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The Diabetes Trials Unit have published the results of two mega-trials, involving over 20,000 participants and 36 countries, shedding new light of the impact of diabetes drugs on the cardiovascular system.

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The EXSCEL trial (EXenatide Study of Cardiovascular Event Lowering) was among the largest ever carried out in type 2 diabetes, setting out to evaluate the safety and efficacy of a once-weekly extended-release formulation of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist. The drug works by mimicking a hormone by reducing blood sugar levels after meals, but its impact on heart disease is unknown.

Launched in 2009 and completed in April 2017, the EXSCEL trial was a Phase IIIb/IV, double-blind, placebo-controlled, global cardiovascular outcomes trial involving 14,752 patients with type 2 diabetes in 35 countries. Participants – who were eligible with or without additional cardiovascular risk factors or prior cardiovascular events – all received usual type 2 diabetes care and were randomized to receive subcutaneous injections of exenatide once-weekly, or a matching placebo. The trial compared the risk of major adverse cardiac events (MACE) – a composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke – in the two groups of patients over an average of 3.2 years.

The team found that the exenatide had no impact on the risk of MACE. However, they found that all-cause mortality was lower with exenatide than placebo. ‘The study results show that exenatide had no adverse effects on cardiovascular health, meaning that the drug can be used safely in people with type 2 diabetes who may have a wide range of existing cardiovascular conditions’, said the DTU’s Prof Rury Holman, who co-led the study with the Duke Research Institute.

The ACE trial (Acarbose Cardiovascular Evaluation) is the largest cardiovascular disease prevention outcome trial in people with coronary heart disease and impaired glucose regulation in China. It was designed to determine whether acarbose, an alphaglucosidase inhibitor licensed in many countries for the treatment of impaired glucose tolerance, could reduce the risk of further cardiovascular events. The team were also interested in whether the rate of development of diabetes in this high-risk population could be lowered with the drug.

Launched in 2009 and completed in April 2017, the ACE trial was a placebo-controlled, cardiovascular outcomes trial involving 6,526 patients with coronary artery disease and impaired glucose regulation from 176 hospitals in the Peoples Republic of China. Participants were randomised to receive acarbose or matching placebo, orally three times daily with meals. The primary endpoint was a five-point composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina or hospitalisation for heart failure in the two groups of patients. The median length of follow-up was five years.

The team found that acarbose doesn’t alter the risk of major adverse cardiovascular events. It did, however, show a significant 18% reduction in the incidence of new-onset diabetes with acarbose, compared with placebo, with a number needed to treat of 41 to prevent one case of diabetes.

Prof Rury Holman, Chair of the study, commented ‘ACE provides reassurance that acarbose may be used safely to improve blood glucose levels in people with coronary heart disease and impaired glucose regulation with no impact on rates of cardiovascular complications or heart failure.

‘The reduced incidence of diabetes seen with acarbose in the ACE trial may, however, help reduce cardiovascular risk in the longer term by delaying the onset of diabetes in the high-risk population studied.’