo is not known, any reduction in its concentrations may potentially off-set the effects associated with increased levels of intact GLP-1 in terms of their effects on glucose homeostasis, and provide a potential explanation for the observation that dual NEP 24.11/DPP-4 inhibition did not further improve glycaemic control [99]. Clearly then, further understanding the complex metabolism, not only of GLP-1, but also of the other potential mediators of the clinical effects of DPP-4 inhibition (Fig. 1) as well as effects of their metabolites is needed and may lead to additional drug targets and/or additional therapeutic targets in addition to T2DM.
    Disclosure
    Introduction Dipeptidyl peptidase 4 (DPP-4) inhibitors are a commonly prescribed drug class in patients with type 2 diabetes mellitus (T2DM) and renal impairment; they are both efficacious and well tolerated when used at appropriate doses according to renal impairment severity. With the exception of linagliptin, which does not require dose adjustment, Summaries of Product Characteristics (SPCs) note that the dose of DPP-4 inhibitors should only be reduced according to the patient\'s renal function.3, 4, 5, 6 In addition, the dose of vildagliptin should be reduced to 50 mg once daily regardless of renal function when used in combination with a sulfonylurea. Nevertheless, 2 recent real-world evidence studies, adopting a range of renal impairment definitions (including those specified in the respective DPP-4 inhibitor SPCs), concluded that at least one third of patients with T2DM and renal impairment when initiated on a DPP-4 inhibitor requiring dose adjustment were prescribed a higher than the SPC-specified dose.7, 8 These findings call into question whether all patients initiated on a DPP-4 inhibitor whose renal function does not indicate dose adjustment are treated in accordance with SPCs.