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NCT Number: NCT01272583

Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery

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.

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Key information

Conditions

Type 1 Diabetes Autoimmune Diseases Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucose Metabolism Disorders Hypoglycemia Immune System Diseases Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–55 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Academic Medical Center

Amsterdam, North Holland, 1100DD, Netherlands

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sitagliptin

Drug

100 mg once daily for six weeks

Other names: Januvia

Placebo

Drug

placebo, once daily for six weeks

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

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

Other

Collaborators

  • Merck Sharp & Dohme LLC

Registry information

Official study 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

Acronym: DARE

Important dates

Study start
2011
Primary completion
2012
Study completion
2012
First posted
Jan 10, 2011
Registry last updated
Mar 14, 2014

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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