title: Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial.
abstract: OBJECTIVE
  Hypoglycaemia caused by glucose-lowering therapy has been linked to cardiovascular (CV) events. The ORIGIN trial provides an opportunity to further assess this relationship.
  
  
  RESULTS
  A total of 12 537 participants with dysglycaemia and high CV-risk were randomized to basal insulin glargine titrated to a fasting glucose of ≤ 5.3 mmol/L (95 mg/dL) or standard glycaemic care. Non-severe hypoglycaemia was defined as symptoms confirmed by glucose ≤ 54 mg/dL and severe hypoglycaemia as a requirement for assistance or glucose ≤ 36 mg/dL. Outcomes were: (i) the composite of CV death, non-fatal myocardial infarction or stroke; (ii) mortality; (iii) CV mortality; and (iv) arrhythmic death. Hazards were estimated before and after adjustment for a hypoglycaemia propensity score. During a median of 6.2 years (IQR: 5.8-6.7), non-severe hypoglycaemic episodes occurred in 41.7 and 14.4% glargine and standard group participants, respectively, while severe episodes occurred in 5.7 and 1.8%, respectively. Non-severe hypoglycaemia was not associated with any outcome following adjustment. Conversely, severe hypoglycaemia was associated with a greater risk for the primary outcome (HR: 1.58; 95% CI: 1.24-2.02, P < 0.001), mortality (HR: 1.74; 95% CI: 1.39-2.19, P < 0.001), CV death (HR: 1.71; 95% CI: 1.27-2.30, P < 0.001) and arrhythmic death (HR: 1.77; 95% CI: 1.17-2.67, P = 0.007). Similar findings were noted for severe nocturnal hypoglycaemia for the primary outcome and mortality. The severe hypoglycaemia hazard for all four outcomes was higher with standard care than with insulin glargine.
  
  
  CONCLUSIONS
  Severe hypoglycaemia is associated with an increased risk for CV outcomes in people at high CV risk and dysglycaemia. Although allocation to insulin glargine vs. standard care was associated with an increased risk of severe and non-severe hypoglycaemia, the relative risk of CV outcomes with hypoglycaemia was lower with insulin glargine-based glucose-lowering therapy than with the standard glycaemic control. Trial Registration (ORIGIN ClinicalTrials.gov number NCT00069784).
authors.forename: Linda G
authors.initials: LG
authors.lastname: Mellbin
authors.forename: Lars
authors.initials: L
authors.lastname: Rydén
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Riddle
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Probstfield
authors.forename: Julio
authors.initials: J
authors.lastname: Rosenstock
authors.forename: Rafael
authors.initials: R
authors.lastname: Díaz
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000139:chemically induced* / Q000401:mortality; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000401:mortality; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced; D011379:Prognosis; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting
keywords: Glargine; Glucose-lowering treatment; Hypoglycaemia; Insulin; Prognosis