QT Interval Abnormalities in Sulfonylurea Treated Type 2 Diabetes: Relationship to Treatment Induced Hypoglycaemia and Glycaemic Variability Determined by Simultaneous Ambulatory Monitoring

Background/Scientific Basis:

Hypoglycaemia is the most common acute complication of diabetes and can limit therapeutic efforts to improve glycaemic control. It is a potential side effect of the drugs used to treat diabetes, particularly with the use of exogenous insulin or insulin secretagogues, such as sulfonylurea (SU) treatment. As many people are prescribed these agents, hypoglycaemia is frequent in clinical practice, particularly as treatment targets have become more stringent. Several studies have demonstrated that insulin-induced hypoglycaemia causes prolongation of corrected QT (QTc) interal (Chugh et al), which is associated with ventricular arrhythmias and sudden death, perhaps as a result of hypokalaemia and an increase in serum catecholamines. Cardiac effects of hypoglycaemia are usually associated with type 1 diabetes and insulin therapy. Hypoglycaemia in type 2 diabetes (T2DM) on oral agents has not, until recently, been considered to be as serious. Recently, hypoglycaemia in T2Dm has come in into focus since the salutary results of the ACCORD, ADVANCE and VADT trails, each of which implicated hypoglycaemia as a cause for increased death. The majority of excess deaths in the intensive treatment group of ACCORD were classified as sudden cardiac death. There is now a growing body of evidence that hypoglycaemia is a pro-arrhythmic event via QT prolongation and particularly in the context of myocardial ischemia which reduces the tolerance of myocardial tissue for the further pro-arrhythmic action of hypoglycaemia.

It is notable that hypoglycaemia occurs commonly in those using SU. For example in the UK Hypoglycaemia Study (UK Hypoglycaemia Study Group) , 7% of individuals treated with SUs had at least one episode of severe (requiring external assistance) hypoglycaemia and the proportion reporting at least one mild (symptomatic, self-treated) episode was 39%, a rate comparable to insulin treatment. Furthermore, the SU receptor functions as the regulatory subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. KATP channels are widely expressed in the heart and vascular smooth muscle cells. There have been long-held concerns that SU effects on these channels may affect ischaemic preconditioning (Cleveland et al), a protective mechanism in the myocardium. This may represent an additive deleterious impact specific to SUs in a hypoglycaemic setting.

Despite these theoretical concerns associated with SU treatment the pro-arrhythmic effects of SU induced hypoglycaemia have not previously been easy to study in ambulatory patients. Now the dual ambulatory technologies of CGMS (Maia et al) and ambulatory ECG (Holter) monitoring provide an opportunity to examine this potential association under real life conditions. Even in the absence of absolute QT prolongation, there is evidence that beat-to-beat QT variability is also a risk marker for sudden death and ventricular arrhythmia (Piccirillo et al). Additionally, glucose variability may also have an impact on cardiac tissue. Habituation to chronic hyperglycaemia could lead to a situation where a sudden decrease to plasma glucose leads to changes in QT interval, even when the glucose falls within the normal range ("relative hypoglycaemia").

A pilot study in our institution of 14 individuals on insulin (3 with T1DM and 11 with T2DM) showed statistically significant prolongation of QTc during periods of hypoglycaemia. The mean difference in QTc during hypos was 7.8ms (p<0.05). An inverse relationship between the magnitude of increase in QTs during hypoglycaemia and baseline QTc was found. The limitations of the pilot study are that it was restricted to those subjects treated with insulin and that relative hypoglycaemia and QT variability were not analysed.