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In previous editorials1-4 we proposed that metformin, pioglitazone, sodium glucose transporter 2 (SGLT2) inhibitors (in particular empagliflozin and canagliflozin) and long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (in particular liraglutide) in combination could complement each other to prevent cardiovascular events and save lives in patients with type 2 diabetes at high cardiovascular risk. Since those editorials, new information has come to light to increase our understanding in the field; in particular, a presentation on 2 October 2018 during the European Association for the Study of Diabetes Congress in Berlin, Germany of the results of the HARMONY Outcomes study5,6 and, on 10 November 2018 during the American Heart Association, Scientific Sessions in Chicago, USA, the results of the DECLARE-TIMI 58 study.7,8 HARMONY Outcomes was a randomised controlled trial of the long-acting GLP-1 receptor agonist (GLP-1RA) albiglutide (which is not commercially available) against placebo in 9,463 patients with type 2 diabetes and established cardiovascular disease.5,6 In line with previous cardiovascular outcome studies, HARMONY Outcomes assessed as its primary outcome the three-point Major Adverse Cardiovascular Events (3-point MACE: cardiovascular death, non-fatal myocardial infarction and non-fatal stroke). There was a 22% reduction in 3-point MACE (HR=0.78, 95% CI 0.68 to 0.90).5,6 By 8 months, mean HbA1c, weight and systolic blood pressure decreased by 0.63%, 0.66 kg and 0.65 mmHg, respectively, in the albiglutide group compared with placebo.5,6 Figure 1 shows side by side the results of the four cardiovascular outcome studies with long-acting GLP-1RAs and is in keeping with a class effect for this group of agents. In making this statement we refer to our previous editorial4 where we proposed that the difference in outcome between the LEADER (liraglutide) and EXSCEL (exenatide QW) cardiovascular outcome studies with regard to statistical significance might be related to the fact that the LEADER patients were at higher cardiovascular risk and had longer exposure to study medication than the EXSCEL patients due to a high discontinuation rate in EXSCEL.4 Although only top line results are available, REWIND, which compared dulaglutide against placebo in 9,931 patients with type 2 diabetes who were at high cardiovascular risk or who had a prior cardiovascular event, also demonEDITORIAL

the british journal of diabetes

Diabetes medications with cardiovascular protection after HARMONY Outcomes and DECLARE-TIMI 58: could metformin, pioglitazone, SGLT2 inhibitors and long-acting GLP-1 receptor agonists complement each other to save lives by different mechanisms?