Transporter 2
17 Mechanisms behind the cardiovascular benefits of these agents are unclear but are independent of improvements in glycaemia. Nevertheless, the positive findings have been largely replicated in a multinational study of real-world health records data in which there was a lower prevalence of established CVD. The results are therefore not directly comparable and not necessarily generalisable to people with T2D who are at lower CVD risk. 9–12 These trials have been conducted in high-risk cohorts with different proportions of people with either established cardiovascular disease (CVD) or with multiple risk factors for atherosclerotic CVD. Reduction in major adverse cardiovascular events was demonstrated with empagliflozin and canagliflozin, but not dapagliflozin or ertugliflozin. Published trials have shown a reduction in heart failure hospitalisation with all agents. While designed to demonstrate safety, SGLT2 inhibitor cardiovascular outcome trials have in fact demonstrated benefit (summarised in Table 1). People with T2D have higher thresholds and greater SGLT2 expression. Typically, glycosuria occurs above a glycaemic threshold of approximately 10 mmol/L. SGLT2 transporters, located in the proximal renal tubule, are responsible for >90% of renal glucose reabsorption. This review summarises the available evidence regarding the efficacy, effectiveness and safety of SGLT2 inhibitors and provides suggestions on how they should be adopted into clinical practice. The latter three are currently available on the Pharmaceutical Benefits Scheme (PBS). Within the past decade, four SGLT2 inhibitors have been approved by the Australian Therapeutic Goods Administration (TGA): canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. 8– 15 In addition, there is growing awareness of the importance of individualising diabetes therapies and glycaemic targets, taking into consideration patients’ risk profiles, comorbidities, age and duration of disease. These regulatory changes have led to revolutionary data demonstrating cardiovascular and renal benefits of sodium–glucose co-transporter-2 (SGLT2) inhibitors and some glucagon-like peptide-1 receptor agonists (GLP-1RAs). 7 In 2008, the United States Food and Drug Administration (US FDA) mandated that all new diabetes treatments be evaluated in large cardiovascular safety outcome trials. It became apparent that a stronger focus on cardiovascular safety of diabetes therapeutics was required when a meta-analysis suggested rosiglitazone may increase myocardial infarction risk. Earlier trials demonstrated that improving glycaemic levels resulted in fewer microvascular complications but without a clear cardiovascular benefit.
1 Glycaemia is known to be associated with microvascular and macrovascular complication risk. More than 1.2 million adult Australians have diabetes, the vast majority having type 2 diabetes (T2D).