Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery

Not Applicable

Completed

Conditions: Type 1 Diabetes
Hypoglycemia

Interventions: Drug: Sitagliptin
Drug: Placebo

Registration Number: NCT01272583

Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 16

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence A (sitagliptin→placebo)	Placebo	Cross-over, both arms reveived the same intervention in different order.
Sequence B (placebo→sitagliptin)	Placebo	Cross-over, both arms reveived the same intervention in different order.
Sequence A (sitagliptin→placebo)	Sitagliptin	Cross-over, both arms reveived the same intervention in different order.
Sequence B (placebo→sitagliptin)	Sitagliptin	Cross-over, both arms reveived the same intervention in different order.

Primary Outcome Measures

Name	Time	Method
Glucagon Response to Acute Hypoglycaemia	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

Name	Time	Method
Epinephrine Response to Acute Hypoglycaemia	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.
Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia	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.
Cortisol Response to Acute Hypoglycaemia	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.
Norepinephrine Response to Acute Hypoglycaemia	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.
Growth Hormone Response to Acute Hypoglycaemia	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.
Symptomatic Hormone Responses to Acute Hypoglycaemia.	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.