Hypoglycemia and Cardiac Arrhythmias in Type 1 Diabetes (Hypo-Heart-1)

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.

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Arrhythmias, Cardiac; Diabetes type1
• Intervention / Treatment: Other: Hypoglycemic combined with either normo or hyperglycemic clamp.

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 Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2900
    • Clinical Metabolic Physiology, SDCC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

24 patients with type 1 diabetes with insulin treatment for ≥ 3 years.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Clamp group; 24 patients with type 1 diabetes.

Other: Hypoglycemic combined with either normo or hyperglycemic clamp.; Twenty-four patients with type 1 diabetes has been recruited for a cross-over study including two experimental days, a combined hypo- and hyperglyemic clamp and a combined hypo- and euglycemic clamp, respectively. Patients will be randomised 1:1 to start with either the combined hypo- and hyperglycemic or the hypo- and euglycemic clamp. The hypo- and hyperglycemic or the hypo- and euglycemic clamp are estimated to last 255 minutes. The two clamp days will be separated by at least 30 days.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Hillerod Hospital, Denmark; University Hospital, Gentofte, Copenhagen
• Investigators: Study Director: Tina Vilsbøll, MD, DMSc, Steno diabetic centre (SDCC)

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2018
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: May 15, 2019
• First Posted (Actual): May 20, 2019

Study Record Updates

• Last Update Posted (Actual): July 8, 2022
• Last Update Submitted That Met QC Criteria: July 6, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Arrhythmias, Cardiac; Physiological Effects of Drugs; Hypoglycemic Agents
• Other Study ID Numbers: H-18034040

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No