Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Bernard Zinman et al. NEJM. Doi: 10.1056/NEJMoa1504720
The withdrawal of rosiglitazone from European markets, following the suggestion that it increased the risk of myocardial infarction in people with type 2 diabetes (T2DM), spawned a generation of cardiovascular outcome trials (CVOTs) for new diabetes therapies. CVOTs are designed to be safety studies, aiming for so-called ‘glycaemic equipoise’; this means that any reduction in HbA1c should be similar in patients receiving the new, active therapy to those receiving placebo. They also have other facets, which make them unlikely to demonstrate CV benefit; they are usually short studies (2-3 years); they often focus on patients with advanced CV disease (where glycaemic control is least likely to provide advantage, and may cause harm) and they mandate optimal control of other CV risk factors (such as blood pressure [BP] and low-density lipoprotein cholesterol). For these reasons, many assumed that CVOTs would show no evidence of harm but also no evidence of superiority. This was largely the case for three studies, which examined the dipeptidyl peptidase-4 inhibitors (saxa-, alo- and sitagliptin) and the ELIXA trial of lixisenatide.
Imagine then, the surprise when results of the EMPA-REG study were presented at the European Association for the Study of Diabetes (EASD) meeting in Stockholm in September 2015. Not only did this CVOT of the sodium glucose co-transporter-2 (SGLT-2) inhibitor, empagliflozin, show a significant reduction in the primary end-point of ‘CV death, non-fatal myocardial infarction or non-fatal stroke’ but there was also a significant reduction in all-cause mortality. The patient cohort was at extremely high CV risk, with median treatment duration of only 3.1 years and benefits were seen within three months of the drug initiation.
Explanation of this unexpected finding will generate more studies, no doubt with focus on non-glycaemic effects of SGLT-2 inhibitors (such as BP and weight reduction and their diuretic action). It will also be of great interest to see if the other two SGLT-2 inhibitor CVOTs show similar results, although they will not complete until after 2017.
Professor Steve Bain