Devoting attention to glucose variability and hypoglycaemia in type 2 diabetes

In the Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), insulin degludec was non-inferior to insulin glargine in terms of cardiovascular events and mortality. However, there were lower rates of severe hypoglycaemia with insulin degludec. DEVOTE investigators now extend these findings by presenting the results of two observational epidemiological analyses based on trial data. In the first of these analyses (DEVOTE 2), Zinman et al (Diabetologia DOI: 10.​1007/​s00125-017-4423-z) demonstrate that, compared with individuals with lower day-to-day fasting glycaemic variability, those with higher day-to-day fasting glycaemic variability had a similar risk of major adverse cardiovascular events (MACE) but a higher risk of severe hypoglycaemia and all-cause mortality. In the second analysis (DEVOTE 3), Pieber et al (Diabetologia DOI: 10.​1007/​s00125-017-4422-0) found that individuals who experienced severe hypoglycaemia had a similar risk of MACE compared with those who never experienced severe hypoglycaemia, but had a more than twofold higher risk of subsequent total mortality and cardiovascular disease (CVD) mortality. The strengths of these studies relate to the availability of high-quality prospective data on adjudicated severe hypoglycaemia, MACE and mortality events in a large number of high-risk insulin-treated individuals with type 2 diabetes. Limitations include the observational nature of the data and thus residual confounding remains possible. Furthermore, the short duration of the trial resulted in limited statistical power for some analyses. Therefore, whilst DEVOTE 2 and DEVOTE 3 raise awareness of the mortality risks associated with glucose variability and severe hypoglycaemia in high-risk, insulin-treated patients with type 2 diabetes, they cannot clarify causal relationships. Preventing severe hypoglycaemia in those with type 2 diabetes should already be a priority in clinical practice. However, findings from future clinical trials are needed to guide physicians on whether it is beneficial to target glucose variability, and risk for severe hypoglycaemia, to reduce the risks for CVD events and mortality in these individuals.