Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Abstract

LeaderT here is a demand from regulators that new treatments for the management of hyperglycaemia in people with type 2 diabetes should not increase cardio vascular risk. 1,2 For most new therapies this will include the performance of a dedicated randomised-controlled cardiovascular outcomes trial (CVOT). This can be conducted prior to licensing, like the SUSTAIN-6 trial with semaglutide, 3 or post-licensing, like the LEADER trial with liraglutide. 4 The results of CVOTs with albiglutide, a once-weekly GLP-1 receptor agonist, and linagliptin, a DPP-4 inhibitor, were presented at the recent meeting of the European Association for the Study of Diabetes (EASD) in Berlin. 5,6 As there are now several completed trials with GLP-1 receptor agonists and DPP-4 inhibitors it is relevant to place the results of these studies in the context of the results of previous studies. Harmony OutcomesAlbiglutide is a once-weekly GLP-1 receptor agonist composed of two copies of modified human GLP-1 fused to human albumin. It was available for clinical use in the US and Europe from 2014. In the summer of 2017 the manufacturer GlaxoSmithKline announced that albiglutide would be withdrawn from the worldwide market by 2018 for economic reasons that were not detailed, and marketing ceased in July 2018. A lack of potency compared to other GLP-1 receptor agonists, 7 and the inconvenience to the patient of having to reconstitute the lyophilised powder with a diluent and wait 15-30 minutes before injection 8 may have contributed to the low use of albiglutide in countries where other onceweekly GLP-1 receptor agonists were available.Harmony Outcomes was a post-licensing CVOT comparing albiglutide and placebo in 9463 people with type 2 diabetes and established cardiovascular disease, including coronary vascular disease, cerebrovascular disease and peripheral arterial disease. 5 Other inclusion criteria included age over 40 years, and HbA1c over 7.0% (53mmol/mol). At baseline 70% of participants had coronary heart disease, 47% had a previous myocardial infarction and 20% were recorded as having baseline heart failure by their local clinical investigator. Subjects were followed for a median of 1.6 years and the primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.Subjects in the albiglutide arm had a statistically significant 22% reduction in MACE compared to the placebo group. This was despite one-quarter of the subjects discontinuing therapy during this short study. Of the components of the MACE outcome, myocardial infarction (fatal or non-fatal) was significantly reduced, with insignificant effects on stroke and cardiovascular death. The number of subjects needed to treat with albiglutide for 1.6 years to prevent one major adverse cardiovascular event was 50. In the placebo group there was as expected a greater use of sulphonylureas and insulin, including greater use of bolus insulin. Hypoglycaemia rates were lower with albiglutide, including le...

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10)

“…5 Based on the results of the LEADER trial, liraglutide was recommended as a treatment option in the treatment guidelines for patients with type 2 diabetes and established cardiovascular disease. [7][8][9] For example, triple therapy, which can include the combination of metformin and a GLP-1RA with basal insulin (or oral antihyperglycaemic drugs), is recommended if a patient with type 2 diabetes has not achieved his/her HbA1c target after 3 months of dual therapy. [7][8][9] For example, triple therapy, which can include the combination of metformin and a GLP-1RA with basal insulin (or oral antihyperglycaemic drugs), is recommended if a patient with type 2 diabetes has not achieved his/her HbA1c target after 3 months of dual therapy.…”

“…6,7 Consensus guidelines support the combination of a basal insulin and a GLP-1RA as a treatment option for individuals with type 2 diabetes. [7][8][9] Combining injectable therapies consisting of basal insulin and a GLP-1RA, usually with metformin (with or without another noninsulin agent), should also be considered if the patient has not achieved the HbA1c target after 3 months of triple therapy using another regimen, 8 or when blood glucose is ≥16.7 mmol/L, HbA1c ≥ 10% (≥86 mmol/mol) or the patient has symptoms of hyperglycaemia. [7][8][9] Combining injectable therapies consisting of basal insulin and a GLP-1RA, usually with metformin (with or without another noninsulin agent), should also be considered if the patient has not achieved the HbA1c target after 3 months of triple therapy using another regimen, 8 or when blood glucose is ≥16.7 mmol/L, HbA1c ≥ 10% (≥86 mmol/mol) or the patient has symptoms of hyperglycaemia.…”

“…[7][8][9] For example, triple therapy, which can include the combination of metformin and a GLP-1RA with basal insulin (or oral antihyperglycaemic drugs), is recommended if a patient with type 2 diabetes has not achieved his/her HbA1c target after 3 months of dual therapy. 7,8 Clinical studies evaluating insulin and GLP-1RA combination therapy (both fixed and free combinations) for type 2 diabetes have shown beneficial effects of this regimen on glycaemic control and body weight, or weight neutrality, versus comparators. 7,8 Clinical studies evaluating insulin and GLP-1RA combination therapy (both fixed and free combinations) for type 2 diabetes have shown beneficial effects of this regimen on glycaemic control and body weight, or weight neutrality, versus comparators.…”

Assessing the severity of Type 2 diabetes using clinical data‐based measures: a systematic review

“…Importantly, the recent consensus report by the American Diabetes Association and the European Association for the Study of Diabetes included a recommendation for providing patient-centred care that takes multimorbidity into account [36]. Such measures will allow researchers to better map and quantify disease trajectories, in relation to health-related and social outcomes, improving clinical trials and observational studies, and eventually allow clinicians to use these measures in practice to provide more individualized healthcare.…”

Nine contemporary therapeutic directions in heart failure

“…Although the precise mechanisms behind these benefits have not been fully elucidated, it has been suggested that the reduction in hospitalisation for heart failure may be related to the therapy’s favourable renal, haemodynamic and metabolic effects 16 17. Given the therapeutic role in prevention of heart failure events in at-risk populations, this drug class has been incorporated into the most recent consensus statement by the European Association for the Study of Diabetes and the American Diabetes Association as second-line therapy (after metformin) in patients with type 2 diabetes mellitus with cardiovascular disease 18. Ongoing studies are assessing whether these agents may be useful in the treatment of heart failure, including in those who do not have diabetes mellitus (NCT03036124, NCT03619213, NCT03057977, NCT03057951, NCT03521934).…”