Many clinicians perceive the risk of severe hypoglycaemia as firmly tethered to the level of glucose control: the tighter the control, the greater the risk. This perception has its roots in the historical association between A1C and hypoglycaemia risk, established in several studies. As a frequently cited example, the DCCT trial found a 3-fold increased risk of severe hypoglycaemia in patients randomized to the intensive management arm of the study.1
In recent years, however, researchers have noted a weakening of this association, both in adults and in children. Notably, a 2017 cross-sectional analysis of three contemporary pediatric diabetes registries found no association between severe hypoglycaemia rates and HbA1c.2 Using data from pediatric (< 18 years old) patients with type 1 diabetes for at least 2 years, the analysis found that HbA1c had no significant bearing on the rate of severe hypoglycaemia, whether examined by source registry, treatment regimen, or age group. Importantly, the lack of association prevailed in both patients treated with insulin injections and those treated with continuous subcutaneous insulin infusion (CSII).
Other studies have reported similar trends, but this analysis stands out in its use of data from multiple prospective diabetes registries. Further, subjects were receiving “usual care” in a variety of clinical settings, thus reflecting real-world practice more faithfully than subjects in randomized clinical trials such as DCCT.
Of course, confounding factors may have biased the results. For example, after experiencing a severe hypoglycaemia event, fear of hypoglycaemia may have led some patients to relax their glycaemic control, thereby raising HbA1c.
While further investigation is recommended to corroborate the study’s findings, these findings are nonetheless encouraging. It stands to reason that advances in treatment, such as the use of insulin analogues, CSII, increased frequency of glucose monitoring, continuous glucose monitoring (CGM), and overall better management approaches may be enabling better glycaemic control without a corresponding increase in hypoglycaemia risk.
The historical relationship between glycaemic control lower glycemic control and risk of severe hypoglycemia has understandably contributed to a fear of hypoglycaemia in patients and their caregivers and stood as an obstacle to optimal glycaemic control.3 The weakening, if not disappearance, of the relationship gives new hope to children with type 1 diabetes.
New era, new definitions
In a parallel development, multiple studies have uncovered a reduction in hypoglycaemic coma and convulsion in children in recent years. This shift has led researchers to revisit the established definition of severe hypoglycaemia in children, which puts an emphasis on coma and convulsion. Recognizing the need for an update in hypoglycaemia classification, the International Society for Pediatric and Adolescent Diabetes (ISPAD) has proposed definitions that align with the IHSG classification system.4 Namely:
- Clinical hypoglycemia alert: A glucose value of ≤3.9 mmol/L (70 mg/dL) can be used as a threshold or “alert” value to prevent hypoglycaemia.
- Clinically important or serious hypoglycaemia: A glucose value of <3.0 mmol/L (54 mg/dL) indicates clinically significant hypoglycaemia that may cause defective glucose counter-regulation and impaired awareness of hypoglycaemia (IAH), with an attendant increase in severe hypoglycaemia risk.5
- Severe hypoglycemia: This refers to an event requiring another person to take corrective action, in alignment with the (adult) definition in the ADA guidelines.6 Given that children sometimes require external assistance for milder hypoglycaemia, caregiver assessment and judgment are required to make the distinction.
While no single glucose level can define hypoglycaemia for all patients, standardized definitions (such as the above) allow comparisons between models of care. In individual patients, keeping careful records of hypoglycaemic events—and possible precipitants—enables clinicians to establish patterns and take corrective action to minimize the risk of severe events. While such events are still too common, modern treatment and educational approaches can significantly reduce their frequency.
- The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993;329:977-986.
- Haynes A et al. Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases. Pediatr Diabetes. 2017;18:643–650.
- Frier BM. Hypoglycemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol 2014;10:711-722.
- Jones TW. Defining relevant hypoglycemia measures in children and adolescents with type 1 diabetes. Pediatric Diabetes. 2017;1–2.
- Davis MR, Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metabol 1991;73:995–1001.
- Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384–1395.