Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

University Hospital, Gentofte, Copenhagen42 enrolled

Overview

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.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Diabetes Mellitus, Type 2 Arrhythmia, Cardiac

Interventions

Combined hyper- and hypoglycaemic clampOTHER

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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.

Time frame: 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

Time frame: Within 12 months

Part 2: Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia

Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia

Time frame: 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

Time frame: Within 12 months

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Within 12 months

Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes