Hypoglycemia and Cardiac Arrhythmias in Type 1 Diabetes

Completed

• Conditions: Hypoglycemia; Arrhythmias, Cardiac; Diabetes type1
• Interventions: Other: Hypoglycemic combined with either normo or hyperglycemic clamp.

• Registration Number: NCT03956173
• Lead Sponsor: Steno Diabetes Center Copenhagen

Brief Summary

The investigators hypothesise that following episodes of hypoglycemia, rebound hyperglycemia may result in a prolonged period of increased QTc and, thereby, increased susceptibility to serious cardiac arrhythmias in patients with type - 1 diabetes.

Detailed Description

In this study, changes in cardiac rhythm, haemodynamic regulation, and hormonal response will be evaluated during insulin-induced hypoglycemia followed by hyperglycemia and euglycemia, respectively, on two separate experimental days. Twenty-four patients with type-1 diabetes are included. Patients are randomised 1:1 to start with either the combined hypo- and hyperglycemic or the hypo- and euglycemic clamp. After an overnight 10 hour fast, participants are admitted for a 255 minute clamp. An individualised insulin infusion will be initiated targeting a plasma glucose level of 5.0-8.0 mmol/l. When the targeted plasma glucose level is achieved, the hyperinsulinemic euglycemic clamp will be initiated at time 0. The insulin infusion will be fixed at an infusion rate 80 mU/m2/min and a 20% glucose infusion will be initiated in order to regulate plasma glucose levels. After 45 min of monitoring at euglycemic plasma glucose level, plasma glucose will be decreased over a period of 30 minutes, targeting 2.5 mmol/l for a period of 60 min in a hyperinsulinemic hypoglycemic clamp. From 135 min to 195 min, plasma glucose levels will be increased to either hyperglycemic level or euglycemic level and will be kept constant for 105 minutes. Echocardiography is performed at baseline, at hypoglycemic level and at hyper-or normoglycemic level. Blood samples are taken every 15 minutes throughout the entire clamp, however bedside plasma glucose is analysed every fifth minute. A Holter-ECG is obtained throughout the entire clamp.

Study Timeline

• Study First Submitted: 2018-10-12
• Study Start: 2018-12-01
• Study First Submitted QC: 2019-05-15
• Study First Posted: 2019-05-20
• Primary Completion: 2021-12-01
• Study Completion: 2021-12-01
• Status Verified: 2022-07
• Last Update Submitted: 2024-11-28
• Last Update Posted: 2024-12-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Informed and written consent
• Type 1 diabetes diagnosed according to the criteria of the World Health Organization (WHO)
• Age 18-70 years
• Insulin treatment for ≥3 years

Exclusion Criteria

• Arrhythmia diagnosed prior to the screening visit
• 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)
• Thyroid dysfunction (except for well-regulated eltroxin 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
Clamp group	Hypoglycemic combined with either normo or hyperglycemic clamp.	24 patients with type 1 diabetes.

Primary Outcome Measures

Name	Time	Method
QTc prolongation.	255 minutes	Difference in mean corrected QT interval (QTc) prolongation during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia

Secondary Outcome Measures

Name	Time	Method
Bradycardia	255 minutes	Difference in non-clinically significant bradycardia (≤45 bpm for 5 seconds) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
Ventricular premature beats	255 minutes	Difference in ventricular premature beats during hyperglycaemia compared to euglycaemia both preceded by insulin-induced hypoglycaemia
Glucagon response	255 minutes	Differences in glucagon response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
Catecholamine response	255 minutes	Differences in catecholamine response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
Cortisol response	255 minutes	Differences in cortisol responses during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
Growth hormone response	255 minutes	Differences in growth hormone response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
Oxidative stress markers (8-iso-PGF2α)	255 minutes	Differences in markers of oxidative stress (8-iso prostaglandin F2α (8-iso-PGF2α)) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
Oxidative stress markers (8-oxoGuo)	255 minutes	Differences in markers of oxidative stress (8-oxo-7,8-dihydroguanosine (8-oxoGuo)) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
QTd dispersion.	255 minutes	Difference in QT dispersion (QTd) during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
Atrial ectopic beats.	255 minutes	Difference in atrial ectopic beats (prematurity threshold 30%),during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
Haemodynamic regulation.	255 minutes	Differences in haemodynamic regulation (measured by echocardiography) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
Inflammatory response	255 minutes	Differences in markers of inflammation (high-sensitive C-reactive peptide (hs-CRP) and interleukin 6 (IL-6)) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia

Trial Locations

Locations (1)

Clinical Metabolic Physiology, SDCC; 🇩🇰 Copenhagen, Denmark