QT Interval Abnormalities in Sulfonylurea Treated Type 2 Diabetes: Relationship to Treatment Induced Hypoglycaemia

QT Interval Abnormalities in Sulfonylurea Treated Type 2 Diabetes: Relationship to Treatment Induced Hypoglycaemia

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

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 drugs used to treat diabetes, particularly with the use of sulfonylurea (SU) treatment. It has been demonstrated that hypoglycaemia causes the prolongation of corrected QT (QTc) interval, which is associated with ventricular arrhythmias and sudden death. Hypoglycaemia in T2DM has recently come into focus with the results of the ACCORD, ADVANCE and VADT trials. In this study, the investigators aim to examine the association of hypoglycaemia and glucose fluctuations on QT-interval and QT variability in patients with type 2 diabetes treated with SU. Patients will be studied using simultaneous Continuous Glucose Monitoring (CGM) and ambulatory ECG monitoring (Holter). Study participants will be recruited from the Diabetes Centre, RPAH or from specialist consulting rooms. They will be required to attend the Diabetes Centre on two occasions. At the first visit, blood will be collected and CGM and Holter monitoring commenced. At Visit 2, i.e. two days later, the patient will return to the Diabetes Centre to have the equipment removed. The data obtained from the CGM and Holter monitor will then be downloaded for review and analysis.

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. Hypothesis: Sulfonylurea induced hypoglycaemia and/or fluctuations in glucose are pro-arrhythmic by prolonging the QTc interval and/or increasing beat-to-beat QTc variability. It is expected that the QT interval will be significantly longer during the hypoglycemic periods compared to the non-hypoglycemic periods in patients in T2DM treated with SU. Aims: To examine the association of hypoglycaemia and glucose fluctuations on QT-interval and QT variability in patients with type 2 diabetes treated with SU. Patients will be studied using simultaneous Continuous Glucose Monitoring (CGM) and ambulatory ECG monitoring (Holter). Potential Significance: The information gained from this study has the potential to improve our understanding of the relationship between hypoglycaemia and cardiac arrhythmia in patients with diabetes. Recruitment Process: Patients with type 2 diabetes attending the Diabetes Centre, Royal Prince Alfred Hospital who fulfils the entry criteria will be approached to participate in this study. They will be approached either when they attend the Diabetes Centre for treatment, or by means of a telephone call. The requirements of the study will be discussed with each potential participant and they will be given a copy of the Participant Information Sheet and Consent Form to take home and read. The proposed number of participants for this study is approximately 30 individuals. Research Interventions: Blood Collection Continuous Glucose Monitoring Home Blood Glucose Monitoring Holter Monitor Risk and Side Effects: We do not anticipate any adverse events associated with study participation. However, there may be some mild discomfort and/or bruising at the site of blood collection, or insertion of the glucose sensor for CGM, or skin irritation from the ECG adhesive tapes required for Holter monitoring.

In this study the interventions will be the simultaneous monitoring of glucose and QT interval via a subcutaneous continuous glucose monitor and a Hoter monitor, respectively.

(i) Continuous Glucose Monitoring A sterile disposable glucose-sensing sensor will be inserted into the subcutaneous tissues in either the abdomen or the upper outer quadrant of the patient's buttock. This sensor automatically measures the change in glucose in interstitial fluid every 5 minutes. The monitor will be worn for two days. (ii)Holter Monitoring The Holter monitor to capture cardiac conduction, specifically QT interval, will be worn for the same period as the continuous glucoe monitor with study participants encouraged to perform regular daily activities.

The nocturnal time period for the study spanned from 11 pm in the evening until 7 am the following morning on two consecutive days. The change in the corrected QT interval during nocturnal hypoglycemia was determined by calculating the difference between the average QTc interval length during periods of hypoglycemia (blood glucose level <3.5 mmol/L) and the average QTc interval length during periods of normoglycemia (blood glucose level >3.5 mmol/L) for the nocturnal time period. The average QTc interval was calculated using an individually optimised correction formula. If the result of average QTc (hypoglycemia) - average QTc (normoglycemia) was positive, the participant experienced QTc prolongation during hypoglycemia. If the result of average QTc (hypoglycemia) - average QTc (normoglycemia) was negative, the participant experienced QTc shortening during hypoglycemia.

The day time period for the study spanned from 7 am in the morning until 11 pm in the evening on two consecutive days. The change in the corrected QT interval during day time hypoglycemia was determined by calculating the difference between the average QTc interval length during periods of hypoglycemia (blood glucose level <3.5 mmol/L) and the average QTc interval length during periods of normoglycemia (blood glucose level >3.5 mmol/L) for the day time period. The average QTc interval was calculated using an individually optimised correction formula. If the result of average QTc (hypoglycemia) - average QTc (normoglycemia) was positive, the participant experienced QTc prolongation during hypoglycemia. If the result of average QTc (hypoglycemia) - average QTc (normoglycemia) was negative, the participant experienced QTc shortening during hypoglycemia.

Pearson's Correlation Coefficient of Delta QTc and a Measure of Glucose Variability, MAGE (Mean Amplitude of Glycemic Excursion).

MAGE, a commonly used index of glucose variability, was calculated using data obtained during continuous glucose monitoring. Analysis of correlation between MAGE and delta QTc was undertaken. Please note delta QTc represents the difference between average QTc length during hypoglycemia and average QTc length during normoglycemia.

The MAGE results (in mmol/L) for the eight participants who experienced nocturnal hypoglycemia are included in the table below.

deltaQTc is the difference in QTc observed during periods of hypoglycemia and periods of normoglycemia (for those participants who experienced nocturnal hypoglycemia)

Inclusion Criteria: Type 2 diabetes A history of symptomatic or documented hypoglycaemia Currently treated with a sulphonylurea ± any anti-diabetic agent/s other than insulin Currently performing home blood glucose monitoring and willing to do seven tests a day during the study period Exclusion Criteria: Type 1 diabetes Current treatment with insulin LBBB and conduction anomalies that preclude QT analysis Drugs that prolong QT interval Family history of Long QT syndrome

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UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007 Jun;50(6):1140-7. doi: 10.1007/s00125-007-0599-y. Epub 2007 Apr 6.

Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation. 1997 Jul 1;96(1):29-32. doi: 10.1161/01.cir.96.1.29.

Maia FF, Araujo LR. Efficacy of continuous glucose monitoring system (CGMS) to detect postprandial hyperglycemia and unrecognized hypoglycemia in type 1 diabetic patients. Diabetes Res Clin Pract. 2007 Jan;75(1):30-4. doi: 10.1016/j.diabres.2006.05.009. Epub 2006 Jun 27.

Piccirillo G, Rossi P, Magri D. The QT variability index: a multidimensional approach to understanding cardiovascular disease. Cardiology. 2011;118(1):42-4. doi: 10.1159/000324476. Epub 2011 Mar 11. No abstract available.