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Diabetes Obes Metab. 2019 Jan 28. doi: 10.1111/dom.13645. [Epub ahead of print]

FDA Guidance on Antihyperglycemic Therapies for Type 2 Diabetes: One Decade Later.

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University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany.
Clinical Development, Therapeutic Area Cardiometabolism, Boehringer Ingelheim, Norway.
Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA.
Dallas Diabetes Research Center at Medical City and University of Texas, Southwestern Medical Center, Dallas, USA.
Clinical Development, Therapeutic Area Cardiometabolism, Boehringer Ingelheim, Germany.


In 2008, the FDA issued a guidance to industry on evaluating the cardiovascular (CV) safety of new antihyperglycemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing 3 novel classes of antihyperglycemic therapies (i.e., DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors) have been completed by end of 2018, with several others ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), whereas 6 agents have demonstrated CV benefits. This experience has led to the first FDA-approved indications for antihyperglycemic medications to reduce the risk for CV death (empagliflozin) and to reduce the risk for MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Due to the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance, the contemporary paradigm for treatment for patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide with reduction in quality of life as well as life expectancy. The cost burden of drug development that may directly impact cost to patients and their insurers of medications proven effective, might be alleviated with modifications to the present guidance. These include areas of trial designs, trial operational aspects, expanding composite outcomes to include broader component CV outcomes, and continued evolution of analytic methodology. The guidance will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. But, the requirement to assess each new antihyperglycemic medication in at least one large-scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favorable efficacy/safety profiles of the medications they prescribe. This article is protected by copyright. All rights reserved.


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