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

• ClinicalTrials.gov Identifier: NCT01272583
• Recruitment Status: Completed
• First Posted: January 10, 2011
• Results First Posted: February 17, 2014
• Last Update Posted: March 14, 2014
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): F Holleman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes; Hypoglycemia	Drug: Sitagliptin; Drug: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Official Title: 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
• Study Start Date: March 2011
• Actual Primary Completion Date: June 2012
• Actual Study Completion Date: October 2012

Arms and Interventions

Arm	Intervention/treatment
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 Name: Januvia; Drug: Placebo; placebo, once daily for six weeks
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 Name: Januvia; Drug: Placebo; placebo, once daily for six weeks

Outcome Measures

Primary Outcome Measures :

1. Glucagon Response to Acute Hypoglycaemia [ Time Frame: Change from initialisation phase to 40 minutes after onset of hypoglycaemia ]
   Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia
2. Glucagon Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20 and 40 minutes ]
   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.

Secondary Outcome Measures :

1. Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ]
   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.
2. Epinephrine Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ]
   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.
3. Norepinephrine Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ]
   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.
4. Growth Hormone Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ]
   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.
5. Cortisol Response to Acute Hypoglycaemia [ Time Frame: 0, 10, 20, 40 minutes ]
   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.
6. Symptomatic Hormone Responses to Acute Hypoglycaemia. [ Time Frame: Change from baseline symptomatic response at hypoglycaemia and 30 minutes after 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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Netherlands

Academic Medical Center

Amsterdam, Noord Holland, Netherlands, 1100DD

Sponsors and Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Frits Holleman, MD,PhD; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

More Information

• Responsible Party: F Holleman, PhD, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• ClinicalTrials.gov Identifier: NCT01272583
• Other Study ID Numbers: DARE_2010
• First Posted: January 10, 2011
• Results First Posted: February 17, 2014
• Last Update Posted: March 14, 2014
• Last Verified: February 2014

Keywords provided by F Holleman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Type 1 diabetes; DPP-4 inhibitor; Glucagon

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Hypoglycemia; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Sitagliptin Phosphate; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action