Effect of Dapagliflozin on IAH in T1DM

Effect of the SGLT-2 Inhibitor Dapagliflozin on Impaired Awareness of Hypoglycemia in Type 1 Diabetes

Approximately 25% of patients with type 1 diabetes have lost the capacity to timely detect hypoglycaemia, a condition referred to as impaired awareness of hypoglycaemia (IAH) that causes a six-fold higher risk of severe, potentially hazardous, hypoglycaemia. IAH is usually the end-result of a process of habituation to recurrent hypoglycaemia that is potentially reversible. Treatment with sodium glucose cotransporter (SGLT)-2 inhibitors (SGLT-2i) in addition to insulin therapy may decrease the incidence of hypoglycaemia in patients with type 1 diabetes. This study will test the hypothesis that treatment with the SGLT-2 inhibitor, dapagliflozin, added to basal-bolus insulin therapy will improve awareness of hypoglycaemia in patients with type 1 diabetes and IAH. In a randomized doubleblind placebo-controlled cross-over trial, patients will be treated for 8 weeks with dapagliflozin (or placebo), after which hypoglycemic symptoms and counterregulatory hormone responses will be examined during a hyperinsulinemic hypoglycemic glucose clamp study.

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Diabetes Mellitus, Type 1; Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Placebo oral capsule

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500HB
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 1 diabetes, disease duration >1 year
• Age >18 years, <75 years
• BMI 19-40 kg/m^2
• Insulin treatment according to basal-bolus insulin regimen (injections or insulin pump)
• Impaired awareness of hypoglycemia as assessed by a score of 3 or more on the modified Dutch translation of the Clarke questionnaire
• Glycated haemoglobin (HbA1c) ≥42 mmol/mol (6%) and ≤75 mmol/mol (9.0%)
• Ability to provide informed consent

Exclusion Criteria:

• Treatment with SGLT-2 inhibitors
• Known intolerance to SGLT-2 inhibitors
• Treatment with loop diuretics or other anti-hypertensive agents
• Treatment with glucose-modifying (other than insulin) or immune-modifying agents (e.g. prednisolon)
• Treatment with pioglitazone
• Use of statins
• A history of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure) or hypotension
• A history of galactose-intolerance, lactase deficiency, glucose-galactose malabsorption
• History of diabetic ketoacidosis requiring medical intervention within 1 month before screening
• Admission to the hospital for hyperglycemia or hypoglycemia within 1 month before screening
• Frequent episodes of severe hypoglycemia within 1 month before screening
• Laser coagulation for proliferative retinopathy (past 6 months)
• Proliferative retinopathy
• Diabetic nephropathy as reflected by an albumin-creatinin ratio ˃ 30 mmol/mg or an estimated glomerular filtration rate (by MDRD) ˂60ml/min/1.73m2
• History of pancreatitis (acute or chronic) or pancreatic cancer
• Use of premixed insulin or of long-acting insulin alone
• Total daily insulin dose requirements <20 units unless on pump treatment
• Pregnancy or unwillingness to undertake measures for birth control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin; Dapagliflozin 10 mg capsule once daily for 8 weeks	Drug: Dapagliflozin; 8 weeks treatment with dapagliflozin on top of insulin treatment; Other Names: Forxiga
Placebo Comparator: Placebo oral capsule; Placebo matched to dapagliflozin 10 mg capsule once daily for 8 weeks	Drug: Placebo oral capsule; 8 weeks treatment with placebo capsules on top of insulin treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom score in response to insulin-induced hypoglycaemia	Symptom scores (autonomic, neuroglycopenic and general) measured during hyperinsulinemic hypoglycaemic glucose clamps. This questionnaire consists of 18 symptoms, which can be scored between 0 (none) to 6 (severe). Total scores range between 0 and 108, the higher the score, the more symptoms patients have during and after hypoglycemia.	45 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Counterregulatory hormone responses to insulin-induced hypoglycaemia	(nor)adrenaline, glucagon, insulin, growth hormone and cortisol responses to hypoglycaemia measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Time until glycaemic recovery from hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Maximal glucose excursion post-hypoglycaemia	Maximal glucose level (mmol/l) measured during the 90 minutes after ending the hypoglycaemic phase of the clamp (during restoration of euglycaemia)	45 minutes
Time until glucose peak post-hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Area under the glucose concentration curve post-hypoglycaemia	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes
Number of severe hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Number of nocturnal hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Number of any hypoglycaemic events during follow-up	measured during follow-up	16 weeks
Time spent under hypoglycaemic conditions measured by glucose sensor monitoring	measured during follow-up	2 weeks
Glucose variability as measured by glucose sensor monitoring	measured during follow-up	2 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory/atherogenic phenotype of circulating monocytes from the participating patients	measured during hyperinsulinemic hypoglycaemic glucose clamps	45 minutes

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2018
• Primary Completion (Actual): December 20, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: May 17, 2018
• First Submitted That Met QC Criteria: June 1, 2018
• First Posted (Actual): June 14, 2018

Study Record Updates

• Last Update Posted (Actual): March 23, 2020
• Last Update Submitted That Met QC Criteria: March 20, 2020
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: T1DM_IAH_dapa

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No