Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors
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MINI REVIEW
Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors Teresa Vanessa Fiorentino1 • Giorgio Sesti1
Received: 29 August 2015 / Accepted: 18 November 2015 Ó Springer Science+Business Media New York 2015
Abstract Previous trials of glucose-lowering strategies in subjects with type 2 diabetes have demonstrated a beneficial effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular complications. The findings of meta-analyses of rosiglitazone trials suggesting that rosiglitazone might increase the risk of myocardial infarction have cast doubt on the cardiovascular safety of glucose-lowering drugs. In 2008, the US Food and Drug Administration has implemented rigorous criteria to approve new glucose-lowering drugs, requiring proof of cardiovascular safety. These regulatory requirements have led to a considerable increase in the number of cardiovascular outcome trials in type 2 diabetes to ensure that newer glucose-lowering drugs are not associated with increased cardiovascular risk. Incretinbased therapies including dipeptidyl peptidase 4 (DPP-4) inhibitors, and injectable glucagon-like peptide 1 (GLP-1) receptor agonists are novel treatment options for patients with inadequate glucose control. Although DPP-4 inhibitors have shown neutral effects on risk factors for cardiovascular diseases, it remains unclear whether treatment with these new glucose-lowering agents might be associated with a reduction in cardiovascular events. The results of the three cardiovascular outcome trials comparing DPP4 inhibitors treatment to placebo in addition to other glucose-lowering drugs have been published. All the three DPP-4 inhibitor cardiovascular outcome trials have shown non-inferiority with regard to cardiovascular safety,
& Giorgio Sesti [email protected] 1
Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Viale Europa, 88100 Catanzaro, Italy
compared with placebo, when added to usual care. In this review, we summarize cardiovascular outcome trials of DPP-4 inhibitors, and provide an overview of these trials and their limitations. Keywords DPP-4 inhibitors Sitagliptin Alogliptin Saxagliptin Cardiovascular disease Cardiovascular safety
Introduction Type 2 diabetes mellitus (T2DM) is recognized as a major risk factor for the development of cardiovascular disease (CVD) [1–3]. Although the mechanism underlying the enhanced cardiovascular risk in T2DM remains undefined, glucose-toxicity at vasculature level is considered a plausible candidate [4–6]. The pivotal UK Prospective Diabetes Study (UKPDS) has demonstrated a beneficial effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular complications [7] with the exception of metformin treatment that was associated with a reduction of the relative risk for fatal and non-fatal myocardial infarction and all-cause mortality in a relatively small group of ove
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