Evaluating the Cardiovascular Safety of New Medications for Type 2 Diabetes: Time to Reassess?

Abstract

The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardiovascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientific community and the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development.

Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial

“…A great interest is devoted to the study of such extra-glycemic effects, and how they may translate into cardiovascular protection [2]. Furthermore, as some glucose-lowering medications have shown to increase the risk for major adverse cardiovascular events (MACE), regulatory agencies require that all new medications demonstrate safety in the pre- and/or post-marketing phase [4], including cardiovascular outcome trials [5]. …”

Metformin Safety Warnings and Diabetes Drug Prescribing Patterns for Older Nursing Home Residents

“…11,12 In recent years, these medication classes may be substituted for metformin more often, especially given mounting evidence that they are not associated with adverse cardiovascular effects as previously thought. 37–39 Lastly, some patients may have a long history of using glucose-lowering medications not captured by the data (i.e., before the six month period of glucose-lowering medication non-use that preceded metformin or sulfonylurea initiation) or with intermittent gaps of more than six months. If that were the case, providers might favor the drug and regimen last observed in their long-term medication history.…”

Getting to the “Heart” of the Matter on Diabetic Cardiovascular Disease: “Thanks for the Memory”

“…The study clearly demonstrated that empagliflozin reduced the primary MACE end point (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) by 14%. There was a 38% reduction in cardiovascular mortality with no significant decrease in nonfatal myocardial infarction or stroke and a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina (13,15). The authors felt that it was unlikely that the reduction in cardiovascular mortality could be explained by empagliflozin’s glycemic or weight effects but rather by its fluid balance and hemodynamic effects, specifically decreased extracellular volume and reduced blood pressure (10).…”

“…These articles comment on the control of risk factors and biomarkers for CVD and provide new updates on outcomes of landmark studies. In addition, we have included commentaries on cardiovascular safety of newer diabetes drugs and provide insights on mechanisms of action for cardioprotection observed with some new agents (4–13). …”

“…The authors concluded that in patients with type 2 diabetes, there was no evidence of increased risk of heart failure or other selected cardiovascular end points for DPP-4 inhibitors relative to sulfonylureas or for saxagliptin relative to sitagliptin. In a very thoughtful commentary to the observation study, Filion and Suissa (12) state that the study by Fu et al “provides some welcome reassurance regarding the [heart failure] risk of DPP-4 inhibitors.” However, they also add that “to impart actual real-world data, such observational studies should ideally strive to evaluate the full spectrum of users of these drugs, not only the treatment-naïve ones.” Finally, in a perspective on the FDA requirements to assess cardiovascular safety of new antihyperglycemic medications, Smith et al (13) report that to date, 17 large, prospective, randomized, controlled post-approval clinical trials (involving approximately 140,000 subjects) have been completed or are ongoing in accordance with a recent FDA Guidance. At this time, five of the completed trials (involving three different drug classes) have been successful in excluding an unacceptable level of ischemic cardiovascular risk.…”