• Beate Karges, Joachim Rosenbauer, Thomas Kapellen, Verena M Wagner, Edith Schober, Wolfram Karges, and Reinhard W Holl.
• Division of Endocrinology and Diabetes, RWTH Aachen University, Aachen, Germany.
• PLoS Med. 2014 Oct 1; 11 (10): e1001742.

BackgroundSevere hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.Methods And FindingsWe analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4 ± 3.8 y, range 1-20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19-1.37) to 1.05 (1.00-1.09) and from 1.39 (1.23-1.56) to 1.01 (0.93-1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6-1.7, p<0.001) and 1.9% (0.8-2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%-6.9% (RR 0.96 and 0.90 each year) and 7.0%-7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.ConclusionsThe previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients. Please see later in the article for the Editors' Summary.

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