Evaluation and Review of Strategies to Assess Cardiovascular Risk in Clinical Trials in Patients with Type 2 Diabetes Mellitus

Abstract

This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online.