Hypoglycemia, Type 1 Diabetes
Conditions
Keywords
Type 1 diabetes, DPP-4 inhibitor, Glucagon
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.
Interventions
DRUGSitagliptin
100 mg once daily for six weeks
DRUGPlacebo
placebo, once daily for six weeks
Sponsors
Merck Sharp & Dohme LLC
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucagon Response to Acute Hypoglycaemia | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Netherlands
Participant flow
Recruitment details
Participants came to the Academic Medical Center in Amsterdam for a screening visit to determine eligibility for the study.
Pre-assignment details
Patients were excluded if they were found to have impaired awareness of hypoglycaemia, had a history of seizures, cardiac arrhythmia (or used beta-adrenoreceptor blockers) and/or acute infection in the 12 weeks before the study, or evidence of severe diabetes complications (autonomic neuropathy, nephropathy or proliferative retinopathy).
Participants by arm
| Arm | Count |
|---|---|
| Sequence A (Sitagliptin→Placebo) Cross-over, both arms reveived the same intervention in different order.
Sitagliptin : 100 mg once daily for six weeks
Placebo : placebo, once daily for six weeks | 8 |
| Sequence B (Placebo→Sitagliptin) Cross-over, both arms reveived the same intervention in different order.
Sitagliptin : 100 mg once daily for six weeks
Placebo : placebo, once daily for six weeks | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Sequence A (Sitagliptin→Placebo) | Sequence B (Placebo→Sitagliptin) | Total |
|---|---|---|---|
| Age, Continuous | 30.5 years | 33.5 years | 31.5 years |
| Region of Enrollment Netherlands | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Glucagon Response to Acute Hypoglycaemia
Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia
Time frame: Change from initialisation phase to 40 minutes after onset of hypoglycaemia
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Glucagon Response to Acute Hypoglycaemia | 1.33 pmol/L |
| Sitagliptin Treatment | Glucagon Response to Acute Hypoglycaemia | 1.0 pmol/L |
| Placebo | Glucagon Response to Acute Hypoglycaemia | 1.33 pmol/L |
p-value: 1ANOVA
Primary
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.
Time frame: 0, 10, 20 and 40 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Glucagon Response to Acute Hypoglycaemia | 120 pmol*minutes/L |
| Sitagliptin Treatment | Glucagon Response to Acute Hypoglycaemia | 125 pmol*minutes/L |
| Placebo | Glucagon Response to Acute Hypoglycaemia | 120 pmol*minutes/L |
p-value: 0.98ANOVA
Secondary
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.
Time frame: 0, 10, 20, 40 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Cortisol Response to Acute Hypoglycaemia | 14480 mU*minutes/L |
| Sitagliptin Treatment | Cortisol Response to Acute Hypoglycaemia | 13190 mU*minutes/L |
| Placebo | Cortisol Response to Acute Hypoglycaemia | 14800 mU*minutes/L |
p-value: 0.76ANOVA
Secondary
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.
Time frame: 0, 10, 20, 40 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Epinephrine Response to Acute Hypoglycaemia | 36.1 nmol*minutes/L |
| Sitagliptin Treatment | Epinephrine Response to Acute Hypoglycaemia | 32.6 nmol*minutes/L |
| Placebo | Epinephrine Response to Acute Hypoglycaemia | 58.7 nmol*minutes/L |
p-value: 0.14ANOVA
Secondary
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.
Time frame: 0, 10, 20, 40 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Growth Hormone Response to Acute Hypoglycaemia | 1299 mU*minutes/L |
| Sitagliptin Treatment | Growth Hormone Response to Acute Hypoglycaemia | 261.5 mU*minutes/L |
| Placebo | Growth Hormone Response to Acute Hypoglycaemia | 1406 mU*minutes/L |
p-value: 0.01ANOVA
p-value: <0.05Dunn's Multiple Comparison Test
Secondary
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.
Time frame: 0, 10, 20, 40 minutes
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baseline | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 intact | 2.000 pmol*minutes/L |
| Baseline | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 total | 562.2 pmol*minutes/L |
| Baseline | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP intact | 455.0 pmol*minutes/L |
| Baseline | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP total | 302.5 pmol*minutes/L |
| Sitagliptin Treatment | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP total | 285.0 pmol*minutes/L |
| Sitagliptin Treatment | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 intact | 43.50 pmol*minutes/L |
| Sitagliptin Treatment | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP intact | 490.0 pmol*minutes/L |
| Sitagliptin Treatment | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 total | 555.0 pmol*minutes/L |
| Placebo | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP total | 342.5 pmol*minutes/L |
| Placebo | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 total | 552.5 pmol*minutes/L |
| Placebo | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GIP intact | 452.5 pmol*minutes/L |
| Placebo | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | GLP-1 intact | 4.500 pmol*minutes/L |
p-value: <0.001ANOVA
p-value: 0.98ANOVA
p-value: 0.049ANOVA
p-value: 0.44ANOVA
Secondary
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.
Time frame: 0, 10, 20, 40 minutes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline | Norepinephrine Response to Acute Hypoglycaemia | 70.0 nmol*minutes/L |
| Sitagliptin Treatment | Norepinephrine Response to Acute Hypoglycaemia | 62.5 nmol*minutes/L |
| Placebo | Norepinephrine Response to Acute Hypoglycaemia | 62.3 nmol*minutes/L |
p-value: 0.22ANOVA
Secondary
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.
Time frame: Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baseline | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Autonomic symptoms score | 1.7 units on a scale |
| Baseline | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Neurologic symptoms score | 2.1 units on a scale |
| Sitagliptin Treatment | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Autonomic symptoms score | 1.3 units on a scale |
| Sitagliptin Treatment | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Neurologic symptoms score | 2.4 units on a scale |
| Placebo | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Autonomic symptoms score | 1.5 units on a scale |
| Placebo | Symptomatic Hormone Responses to Acute Hypoglycaemia. | Neurologic symptoms score | 2.1 units on a scale |