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Implications of the recent CVOTs in type 2 diabetes: The right place for DPP-IV inhibitors today

Published:October 30, 2019DOI:https://doi.org/10.1016/j.diabres.2019.107906
      The use of small molecule inhibitors of the enzyme dipeptidyl peptidase IV (DPP4i) was proposed in 1998 as an approach to the management of diabetes, acting by reducing glucagon-like peptide 1 (GLP-1) degradation and hence potentiating its insulinotropic effect [
      • Deacon C.F.
      • Hughes T.E.
      • Holst J.J.
      Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig.
      ]. By 2005, effects of the DPP4i vildagliptin [
      • Mari A.
      • Sallas W.M.
      • He Y.L.
      • Watson C.
      • Ligueros-Saylan M.
      • Dunning B.E.
      • et al.
      Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes.
      ] and sitagliptin [
      • Herman G.A.
      • Stevens C.
      • Van Dyck K.
      • Bergman A.
      • Yi B.
      • De Smet M.
      • et al.
      Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.
      ] were reported in human trials, leading to the development of a class of drugs whose use among US Medicare beneficiaries alone accounted for expenditure of $1.5 billion in 2012, increasing to $3.9 billion in 2017 [
      • Sumarsono A.
      • Everett B.M.
      • McGuire D.K.
      • Fonarow G.C.
      • Butler J.
      • Pandey A.
      • et al.
      Trends in aggregate use and associated expenditures of antihyperglycemic therapies among US medicare beneficiaries between 2012 and 2017.
      ]. During these two decades, there have been tremendous changes in our understanding of the outcomes of treatment of type 2 diabetes (T2D), with questions raised about potential harms of rosiglitazone by some authors [
      • Nissen S.E.
      • Wolski K.
      Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
      ], although debated [
      • Bloomgarden Z.T.
      The Avandia debate.
      ], leading to an administrative decision by the US FDA that all treatments for T2D are required to undergo clinical trials to determine whether they are safe in persons with cardiovascular disease (CVD), considerably increasing the cost of developing such treatment [
      • McGuire D.K.
      • Marx N.
      • Johansen O.E.
      • Inzucchi S.E.
      • Rosenstock J.
      • George J.T.
      FDA guidance on antihyperglyacemic therapies for type 2 diabetes: one decade later.
      ].
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