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Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors

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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. Incretin-based 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 DPP-4 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, 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.

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Funding

Professor Giorgio Sesti has received consultancy fees from Merck, Novo Nordisk, Janssen, Servier, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Intarcia, and Sanofi; and speaking fees from Novo Nordisk, Merck, Boehringer Ingelheim, Eli Lilly, Sanofi, Janssen, and Novartis.

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  1. Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Viale Europa, 88100, Catanzaro, Italy

    Teresa Vanessa Fiorentino & Giorgio Sesti

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Correspondence to Giorgio Sesti.

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Fiorentino, T.V., Sesti, G. Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors. Endocrine 53, 373–380 (2016). https://doi.org/10.1007/s12020-015-0811-7

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