FDA Panel to Review 2008 Guide on CV Trials for Diabetes Drugs

Miriam E. Tucker

October 24, 2018

The US Food and Drug Administration (FDA) is now taking a second look at its 2008 guidance recommending that manufacturers conduct trials to prove cardiovascular safety for all drugs intended for the treatment of type 2 diabetes.

On October 24 and 25, 2018, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee will discuss the original rationale for the 2008 guidance, as well as the lessons learned from the eight clinical trials that have been conducted based on the guidance — including their costs versus benefits — and whether changes are needed at this time.

The guidance arose out of concerns about cardiovascular harm arising from older studies, but none of the eight trials have identified excess cardiovascular risk from the drugs in question, and three have actually shown benefit.

"Now that we have results of several trials and 10 years of experience with drug development under the guidance, it seems apropos to review what we have learned and consider what changes to the approach, if any, are necessary," according to the FDA briefing documents posted online ahead of the meeting.

The meeting starts today, and tomorrow the panel will vote on the specific question of "whether an unacceptable increase in cardiovascular risk needs to 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."

The panel will also be asked to discuss broader issues pertaining to the guidance. These include its impact on drug assessment, the inclusion of high-risk patients in order to obtain statistically significant numbers of endpoints, and the specific numeric cut-offs for exclusion of cardiovascular risk.

Another discussion point will be how the cardiovascular safety findings for one drug should or shouldn't be applied to other drugs in the same class.

Prior to the guidance, clinical trials for glucose-lowering drugs were typically short (6-12 months), with evaluation of cardiovascular safety based on a small number of events in people who weren't necessarily at high risk for them.

The 2008 FDA document changing that paradigm was prompted by data from several sources, including the randomized ACCORD trial that was stopped early because of a significant 22% increased risk for death in the intensive glucose-lowering arm, and a meta-analysis of 42 trials of rosiglitazone (Avandia, GlaxoSmithKline) that suggested increased risks of both myocardial infarction and cardiovascular mortality.

Among the eight major cardiovascular safety outcomes trials conducted since the guidance, there was an increased risk of hospitalization for heart failure with the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (Onglyza, AstraZeneca) in SAVOR-TIMI 53, but no increase was seen in the primary composite of major cardiovascular endpoints. No cardiovascular harms from any other type 2 diabetes drugs were seen in the other seven trials.

On the other hand, three of the trials — EMPA-REG OUTCOME with the sodium-glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), LEADER with the glucagon-like peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk), and CANVAS with another SGLT2 inhibitor, canagliflozin (Invokana, Janssen) — all showed cardiovascular benefit with those respective drugs.

"Overall, the assessment of cardiovascular risk as recommended by the guidance has led to greater specificity, more data for consideration, and additional data in a population of patients that was not well represented previously," the FDA briefing document notes.

To the advisory panel, the FDA says: "Taking all of this into consideration we will ask you to provide your thoughts on the guidance and your recommendations for evaluating this concern [cardiovascular safety of diabetes drugs] moving forward."

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