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

• ClinicalTrials.gov Identifier: NCT03956173
• Recruitment Status: Active, not recruiting
• First Posted: May 20, 2019
• Last Update Posted: September 2, 2021
• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: University Hospital, Gentofte, Copenhagen; Hillerod Hospital, Denmark
• Information provided by (Responsible Party): Steno Diabetes Center Copenhagen

Study Description

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.

Condition or disease	Intervention/treatment
Diabetes type1; Hypoglycemia; Arrhythmias, Cardiac	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 Design

• Study Type: Observational
• Estimated Enrollment: 24 participants
• Observational Model: Case-Crossover
• Time Perspective: Prospective
• Official Title: Hypoglycemia and Cardiac Arrhythmias in Type 1 Diabetes
• Actual Study Start Date: December 1, 2018
• Estimated Primary Completion Date: December 1, 2021
• Estimated Study Completion Date: December 1, 2021

Groups and Cohorts

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.

Outcome Measures

Primary Outcome Measures :

1. QTc prolongation. [ Time Frame: 255 minutes ]
   Difference in mean corrected QT interval (QTc) prolongation during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia

Secondary Outcome Measures :

1. QTd dispersion. [ Time Frame: 255 minutes ]
   Difference in QT dispersion (QTd) during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
2. Atrial ectopic beats. [ Time Frame: 255 minutes ]
   Difference in atrial ectopic beats (prematurity threshold 30%),during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
3. Bradycardia [ Time Frame: 255 minutes ]
   Difference in non-clinically significant bradycardia (≤45 bpm for 5 seconds) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
4. Ventricular premature beats [ Time Frame: 255 minutes ]
   Difference in ventricular premature beats during hyperglycaemia compared to euglycaemia both preceded by insulin-induced hypoglycaemia
5. Glucagon response [ Time Frame: 255 minutes ]
   Differences in glucagon response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
6. Catecholamine response [ Time Frame: 255 minutes ]
   Differences in catecholamine response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
7. Growth hormone response [ Time Frame: 255 minutes ]
   Differences in growth hormone response during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
8. Cortisol response [ Time Frame: 255 minutes ]
   Differences in cortisol responses during hyperglycemia compared to euglycemia both preceded by insulin induced hypoglycemia
9. Haemodynamic regulation. [ Time Frame: 255 minutes ]
   Differences in haemodynamic regulation (measured by echocardiography) during hyperglycemia compared to euglycemia both preceded by insulin-induced hypoglycemia
10. Inflammatory response [ Time Frame: 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
11. Oxidative stress markers (8-iso-PGF2α) [ Time Frame: 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
12. Oxidative stress markers (8-oxoGuo) [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

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

Criteria

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)

Contacts and Locations

Locations

Denmark

Clinical Metabolic Physiology, SDCC

Copenhagen, Denmark, 2900

Sponsors and Collaborators

Steno Diabetes Center Copenhagen

University Hospital, Gentofte, Copenhagen

Hillerod Hospital, Denmark

Investigators

• Study Director: Tina Vilsbøll, MD, DMSc; Steno diabetic centre (SDCC)

More Information

• Responsible Party: Steno Diabetes Center Copenhagen
• ClinicalTrials.gov Identifier: NCT03956173
• Other Study ID Numbers: H-18034040
• First Posted: May 20, 2019
• Last Update Posted: September 2, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Arrhythmias, Cardiac; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Hypoglycemic Agents; Physiological Effects of Drugs