Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion

Abstract

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

In‐hospital and 1‐year mortality associated with diabetes in patients with acute heart failure: results from the ESC‐HFA Heart Failure Long‐Term Registry

“…To date, no new sound adverse cardiovascular safety signal (including the risk for HF) has arisen from the trials with incretin‐based therapies (i.e. dipeptidyl peptidase 4 inhibitors and glucagon‐like peptide 1 receptor agonists), and there is now evidence of benefit from the EMPA‐REG trial with empagliflozin, a sodium–glucose co‐transporter 2 inhibitor …”

Insulin glargine/lixisenatide in type 2 diabetes: a profile of its use

“…The CV safety of ADs is also important to determine [45], with the EMA recommending a long-term, controlled outcome study with 18-24 months of follow-up for ADs suspected to have an adverse CV effect [46]. A dedicated CV outcome trial was not necessary for insulin glargine/lixisenatide, as such studies conducted separately with each of its components (+ standard care) identified no safety concerns.…”

Inhibition of the Sodium–Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2

“…Specifically, the upper bound of the 95% confidence limit of the hazard ratio for major adverse cardiac events (nonfatal myocardial infarction, non-fatal stroke, or cardiovascular death) should not exceed 1.30 at the end of the trial nor > 1.80 at any interim analysis (Guidance, 2008). The shortcoming of this guidance is that it ignored the important connections between T2DM and the risk of HF, progression of kidney disease, and other organ system illnesses (Zannad et al, 2016). Additionally, while it leveraged the endpoints that were associated with hyperglycemia (MI, stroke, cardiovascular death) it failed to provide a framework that could adapt to the mechanism of action of the drug or consider important unique safety events for adjudication (e.g.…”