Risk of Nocturnal Hypoglycemia and Arrhythmias With Sitagliptin Versus Glimepiride in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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This exploratory double blind randomized active controlled study is designed to assess the effects of a treatment with therapeutical dosage of sitagliptin versus therapeutical dosage of glimepiride as add on therapy in patients with diabetes mellitus type 2 (T2DM) patients inadequately controlled on metformin monotherapy.

Detailed Description
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Type 2 Diabetes is associated with an increased cardiovascular morbidity and mortality. Among patients insufficiently controlled with metformin multimorbidity and polypharmacy is common that makes the patients frail for cardiovascular complications related to hypoglycemic events. This exploratory double blind randomized active controlled study is designed to assess the effects of a treatment with therapeutical dosage of sitagliptin versus therapeutical dosage of glimepiride as add on therapy in patients with T2DM patients inadequately controlled on metformin monotherapy. Examinations will be performed as a 5 day recording of subcutaneous glucose concentration (CGMS) and holder ECG (AMEDTEC) at baseline and after a 12 weeks treatment with sitagliptin or glimepiride as active comparators used in combination with metformin. With recording of nocturnal hypoglycemia and arrhythmias it is aimed to evaluate favorable glycemic profile under treatment with sitagliptin compared to glimepiride. The primary objective is risk of serious HE for both drugs. The glycemic profile of sitagliptin as add-on therapy to metformin seems to be favorable compared to sulfonylureass such as glimepiride. Treatment with sitagliptin as add-on to metformin therapy causes less glycemic fluctuations and may be associated with lower oxidative stress and down regulation of low grade inflammation. This hypothesis will be tested as an explorative double blind study.

Official Title
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Randomized Double Blind Parallel Design Study Comparing Risk of Nocturnal Hypoglycemia and Critical Arrhythmia With Sitagliptin Versus Glimepiride in Patients With Type 2 Diabetes Insufficiently Controlled With Metformin Monotherapy

Conditions
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Diabetes Mellitus Type 2

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: type 2 diabetes age 40-80 years stable dose of ≥ 1500 mg metformin or maximal tolerated dose of metformin for > 6 weeks HbA1c ≥ 7 % - ≤ 9.0% for age < 65 years and ≥ 7.5 % - ≤ 9.0% for age ≥ 65 years able and trained to perform SMBG the informed consent form must be signed before any study specific tests or procedures are done ability to understand and follow study-related instructions Exclusion Criteria: Type 1 diabetes previous treatment with insulin, GLP1 analogues and SU in < 6 month HbA1c > 9 % or FPG > 15 mmol/l at randomization renal impairment with eGFR < 60 ml/min medical history of severe hypoglycemia defined as necessity of medical assistance in < 1 year major cardiovascular event (MACE) in medical history < 6 months preexisting atrial fibrillation, , AV block ≥II degree, pace-maker, implanted defibrillator major cardiovascular event in medical history < 6 months heart failure NYHA ≥ III contraindications to glimepiride and sitagliptin or to any excipients according to product information severe cognitive deficits Patients who are disable to read and understand informative aspects of the trial Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) Inability to comply with study procedures Pregnant or breast-feeding woman and woman without adequate method of contraception

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients receiving Sitagliptin 100 mg+ Glimepiride-placebo (adapted dosage) | Drug: Sitagliptin<br>* Sitagliptin will be given in a daily dosage of 100 mg<br>Drug: Glimepiride-Placebo<br>* Glimepiride-Placebo will be given additional to Sitagliptin (blinded). It will be given in a starting daily dosage of 1 mg which will be adapted up to 6 mg<br>|
| Active Comparator: Arm B<br>Glimepiride (adapted dosage) + Sitagliptin 100 mg Placebo | Drug: Glimepiride<br>* Glimepiride will be given in a starting daily dosage of 1 mg which will be adapted up to 6 mg<br>Drug: Sitagliptin-Placebo<br>* Sitagliptin-Placebo will be given additional to Glimepiride (blinded). It will be given in a daily dosage of 100 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Hypoglycemic Episodes (HE) Under Treatment With Sitagliptin Compared to Glimepiride | measurement of hypoglycemic episodes including event duration at baseline and EOT after 12 weeks of treatment and measurement of time spent below critical values for hypoglycemic episodes are the primary objectives of this study. We will calculate overall episodes/time (5 days) and nocturnal episodes. | 12 weeks (at baseline and at EOT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence and Number of Nocturnal Ventricular Arrhythmias | measurement of nocturnal ventricular arrhythmias at baseline and EOT (after 12 weeks of treatment) - per patient, couplets per patient, triplets per patient) | 12 weeks (at baseline and at EOT) | 
| Glycemic Variability (Profile) of Sitagliptin Compared to Glimepiride | The glycemic profile is defined as the area under the glucose-timeprofile obtained by continuous glucose monitoring (5 days baseline and 5 days after 12 weeks of each treatment) | 12 weeks (at baseline and at EOT) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes mellitus type 2, nocturnal hypoglycemia, metformin monotherapy