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

NCT04800536 | Completed DMC

• 1 other identifier: H-20033627
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Type 1 Diabetes

Keywords

Plasma glucose decline rate; Cardiovascular disease; Sudden cardiac death; Glycaemic variability

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Cardiac function

  0-255 minutes

• Heart rate variability

  0-255 minutes

• Haemostatic balance

  0-255 minutes

• Endothelial activation and damage

  0-255 minutes

• Plasma glucose decline rate and counterregulatory hormonal response

  0-255 minutes

Study Arms (2)

Cardiovascular effects of rapidly declining plasma glucose

EXPERIMENTAL

A combined hyperglycaemic and euglycaemic clamp with a rapidly declining plasma glucose (\>0.15 mmol/l/min). Plasma glucose will be measured every 5 minute and cardiovascular effects of the plasma glucose decline rate will be assessed using Holter-ECG, echocardiography, thrombelastography and blood sampling.

Other: Rapidly declining plasma glucose

Cardiovascular effects of slowly declining plasma glucose

EXPERIMENTAL

A combined hyperglycaemic and euglycaemic clamp with slowly declining plasma glucose (\<0.085 mmol/l/min). A combined hyperglycaemic and euglycaemic clamp with a slowly declining plasma glucose (\>0.15 mmol/l/min). Plasma glucose will be measured every 5 minute and cardiovascular effects of the plasma glucose decline rate will be assessed using Holter-ECG, echocardiography, thrombelastography and blood sampling.

Other: Slowly declining plasma glucose

Interventions

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).

Cardiovascular effects of rapidly declining plasma glucose

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).

Cardiovascular effects of slowly declining plasma glucose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Steno Diabetes Center Copenhagen: lead
• University Hospital, Gentofte, Copenhagen: collaborator
• Rigshospitalet, Denmark: collaborator

Study Sites (1)

Steno Diabetes Center Copenhagen - Gentofte Hospital

Copenhagen, 2900, Denmark

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Cardiovascular Diseases; Death, Sudden, Cardiac

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2021
• First Posted: March 16, 2021
• Study Start: June 1, 2021
• Primary Completion: December 16, 2021
• Study Completion: April 1, 2023
• Last Updated: April 12, 2024

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)