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Completed

NCT Number: NCT03150030

Hypoglycaemia and Cardiac Arrhythmias in Type 2 Diabetes

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.

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Key information

Conditions

Diabetes Mellitus, Type 2 Arrhythmia, Cardiac Arrhythmias, Cardiac Cardiovascular Diseases Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Heart Diseases Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Gentofte Hospital

Hellerup, 2900, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Combined hyper- and hypoglycaemic clamp

Other

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.

Loop recorder (Reveal LINQ, Medtronic, Minneapolis, MN, USA)

Device

Implantation of a loop-recorder

Continuous glucose monitoring (iPro2, Medtronic, Minneapolis, MN, USA)

Device

Monitoring with a continuous glucose monitor

Primary outcomes

  1. Part 1: Clinically relevant arrhythmias

    Time frame: 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.

  2. Part 2: Prevalence of clinically relevant arrhythmias as defined above

    Time frame: Within 12 months

    Prevalence of clinically relevant arrhythmias as defined above

  3. Part 2: Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia

    Time frame: Within 12 months

    Clinically relevant arrhythmias during hypoglycaemia compared to euglycaemia

  4. Part 2: Difference in MAGE

    Time frame: Within 12 months

    Difference in mean amplitude of glycaemic excursions (MAGE) two hours preceding an arrhythmic event versus MAGE during non-event

Secondary outcomes

  1. Part 1: Differences in mean corrected QT interval (QTc)

    Time frame: 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

  2. Part 1: Difference in counter regulatory hormonal response

    Time frame: 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

  3. Part 1: Differences in haemodynamic regulation

    Time frame: 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

  4. Part 2: Clinical relevant arrhythmias during low glucose variability compared to high glucose variability.

    Time frame: 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

  5. Part 2: The relationship between cardiovascular disease at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV

    Time frame: 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

  6. Part 2: The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV

    Time frame: Within 12 months

    The relationship between pharmacological treatment at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV

  7. Part 2: The relationship between diabetes complication status at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV

    Time frame: Within 12 months

    The relationship between diabetes complication status (neuropathy, nephropathy, retinopathy) at baseline and clinically relevant arrhythmias in relation to hypoglycaemia and HGV

  8. Part 2: Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias

    Time frame: Within 12 months

    Correlation between prevalence and total duration of hypoglycaemia and risk of clinically relevant arrhythmias

  9. Part 2: Correlation between plasma glucose variation and risk of clinical relevant arrhythmias

    Time frame: 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

Sponsors and collaborators

Lead sponsor

University Hospital, Gentofte, Copenhagen

Other

Registry information

Acronym: HYPO-HEART

Important dates

Study start
2017
Primary completion
2020
Study completion
2020
First posted
May 11, 2017
Registry last updated
Nov 2, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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