On Oct. 25, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended that the U.S. Food and Drug Administration (FDA) revise existing guidance on the cardiovascular safety of diabetes drugs to reflect knowledge gained since the advent of the guidance in 2008. The EMDAC voted 10 to 9 that an unacceptable increase in cardiovascular risk should be excluded for all new drugs to improve glycemic control in patients with type 2 diabetes, regardless of the presence or absence of a signal for cardiovascular risk in the development program. However, each member of the committee acknowledged that the narrow nature of the vote obscured significant agreement across the panel regarding the need for revision and the substance of those revisions. Specifically, committee members highlighted desires to collect more information preapproval; increase the patient population included in the Phase 2 and Phase 3 trials; expand the safety outcomes considered to include heart failure, peripheral artery disease and others beyond the traditional MACE endpoints; and lengthen follow up for clinical trial participants.

Committee members disagreed on the need for continued randomized, double blinded, placebo-controlled trials. While some emphasized their importance, others indicated a willingness to explore the use of newer methods, such as observational studies and pragmatic trials, to identify cardiovascular safety.

The FDA convened the two-day meeting to discuss existing guidance on the cardiovascular safety of diabetes drugs, which was issued a decade ago after studies identified potential cardiovascular safety signals in studies of diabetes drugs. Under the current guidance, all applications seeking approval for novel antidiabetic agents must include a study on the effects of the novel agents on cardiovascular risk.

Public commenters, ranging from industry representatives, patients and patient organizations, and invited presenters agreed on the need for continued study of the cardiovascular safety of diabetes drugs but disagreed on the specifics. Many commenters recommended the use of modern study techniques, including registry-based clinical trials, pragmatic trials and real world evidence. There was also a discussion regarding the opportunity costs, for both public health and industry, of continuing such requirements for patients.

"Over the course of the last decade, our awareness of the connection between diabetes treatments and cardiovascular outcomes has increased tremendously. Outcomes trials performed since publication of the guidance provided us with a great deal of additional information, but they also raised many new questions," said Richard J. Kovacs, MD, FACC, ACC Vice President. "The Committee has appropriately highlighted the need for pausing to consider whether we have the correct information or whether we should be asking different questions and/or using different types of trials. The information generated by the guidance has forced clinicians to face the realities of cost and value consideration, generating winners and losers among the drugs under development."

Clinical Topics: Heart Failure and Cardiomyopathies, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure

Keywords: ACC Advocacy, Diabetes Mellitus, Type 2, Peripheral Arterial Disease, Pharmaceutical Preparations, Public Health, Cardiovascular Diseases, United States Food and Drug Administration, Risk Factors, Blood Glucose, Cardiovascular System, Heart Failure, Registries

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