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NCT Number: NCT04800536

Cardiovascular Effects of Rapidly Declining Plasma Glucose in Patients With Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune metabolic disease characterised by impaired lack of endogenous insulin causing elevated plasma glucose levels and increased risk of microvascular and macrovascular complications. With respect to the cardiovascular system, patients with T1D have an up to 10-fold increased risk of sudden cardiac death compared to healthy individuals. Furthermore, diabetes constitutes a hypercoagulable state, which to some extent may explain why cardiovascular disease still is a major cause of mortality in patients with T1D. Due to treatment with exogenously delivered insulin, glycaemic variability with intra-day and inter-day plasma glucose concentrations fluctuating between high levels (peaks) and low levels (nadirs), are inevitable in patients with T1D. A potentially important factor in development of cardiovascular disease, associated with glycaemic variability, is the rate of increase and/or decline of plasma glucose. The aim of this study is to test the hypothesis that a rapid plasma glucose decline from a hyperglycaemic level to an euglycaemic level can induce changes in QT-interval and blood coagulation in a proarrhythmogenic and prothrombotic way.

Twenty patients with T1D with a 1:1 distribution with chronic hyperglycaemia (HbA1C ≥63 mmol/mol) and with well-controlled diabetes (HbA1C ≤53 mmol/mol) will be recruited for a crossover study including two test days (protocols), P-rapid, a combined hyperglycaemic and euglycaemic clamp with rapidly declining plasma glucose and P-slow, a combined hyperglycaemic and euglycaemic clamp with slowly declining plasma glucose. Patients will be randomised 1:1 to start with P-rapid or P-slow. The cardiovascular effects will be investigated using Holter-ECG, Thrombelastography, Echocardiography and blood sampling.

Given that cardiovascular disease is a major cause of death in patients with T1D and that patients with diabetes may be more susceptible for cardiac arrhythmias and thrombotic events compared to healthy individuals, it is important to identify cardiovascular risk factors related to acute changes in plasma glucose in order to improve prevention strategies and therapy.

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Key information

Conditions

Type 1 Diabetes Autoimmune Diseases Cardiovascular Diseases Death Death, Sudden Death, Sudden, Cardiac Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucose Metabolism Disorders Heart Arrest Heart Diseases Immune System Diseases Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Steno Diabetes Center Copenhagen - Gentofte Hospital

Copenhagen, 2900, Denmark

Who can participate

Healthy volunteers accepted: No

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

Inclusion criteria

- chronic hyperglycaemia cohort

  • Informed and written consent
  • Type 1 diabetes
  • Age ≥18 years
  • C-peptide negative (<0.2 nmol/l)
  • Insulin treatment for ≥1 year
  • HbA1C ≥63 mmol/mol

Inclusion criteria

- well-controlled cohort

  • Informed and written consent
  • Type 1 diabetes
  • Age ≥18 years
  • C-peptide negative (<0.2nmol/l)
  • Insulin treatment for ≥1 year
  • HbA1C ≤53 mmol/mol

Exclusion criteria

- both cohorts

  • Arrhythmia diagnosed prior to or at the time of the screening visit
  • ECG with left or right bundle branch block diagnosed prior to the screening visit.
  • Implantable cardioverter defibrillator or pacemaker at the time of inclusion
  • Heart failure diagnosed prior to the screening visit (left ventricular ejection fraction < 45%)
  • Structural heart disease (Wolf-Parkinson-White syndrome, congenital heart disease, severe valve disease)
  • Thyroid dysfunction (except for well-regulated myxoedema)
  • Anaemia (male: haemoglobin <8.0 mmol/l; female: haemoglobin <7.0 mmol/l)
  • Treatment with anticoagulant or antiplatelet treatment
  • Bleeding disorder diagnosed prior to the screening visit

Withdrawal criteria

  • The participants may withdraw at will at any time

Treatment and study plan

Rapidly declining plasma glucose

Other

Acute plasma glucose decline, divided into the following three phases: 1) Hyperglycaemic phase (plasma glucose 15 mmol/l), 2) Rapid plasma glucose decline phase and 3) Euglycaemic phase (plasma glucose 4.5-5.5 mmol/l).

Slowly declining plasma glucose

Other

Acute plasma glucose decline, divided into the following three phases: 1) Hyperglycaemic phase (plasma glucose 15 mmol/l), 2) Slow plasma glucose decline phase and 3) Euglycaemic phase (plasma glucose 4.5-5.5 mmol/l).

Primary outcomes

  1. QTc interval

    Time frame: 0-255 minutes

    Difference in mean QTc (ms) interval from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

Secondary outcomes

  1. Cardiac function

    Time frame: 0-255 minutes

    Difference in ventricular systolic function (measured by echocardiography) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  2. Heart rate variability

    Time frame: 0-255 minutes

    Difference in the sympathetic/parasympathetic balance (measured by heart rate variability) during a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  3. Haemostatic balance

    Time frame: 0-255 minutes

    Difference in activation of coagulation and fibrinolysis (measured by TEG) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  4. Endothelial activation and damage

    Time frame: 0-255 minutes

    Difference in endothelial activation and damage (measured by Syndecan-1, Soluble thrombomodulin and sVE-cadherin) (ng/ml) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  5. Plasma glucose decline rate and counterregulatory hormonal response

    Time frame: 0-255 minutes

    Difference in counterregulatory hormonal response (plasma glucagon, catecholamines, cortisol, and growth hormone) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  6. Plasma glucose decline rate and oxidative stress

    Time frame: 0-255 minutes

    Difference in vascular oxidative stress (Tetrahydrobiopterin/dihydrobiopterin ratio, Dehydroascorbic acid/Ascorbic acid ratio, Asymmetric dimethylarginine/Arginine ratio, Malondialdehyde) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

  7. Plasma glucose decline rate and potassium

    Time frame: 0-255 minutes

    Difference in plasma potassium concentration during a rapid plasma glucose decline compared to a slow plasma glucose decline from a hyperglycaemic level to an euglycaemic level.

  8. Plasma glucose decline rate and symptomatic response

    Time frame: 0-255 minutes

    Difference in symptomatic response (Edinburgh hypoglycaemia symptom scale) from a hyperglycaemic level to an euglycaemic level preceded by a rapid plasma glucose decline compared to a slow plasma glucose decline in patients with T1D with chronic hyperglycaemia and well-controlled diabetes, respectively.

Sponsors and collaborators

Lead sponsor

Steno Diabetes Center Copenhagen

Other

Collaborators

  • Rigshospitalet, Denmark
  • University Hospital, Gentofte, Copenhagen

Registry information

Important dates

Study start
2021
Primary completion
2021
Study completion
2023
First posted
Mar 16, 2021
Registry last updated
Apr 12, 2024

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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