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

• Published in: Diabetologia 2018-01, Vol.61 (1), p.58-65
• Main Authors: Pieber, Thomas R., Marso, Steven P., McGuire, Darren K., Zinman, Bernard, Poulter, Neil R., Emerson, Scott S., Pratley, Richard E., Woo, Vincent, Heller, Simon, Lange, Martin, Brown-Frandsen, Kirstine, Moses, Alan, Barner Lekdorf, Jesper, Lehmann, Lucine, Kvist, Kajsa, Buse, John B.
• Format: Article
• Language: English
• Subjects: Cardiovascular diseases; Cerebral infarction; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - mortality; Double-Blind Method; Female; Glycated Hemoglobin A - metabolism; Health risk assessment; Human Physiology; Humans; Hypoglycemia; Hypoglycemia - drug therapy; Hypoglycemia - metabolism; Hypoglycemia - mortality; Hypoglycemic Agents - therapeutic use; Insulin; Insulin Glargine - therapeutic use; Insulin, Long-Acting - therapeutic use; Internal Medicine; Kidneys; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mortality; Myocardial infarction
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-017-4422-0

Aims/hypothesis The 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. Methods In 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. Results There 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