Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.

Abstract

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

• Authors: Javed Butler, Milton Packer, Stephen J Greene, Mona Fiuzat, Stefan D Anker, Kevin J Anstrom, Peter E Carson, Lauren B Cooper, Gregg C Fonarow, Adrian F Hernandez, James L Januzzi Jr, Mariell Jessup, Rita R Kalyani, Sanjay Kaul, Mikhail Kosiborod, JoAnn Lindenfeld, Darren K McGuire, Marc S Sabatine, Scott D Solomon, John R Teerlink, Muthiah Vaduganathan, Clyde W Yancy, Norman Stockbridge, Christopher M O'Connor
• Journal: Circulation (Circulation) Vol. 140 Issue 25 Pg. 2108-2118 (12 17 2019) ISSN: 1524-4539 [Electronic] United States
• PMID: 31841369 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• SLC5A2 protein, human
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors

Topics

• Cardiovascular Diseases (blood, drug therapy, epidemiology)
• Clinical Trials as Topic (methods)
• Diabetes Mellitus, Type 2 (blood, drug therapy, epidemiology)
• Endpoint Determination
• Heart Failure (blood, drug therapy, epidemiology)
• Humans
• Research Report (standards)
• Sodium-Glucose Transporter 2 (blood)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)
• Treatment Outcome