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

Type 1 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04800536
• Other study ID #: H-20033627
• Status: Completed
• Phase: N/A
• Start date: June 1, 2021
• Est. completion date: April 1, 2023

Study information

• Verified date: May 2022
• Source: Steno Diabetes Center Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: April 1, 2023
• Est. primary completion date: December 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Other:
• Rapidly declining plasma glucose
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
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).

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center Copenhagen - Gentofte Hospital	Copenhagen

Sponsors (3)

Lead Sponsor	Collaborator
Steno Diabetes Center Copenhagen	Rigshospitalet, Denmark, University Hospital, Gentofte, Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	QTc interval	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.	0-255 minutes
Secondary	Cardiac function	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.	0-255 minutes
Secondary	Heart rate variability	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.	0-255 minutes
Secondary	Haemostatic balance	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.	0-255 minutes
Secondary	Endothelial activation and damage	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.	0-255 minutes
Secondary	Plasma glucose decline rate and counterregulatory hormonal response	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.	0-255 minutes
Secondary	Plasma glucose decline rate and oxidative stress	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.	0-255 minutes
Secondary	Plasma glucose decline rate and potassium	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.	0-255 minutes
Secondary	Plasma glucose decline rate and symptomatic response	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.	0-255 minutes