Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

Completed

• Conditions: Arrhythmia, Cardiac; Diabetes Mellitus, Type 2
• Interventions: Other: Combined hyper- and hypoglycaemic clamp; Device: Loop recorder (Reveal LINQ, Medtronic, Minneapolis, MN, USA); Device: Continuous glucose monitoring (iPro2, Medtronic, Minneapolis, MN, USA)

• Registration Number: NCT03150030
• Lead Sponsor: University Hospital, Gentofte, Copenhagen

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-02-01
• Study First Submitted: 2017-04-25
• Study First Submitted QC: 2017-05-10
• Study First Posted: 2017-05-11
• Primary Completion: 2020-01-06
• Study Completion: 2020-01-06
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-30
• Last Update Posted: 2020-11-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 42

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)

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients with type 2 diabetes	Loop recorder (Reveal LINQ, Medtronic, Minneapolis, MN, USA)	Insulin-treated type 2 diabetes with diabetic complications
Healthy controls	Combined hyper- and hypoglycaemic clamp	Healthy control subjects
Patients with type 2 diabetes	Continuous glucose monitoring (iPro2, Medtronic, Minneapolis, MN, USA)	Insulin-treated type 2 diabetes with diabetic complications
Patients with type 2 diabetes	Combined hyper- and hypoglycaemic clamp	Insulin-treated type 2 diabetes with diabetic complications

Primary Outcome Measures

Name	Time	Method
Part 1: Clinically relevant arrhythmias	0-240 min during the combined hyper- and hypoglycaemic clamp	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.
Part 2: Difference in MAGE	Within 12 months	Difference in mean amplitude of glycaemic excursions (MAGE) two hours preceding an arrhythmic event versus MAGE during non-event
Part 2: Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia	Within 12 months	Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia
Part 2: Prevalence of clinically relevant arrhythmias as defined above	Within 12 months	Prevalence of clinically relevant arrhythmias as defined above

Secondary Outcome Measures

Name	Time	Method
Part 1: Differences in mean corrected QT interval (QTc)	0-240 min during the combined hyper- and hypoglycaemic clamp	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
Part 1: Difference in counter regulatory hormonal response	0-240 min during the combined hyper- and hypoglycaemic clamp	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
Part 2: Clinical relevant arrhythmias during low glucose variability compared to high glucose variability.	Within 12 months	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
Part 2: The relationship between cardiovascular disease at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV	Within 12 months	The relationship between cardiovascular disease (heart failure and ischaemic heart disease) at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV
Part 2: The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV	Within 12 months	The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV
Part 2: The relationship between diabetes complication status at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV	Within 12 months	The relationship between diabetes complication status (neuropathy, nephropathy, retinopathy) at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV
Part 2: Correlation between plasma glucose variation and risk of clinical relevant arrhythmias	Within 12 months	Correlation between plasma glucose variation (variation in plasma glucose (Δ mmol/l) within two hours of the event) and risk of clinical relevant arrhythmias
Part 2: Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias	Within 12 months	Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias
Part 1: Differences in haemodynamic regulation	0-240 min during the combined hyper- and hypoglycaemic clamp	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

Trial Locations

Locations (1)

Gentofte Hospital; 🇩🇰 Hellerup, Denmark