Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

Study Overview
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Brief Summary
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Twenty-one patients with insulin-treated type 2 diabetes with diabetic complications will be recruited to Part 1 of the study, a three-hour combined hyper- and hypoglycaemic clamp, along with a control group of twenty-one individuals with normal glucose tolerance matched for age, gender, and body mass index. Patients with type 2 diabetes will be scheduled for a three-week run-in period with LR and CGM prior to participation in Part 1. Only patients with a well-functioning loop-recorder and who can comply with CGM will be included. Patients with type 2 diabetes will continue in part 2 of the study, a one year observational study employing CGM and LR and clinical examination after 1, 3, 6, 9, and 12 months and an extended observation period of 2 years employing LR and clinical examination.

Official Title
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Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Arrhythmia, Cardiac

Intervention / Treatment
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* Other: Combined hyper- and hypoglycaemic clamp
* Device: Loop recorder (Reveal LINQ, Medtronic, Minneapolis, MN, USA)
* Device: Continuous glucose monitoring (iPro2, Medtronic, Minneapolis, MN, USA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with type 2 diabetes Informed and written consent Type 2 diabetes diagnosed according to the criteria of the World Health Organization (WHO) Treatment with insulin Glycated haemoglobin A1c (HbA1c) ≤58 mmol/mol One or more clinical relevant complications to diabetes defined as: peripheral neuropathy with vibration perception threshold of > 25 volt determined by biothesiometry, moderate to severe retinopathy, nephropathy (creatinine >130 μmol/l and/or albuminuria), and/or macrovascular disease. Macrovascular disease is defined as coronary disease (stable angina pectoris or previous unstable angina pectoris or myocardial infarct), cerebrovascular disease (previous stroke or transitional cerebral ischaemia), and peripheral vascular disease (previous intermittent claudication or prior acute ischemia) Well-functioning LR during run-in period (acceptable readings judged by an arrhythmologist) Participation in the extended study Healthy individuals HbA1c ≤42 mmol/mol Fasting plasma glucose ≤6.1 mmol/l Exclusion Criteria: Patients with type 2 diabetes Arrhythmia diagnosed prior to or at the time of inclusion Implantable cardioverter defibrillator (ICD) or pacemaker at the time of inclusion Severe heart failure (left ventricular ejection fraction <25%) Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) Insulin naïve patients with type 2 diabetes Thyroid dysfunction (except for well-regulated eltroxine substituted myxoedema) Unable to comply with daily CGM during run-in period Anemia (male: hemoglobin < 8.0; female: hemoglobin < 7.0 mmol/l) Healthy individuals Type 1 or type 2 diabetes Prediabetes (HbA1c >42 mmol/l and/or fasting plasma glucose >6.1 mmol/l) Family history of diabetes (type 1 og type 2 diabetes) Arrhythmia diagnosed prior to or at the time of inclusion ICD or pacemaker at the time of inclusion Severe heart failure (left ventricular ejection fraction <25%) Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease) Thyroid dysfunction (except for well-regulated eltroxine substituted myxoedema) Anemia (male: hemoglobin < 8.0; female: hemoglobin < 7.0 mmol/l)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with type 2 diabetes<br>Insulin-treated type 2 diabetes with diabetic complications | Other: Combined hyper- and hypoglycaemic clamp<br>* During the entire clamp, participants will be monitored by ECG, pulse oximetry, and blood pressure and plasma glucose will be measured bedside every fifth minute. Additionally, patients with type 2 diabetes will be monitored by a loop recorder (LR) and a continuous glucose monitor (CGM). Comparison of LR and CGM recordings with the recordings obtained by ECG Holter monitor and blood sampling will be used for validation of the method used in Part 2 of the study. Blood samples will be drawn and analysed for changes in electrolytes, insulin, glucagon, catecholamines and cortisone. A cardiac haemodynamic evaluation will be performed by echocardiography at baseline, hyperglycaemia, and hypoglycaemia.<br>Device: Loop recorder (Reveal LINQ, Medtronic, Minneapolis, MN, USA)<br>* Implantation of a loop-recorder<br>Device: Continuous glucose monitoring (iPro2, Medtronic, Minneapolis, MN, USA)<br>* Monitoring with a continuous glucose monitor<br>|
| Healthy controls<br>Healthy control subjects | Other: Combined hyper- and hypoglycaemic clamp<br>* During the entire clamp, participants will be monitored by ECG, pulse oximetry, and blood pressure and plasma glucose will be measured bedside every fifth minute. Additionally, patients with type 2 diabetes will be monitored by a loop recorder (LR) and a continuous glucose monitor (CGM). Comparison of LR and CGM recordings with the recordings obtained by ECG Holter monitor and blood sampling will be used for validation of the method used in Part 2 of the study. Blood samples will be drawn and analysed for changes in electrolytes, insulin, glucagon, catecholamines and cortisone. A cardiac haemodynamic evaluation will be performed by echocardiography at baseline, hyperglycaemia, and hypoglycaemia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Clinically relevant arrhythmias | Composite endpoint including atrial fibrillation, brady-arrhythmias and tachy-arrhythmias. Clinically relevant brady-arrhythmias are defined as sinus arrest for more than 3 seconds, frequency below 30 beats per minute (bpm), or high grade atrioventricular (AV) block including Mobitz Type II and third-degree AV block. Clinically relevant tachy-arrhythmias are defined as sustained ventricular tachycardia (duration >30 seconds), and non-sustained ventricular tachycardia. | 0-240 min during the combined hyper- and hypoglycaemic clamp | 
| Part 2: Prevalence of clinically relevant arrhythmias as defined above | Prevalence of clinically relevant arrhythmias as defined above | Within 12 months | 
| Part 2: Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia | Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia | Within 12 months | 
| Part 2: Difference in MAGE | Difference in mean amplitude of glycaemic excursions (MAGE) two hours preceding an arrhythmic event versus MAGE during non-event | Within 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Differences in mean corrected QT interval (QTc) | Differences in mean corrected QT interval (QTc) between patients with type 2 diabetes and matched normal glucose tolerant individuals during the combined hyper- and hypoglycaemic clamp | 0-240 min during the combined hyper- and hypoglycaemic clamp | 
| Part 1: Difference in counter regulatory hormonal response | Difference in counter regulatory hormonal response between patients with type 2 diabetes and matched normal glucose tolerant individuals during the combined hyper- and hypoglycaemic clamp | 0-240 min during the combined hyper- and hypoglycaemic clamp | 
| Part 1: Differences in haemodynamic regulation | Differences in haemodynamic regulation (measured by echocardiography) between patients with type 2 diabetes and matched normal glucose tolerant individuals during a combined hyper- and hypoglycaemic clamp | 0-240 min during the combined hyper- and hypoglycaemic clamp | 
| Part 2: Clinical relevant arrhythmias during low glucose variability compared to high glucose variability. | Clinical relevant arrhythmias during low glucose variability (LGV), defined as variations in plasma glucose below or equal to 5 mmol/l within two hours preceding an arrhythmic event, compared to high glucose variability (HGV), defined as variations in plasma glucose above 5 mmol/l within two hours preceding an arrhythmic event | Within 12 months | 
| Part 2: The relationship between cardiovascular disease at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | The relationship between cardiovascular disease (heart failure and ischaemic heart disease) at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | Within 12 months | 
| Part 2: The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | Within 12 months | 
| Part 2: The relationship between diabetes complication status at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | The relationship between diabetes complication status (neuropathy, nephropathy, retinopathy) at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV | Within 12 months | 
| Part 2: Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias | Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias | Within 12 months | 
| Part 2: Correlation between plasma glucose variation and risk of clinical relevant arrhythmias | Correlation between plasma glucose variation (variation in plasma glucose (Δ mmol/l) within two hours of the event) and risk of clinical relevant arrhythmias | Within 12 months |