Severe hypoglycemia and risks of vascular events and death.

BACKGROUND Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.).

[1]  R. Heine,et al.  Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study , 2010, The Lancet.

[2]  Michael E. Miller,et al.  The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study , 2010, BMJ : British Medical Journal.

[3]  Thomas E. Moritz,et al.  Intensive glucose control and macrovascular outcomes in type 2 diabetes , 2009, Diabetologia.

[4]  H. Krumholz,et al.  Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. , 2009, JAMA.

[5]  R. Freeman,et al.  Antecedent Hypoglycemia Impairs Autonomic Cardiovascular Function , 2009, Diabetes.

[6]  Grant D. Huang,et al.  Glucose control and vascular complications in veterans with type 2 diabetes. , 2009, The New England journal of medicine.

[7]  B. Howard,et al.  Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials , 2009, Diabetes Care.

[8]  J. Nunnelee.  Review of an article: The ADVANCE Collaborative Group. (2008). Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. NEJM 2008;358:2560-2572. , 2008 .

[9]  B. Frier,et al.  Vascular disease and diabetes: is hypoglycaemia an aggravating factor? , 2008, Diabetes/metabolism research and reviews.

[10]  Diederick Grobbee,et al.  Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. , 2008, The New England journal of medicine.

[11]  Michael E. Miller,et al.  Effects of intensive glucose lowering in type 2 diabetes. , 2008, The New England journal of medicine.

[12]  H. Krumholz,et al.  Glucometrics in Patients Hospitalized With Acute Myocardial Infarction: Defining the Optimal Outcomes-Based Measure of Risk , 2008, Circulation.

[13]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[14]  P. Schwartz,et al.  Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function. , 2007, Journal of the American College of Cardiology.

[15]  Anushka Patel,et al.  Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial , 2007, The Lancet.

[16]  P. Cryer.  Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. , 2005, Diabetes.

[17]  R. Giugliano,et al.  U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. , 2005, Journal of the American College of Cardiology.

[18]  Darren K Mcguire,et al.  Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. , 2005, European heart journal.

[19]  Braxton D Mitchell,et al.  The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. , 2003, Diabetes care.

[20]  Benjamin Cheong,et al.  Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. , 2002, Diabetes care.

[21]  Daniel Zelterman,et al.  Modeling Survival Data: Extending the Cox Model , 2002, Technometrics.

[22]  Stephen MacMahon,et al.  Reliable assessment of the effects of treatment on mortality and major morbidity, II: observational studies , 2001, The Lancet.

[23]  J. Bigger,et al.  Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction , 1998, The Lancet.

[24]  R. J. Hayes,et al.  United Kingdom Prospective Diabetes Study 24: A 6-Year, Randomized, Controlled Trial Comparing Sulfonylurea, Insulin, and Metformin Therapy in Patients with Newly Diagnosed Type 2 Diabetes That Could Not Be Controlled with Diet Therapy , 1998, Annals of Internal Medicine.

[25]  D. Hosmer,et al.  A comparison of goodness-of-fit tests for the logistic regression model. , 1997, Statistics in medicine.

[26]  M. Feinglos,et al.  Hypoglycemia-Induced Angina Pectoris in a Patient with Diabetes Mellitus , 1994, Annals of Internal Medicine.

[27]  J. Fleiss,et al.  The ability of several short-term measures of RR variability to predict mortality after myocardial infarction. , 1993, Circulation.

[28]  E. DeLong,et al.  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. , 1988, Biometrics.

[29]  Michael E. Miller,et al.  ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES STUDY GROUP. EFFECTS OF INTENSIVE GLUCOSE LOWERING IN TYPE 2 DIABETES , 2010 .

[30]  M. Orho-Melander,et al.  Functional characterisation of the glucokinase regulatory protein gene variant P446L shows diminished regulation by fructose-6 phosphate resulting in increased glucokinase activity , 2009 .

[31]  Peter M. Rothwell,et al.  Reliable assessment of the effects of treatments on mortality and major morbidity , 2007 .