Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery (DARE)

Effects of 6 Weeks Treatment With a Dipeptidyl Peptidase 4 Inhibitor on Counterregulatory and Incretin Hormones During Acute Hypoglycaemia in Patients With Type 1 Diabetes: a Randomized Double Blind Placebo-controlled Cross-over Study

Hypoglycaemia is a well-known complication of insulin treated diabetes. The counterregulatory response to hypoglycaemia, with glucagon as the most important mediator, is initially diminished within a few years of onset of Type 1 diabetes and subsequently lost and thus increasing the risk of hypoglycaemia. Dipeptidyl Peptidase (DPP)-4 inhibitors augment the glucagon response to insulin-induced hypoglycaemia in type 2 diabetes. The investigators hypothesize that treatment with a DPP-4 inhibitor in patients with type 1 diabetes will recover the alpha cell response to hypoglycaemia.

Study Overview

• Status: Completed
• Conditions: Hypoglycemia; Type 1 Diabetes
• Intervention / Treatment: Drug: Sitagliptin; Drug: Placebo

Detailed Description

The 16 type 1 patients will be randomised to one of two treatment sequences: DPP-4 inhibitor followed by placebo or placebo followed by a DPP-4 inhibitor. Each treatment period lasts 6 weeks, so all patients will receive treatment for 12 weeks in total. Induction of hypoglycaemia will take place at 0 weeks, 6 weeks and 12 weeks to determine the glucagon response.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1100DD
      • Academic Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Type 1 Diabetes Mellitus 5-20 years duration
• C-peptide negative
• Willing and able to give written informed consent

Exclusion Criteria:

• Impaired awareness of hypoglycaemia
• BMI > 27 kg/m2
• Evidence of severe diabetes complications (autonomic neuropathy, macroalbuminuria, proliferative retinopathy)
• Acute illness within 3 months before the study
• Significant renal impairment (creatinine clearance < 50ml/min)
• Use of beta-adrenoreceptor blockers
• Cardiac history (previous arrhythmia)
• History of epilepsy

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Sequence A (sitagliptin→placebo); Cross-over, both arms reveived the same intervention in different order.	Drug: Sitagliptin; 100 mg once daily for six weeks; Other Names: Januvia; Drug: Placebo; placebo, once daily for six weeks
Other: Sequence B (placebo→sitagliptin); Cross-over, both arms reveived the same intervention in different order.	Drug: Sitagliptin; 100 mg once daily for six weeks; Other Names: Januvia; Drug: Placebo; placebo, once daily for six weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucagon Response to Acute Hypoglycaemia	Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia	Change from initialisation phase to 40 minutes after onset of hypoglycaemia
Glucagon Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20 and 40 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20, 40 minutes
Epinephrine Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20, 40 minutes
Norepinephrine Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20, 40 minutes
Growth Hormone Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20, 40 minutes
Cortisol Response to Acute Hypoglycaemia	Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.	0, 10, 20, 40 minutes
Symptomatic Hormone Responses to Acute Hypoglycaemia.	The symptomatic responses to hypoglycaemia were assessed using a standard validated symptom questionnaire adapted for experimental hypoglycaemia (McCrimmon et al (2003) Diabet.Med. 20: 507-509). A 7-point Likert scale (1=symptom absent; 7=symptom experienced with great intensity) was used to score presence and intensity of autonomic and neuroglycopenic symptoms of hypoglycaemia. Symptom scores were obtained during the initialisation phase, at occurrence of autonomic reaction and again 30 minutes later. For analyses the scale was considered as a continuous variable.	Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Frits Holleman, MD,PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: January 5, 2011
• First Submitted That Met QC Criteria: January 7, 2011
• First Posted (Estimate): January 10, 2011

Study Record Updates

• Last Update Posted (Estimate): March 14, 2014
• Last Update Submitted That Met QC Criteria: February 14, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Type 1 diabetes; Glucagon; DPP-4 inhibitor
• 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; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: DARE_2010