![]() ![]() This trial enrolled a patient population of high CV risk with a long duration of T2DM and established CVD: almost 50% of the patients had a history of myocardial infarction (MI), 75% had multivessel coronary artery disease and 10% had a history of heart failure. All patients received a background of standard secondary prevention therapy and anti-hyperglycaemic agents.ħ,020 patients were randomised to receive either placebo or empagliflozin. All 3 CVOTs were multicentre randomised, double-blind, placebo-controlled trials, designed to evaluate the cardiovascular safety of oral SGLT2 inhibitors in type 2 diabetes mellitus (T2DM) patients with either established cardiovascular disease (CVD) or high cardiovascular (CV) risk. ![]() This blog will summarise the three landmark CVOTs for SGLT2 inhibitors, which all yielded fascinating results: EMPA-REG OUTCOME (Empagliflozin), CANVAS Program (Canagliflozin and DECLARE-TIMI 58 (Dapagliflozin). The green bars represent the SGLT2 inhibitor trials and the next sections will focus on three landmark CVOTs: EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58. ![]() A timeline illustrating the CVOTs for the novel anti-hyperglycaemic drugs is shown in Figure 1. ![]() Since then there has been a significant growth in the number of cardiovascular outcome trials (CVOT) for the new generation anti-hyperglycamic drugs which includes the DPP-4 inhibitors, GLP-1 receptor agonists and SGLT2 inhibitors. Therefore, in 2008 the U.S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) released a joint guideline calling for the demonstration of cardiovascular safety of novel anti-hyperglycaemic drugs in diabetes patients. However, the trials from previous generation anti-hyperglycaemic medications on CV risk have yielded conflicting results, with the most concerning being the thiazolidinediones (rosiglitazone and pioglitazone) and their associated increase in heart failure rates. That was the basis behind the use of metformin, sulphonylureas and insulin as part of standard medical therapy. The mainstay treatment of diabetes has predominantly centered on reducing hyperglycaemia with the belief that having good glycaemic control may reduce the cardiovascular (CV) risk from diabetes. In other words, this is an anti-hyperglycaemic drug that was designed to work on the kidneys (there are no known SGLT2 receptors in the heart). SGLT2 inhibition reduces hyperglycaemia due to glycosuria while leading to the restoration of tubuloglomerular feedback (impaired in diabetes) and the normalisation of glomerular filtration rate (GFR). SGLT2 is a low affinity, high capacity sodium-glucose cotransporter that is expressed almost exclusively in the kidney and accounts for about 90% of renal glucose reabsorption. What are SGLT2 inhibitors and how did the excitement around SGLT2 inhibitors begin? The SGLT2 inhibitor that was referred to by Lo et al was empagliflozin but since then, two landmark SGLT2 inhibitor trials involving canagliflozin and dapagliflozin have been published and have affirmed the hypothesis that SGLT2 inhibitors may exert cardioprotective and renoprotective effects independent of its glucose-lowering effects. Back in 2018, Lo et al concluded that SGLT2 inhibitors were probably efficacious for glucose-lowering and reducing blood pressure and heart failure in patients with diabetes and chronic kidney disease. Since the Cochrane Systematic Review by Lo et al, several clinical trials on SGLT2 inhibitors have yielded unexpected and fascinating findings. Unexpected positive findings from the latest cardiovascular outcome trials on SGLT2 inhibitors since the 2018 Cochrane review SGLT2 inhibitors were one of the drugs included in the 2018 Cochrane Systematic Review: Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease by Lo et al. In a blog for health professionals, Cardiology Registrar Dr Ven Gee LIM reviews the latest evidence surrounding the new generation anti-diabetic agent Sodium Glucose cotransporter 2 (SGLT2) inhibitors. ![]()
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