Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery

Study Overview
=================
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.

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.

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

Conditions
-----------------
Type 1 Diabetes, Hypoglycemia

Intervention / Treatment
-----------------
* Drug: Sitagliptin
* Drug: Placebo


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 1 diabetes, DPP-4 inhibitor, Glucagon