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

Phase 4

Terminated

Interventions: Drug: Sitagliptin
Drug: Glimepiride
Drug: Sitagliptin-Placebo
Drug: Glimepiride-Placebo

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Arm A	Sitagliptin	Patients receiving Sitagliptin 100 mg+ Glimepiride-placebo (adapted dosage)
Arm B	Glimepiride	Glimepiride (adapted dosage) + Sitagliptin 100 mg Placebo
Arm B	Sitagliptin-Placebo	Glimepiride (adapted dosage) + Sitagliptin 100 mg Placebo
Arm A	Glimepiride-Placebo	Patients receiving Sitagliptin 100 mg+ Glimepiride-placebo (adapted dosage)

Primary Outcome Measures

Name	Time	Method
Number of Hypoglycemic Episodes (HE) Under Treatment With Sitagliptin Compared to Glimepiride	12 weeks (at baseline and at EOT)	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.

Secondary Outcome Measures

Name	Time	Method
Glycemic Variability (Profile) of Sitagliptin Compared to Glimepiride	12 weeks (at baseline and at EOT)	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)
Occurence and Number of Nocturnal Ventricular Arrhythmias	12 weeks (at baseline and at EOT)	measurement of nocturnal ventricular arrhythmias at baseline and EOT (after 12 weeks of treatment) - per patient, couplets per patient, triplets per patient)