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Cardiovascular Risk Reduction Review Antihyperglycemic Medications and Cardiovascular Risk Reduction Sarah L Anderson and Joel C Marrs Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, US C ardiovascular disease (CVD) remains a leading cause of death in patients with type 2 diabetes (T2D). In addition to glycemic control, a major focus of diabetes treatment involves cardiovascular (CV) risk reduction. In 2008, the US Food and Drug Administration (FDA) instituted a new requirement that new drugs developed and studied for the treatment of T2D must undergo CV safety testing. Since the advent of this new policy, canagliflozin, empagliflozin, liraglutide and semaglutide have demonstrated superior CV event reduction – via a composite of reduction in CV death, nonfatal myocardial infarction (MI), and nonfatal stroke – compared with placebo in patients with T2D and existing CVD, or at high risk of CVD. Multiple studies are underway to evaluate the CV outcomes of other antihyperglycemic agents. In a time when there are numerous drugs in the T2D armamentarium, positive CV outcomes data influence drug selection and aids practitioners in making more individualised therapeutic recommendations for their patients. Keywords Diabetes, cardiovascular disease, antihyperglycemic, glucagon-like peptide-1 receptor agonists (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors Disclosure: Sarah L Anderson and Joel C Marrs have nothing to declare in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 25 May 2017 Accepted: 13 July 2017 Citation: European Endocrinology, 2017;13(2):86–90 Corresponding Author: Sarah L Anderson; Mail Stop C238, 12850 E. Montview Blvd., room V20-2129, Aurora, Colorado, 80045, US. E: Cardiovascular disease (CVD) is a common cause of morbidity and mortality in patients with type 2 diabetes (T2D). Patients with T2D have approximately twice the risk of developing CVD compared with the non-diabetic population, independent of other traditional CVD risk factors. 1 Although the rate of death from CVD in patients with T2D is declining, it still exceeds that of the non-diabetic population. 2 Improved glycaemia in patients with T2D may improve CVD and CVD-related death; however, it is still unclear whether optimal glycaemic control reduces the incidence of either of these. 3 In several studies published during the past 10 years, improved glycaemic control and/ or addition of an antihyperglycaemic agent to a patient with T2D were associated with negative or neutral impact on cardiovascular (CV) outcomes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial demonstrated an increased risk of CV events and mortality in patients who received an intensive glucose-lowering intervention. 4 The Rosiglitazone Evaluated for CV Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial showed that the addition of rosiglitazone to therapy in patients with T2D increased the incidence of heart failure (HF). 5 While the RECORD study was in progress, a meta-analysis of 42 trials involving patients with T2D who received rosiglitazone revealed an increased risk of myocardial infarction (MI) and CV- related death in patients who received the drug. 6 Despite the increased incidence of CVD and excess mortality attributed CVD-related deaths in the T2D population, it was not until these phase 4 studies unmasked a potential link between antihyperglycaemic agents and CV risk that the US Food and Drug Administration (FDA) required that new drug therapies for T2D undergo assessment of CV safety. 7 The European Medicines Agency (EMA) followed with a similar requirement in 2012. 8 In order to meet the FDA requirements, antihyperglycaemic CV outcomes trials in patients with T2D must include patients with advanced CVD, elderly patients and patients with renal dysfunction. These studies must track and include at least 24 months’ CV safety data. Trials can be designed as non-inferiority or superiority and there are specific statistical requirements defining each trial type. 7 Since this requirement to evaluate the CV safety of antihyperglycaemic agents was enacted, four studies have demonstrated that specific antihyperglycaemic agents (canagliflozin, empagliflozin, liraglutide and semaglutide) have beneficial effects on CV outcomes. Numerous other CV outcomes studies are ongoing with aspirations to demonstrate the same. In this review, we present the studies that have demonstrated a beneficial association between antihyperglycaemic agent use and CVD risk lowering, the ongoing CV outcomes trials with approved and investigational antihyperglycaemic agents, and reflect on the implications of these data for clinical practice. Positive cardiovascular outcome studies Positive CV risk-lowering findings in major clinical trials for antihyperglycaemic agents over the last two years have been essential to modifying the approach to glycaemic management and CV risk reduction therapy for patients with T2D. Sodium-glucose cotransporter-2 (SGLT2) inhibitors 86 TOU C H ME D ICA L ME D IA