The impact of cardiovascular outcome trials on the choice of insulins in the management of type 2 diabetes mellitus: An expert review

Abstract

Introduction. This expert review aims to address the epidemiology and pathophysiology of cardiovascular disease (CVD) in persons with type 2 diabetes mellitus (T2DM), help understand the various statistical considerations and interpretational nuances of cardiovascular outcome trials (CVOTs) in general, and discuss in particular, the CVOTs with insulins, and their impact on the choice of insulins in day-to-day clinical practice. Material and methods. The expert panel critically analysed published data from observational studies, randomized clinical trials, meta-analyses and CVOTs regarding cardiovascular (CV) safety of insulin preparations, and agreed on a series of consensus statements supported by available scientific evidence and the collective clinical judgement of the experts. Results. A proportion of persons with T2DM have a high risk of CVD and CV mortality, which is partly contributed by insulin resistance-related, and hyperglycaemiarelated, risk factors. Over the past decade, CVOTs have become an integral part of the drug approval process of anti-diabetic therapies by the United States Food and Drug Administration (FDA). Most insulin preparations in use today, barring a few modern insulins, were introduced much before this regulatory requirement was put in place, and hence, have not undergone rigorous CVOTs. There is a large body of observational data concerning the CV safety of insulin preparations, which are often confusing and, at times, contradictory. In this background, it is reassuring to note that CVOTs of two basal insulin analogues, namely insulin glargine, studied in the Basal Insulin and Cardiovascular and Other Outcomes in Dysglycaemia Trial (ORIGIN), and insulin degludec, studied in the Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes Trial (DEVOTE), established their long-term CV safety. The DEVOTE trial provided additional safety data reporting fewer severe hypoglycaemic events with insulin degludec in comparison to insulin glargine. Conclusions. This review critically analyses the two CVOTs of basal insulin analogues, in tandem with a general review of the methodological and interpretational aspects of CVOTs in general. The long-term CV safety of analogue basal insulins is discussed. The lack of CVOTs with prandial and pre-mixed insulins, either human or analogue, was identified as the main research gap in this area.