DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality

Abstract

Aims/hypothesisThe double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.MethodsIn DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.ResultsThere was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.Conclusions/interpretationThe results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outco...

Haemoglobin A1c variability is a strong, independent predictor of all‐cause mortality in patients with type 2 diabetes

“…The independent association of HbA1c variability with all‐cause mortality is consistent with a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and two previous retrospective studies of limited size, which also found no correlation between HbA1c‐MEAN and mortality after adjusting for HbA1c‐SD or HbA1c‐CV . In addition, our findings are consistent with studies reporting a relationship between visit‐to‐visit (day‐to‐day) variations in fasting glucose and mortality, including the recent Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) …”

Exposure to hypoglycemia and risk of stroke

“…However, no association between prior exposure to severe hypoglycemia and stroke was observed . Recently published secondary analysis of the double‐blind Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) trial also evaluated the association between exposure to severe hypoglycemia and a major adverse cardiovascular event (MACE), defined as either cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke . This study observed an association between exposure to severe hypoglycemia and all‐cause mortality.…”

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)

“…Further complicating treatment, patients aged 65 years or older are more susceptible to severe hypoglycaemic events than younger patients, in part because of a reduced ability to recognize and respond to symptoms . Severe hypoglycaemia has been shown to be associated with a higher risk of adverse cardiovascular (CV) events and mortality . In addition, severe hypoglycaemic episodes can increase utilization of healthcare resources .…”