Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet

Study Overview
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Brief Summary
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Background: Metformin is the first drug of choice in obese patients with type-2 diabetes (T2DM) due to its antiglycaemic as well as its cardiovascular protective potentials. In non-obese T2DM patients insulin-secretagogues are empirically used as first choice. The aim of this study was to evaluate the effect of metformin versus an insulin-secretagogue, repaglinide on glycaemic regulation and non-glycaemic cardiovascular risk markers in non-obese patients with T2DM. Methods: Single-center, randomised, double-masked, double-dummy, cross-over-study of 96 non-obese (BMI ≤ 27 kg/m2) Caucasian T2DM-patients. After a one month run-in on diet-only treatment, patients were randomised to either repaglinide 2mg three times a day (t.i.d). followed by metformin 1g twice a day (b.i.d.) or vice versa each for a period of four months with a one month wash-out between interventions.

Official Title
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Effect of Metformin Versus Repaglinide Treatment on Glycemic Control and Non-Glycaemic Cardiovascular Risk Factors in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Metformin
* Drug: Repaglinide
* Drug: Placebo-Metformin.
* Drug: Placebo-Repaglinide.
* Other: Diet-only.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type-2 diabetes, defined as: Age at onset of diabetes ≥ 40 years Fasting serum C-peptide ≥ 300 pmol/l or a non-fasting or glucagon-stimulated serum C-peptide ≥ 600 pmol/l No history of ketonuria or ketoacidosis. BMI ≤ 27 kg/m2. Fasting plasma-glucose ≥ 6.5 mmol/l after at least one month of diet-only treatment. HbA1c ≤ 9.5% at ongoing oral anti-hyperglycaemic agents. HbA1c ≥ 6.5% after minimum one month of diet-only treatment. Weight-loss of no more than 5.0 kg during the last 6 months prior to enrolment. Exclusion Criteria: Type-1 diabetes Insulin-treated type-2 diabetes Secondary diabetes, heart-failure Serum-creatinine above the upper limit Serum-ASAT elevated more than 3 fold above the upper limit Factor II-VII-X decreased below 0.7 Ongoing coexisting illnesses with a life-shortening prognosis Mental retardation or reduced intellectual behaviour Pregnancy History of drug-abuse or HbA1c>10.5% at two separate visits with at least one month interval during treatment-periods.

Ages Eligible for Study
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Minimum Age: 40 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 4<br>Metformin plus placebo-Repgalinide. Double-masked, randomized. Duration: Four months. | Drug: Metformin<br>* Tablet Metformin 500 mg; Dosage: 1000 mg two times daily. Duration: Four months.<br>Drug: Placebo-Repaglinide.<br>* Tablet Placebo (corresponding to 1 mg Repaglinide). Dosage: 2 tablets three times daily. Duration: Four months.<br>|
| Active Comparator: 2<br>Repaglinide plus Placebo-Metformin. Double-masked, randomized. Duration: Four months. | Drug: Repaglinide<br>* Tablet Repaglinide 1 mg; Dosage: 2 mg three times daily. Duration: Four months.<br>Drug: Placebo-Metformin.<br>* Tablet Placebo (corresponding to 500 mg Metformin). Dosage: 2 tablets two times daily. Duration: Four months.<br>|
| Other: 1<br>Run-in period: Treatment: Diet-only. Duration: One month. | Other: Diet-only.<br>* Diet-only treatment. Duration: One month.<br>|
| Other: 3<br>Wash-out period: Treatment: Diet-only: Duration: One month. | Other: Diet-only.<br>* Diet-only treatment. Duration: One month.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HaemoglobinA1c |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Home-monitored 7-point plasma-glucose profiles |  |  | 
| Body-weight |  |  | 
| Waist- and hip-circumference |  |  | 
| Fasting and postprandial (after a standard test-meal) measures of plasma-glucose, insulin, c-peptide, free fatty acids, lipoproteins, triglycerides and other markers related to lipid-metabolism (e.g. apo-lipoproteins, lipoprotein particle size etc.). |  |  | 
| Biomarkers related to inflammation, endothelial dysfunction and fibrinolysis (e.g. hs-CRP, TNF-alpha, IL-6, ICAM, VCAM, E-selectin, vWF, PAI-1 and t-PA, adiponectin, ADMA, AGE-peptides). |  |  | 
| Albuminuria and 24-hour blood-pressure measurements. |  |  | 
| Platelet aggregation, markers of platelet activity and fibrinolytic markers fasting as well as before and after physical activity. |  |  | 
| DNA for genotyping. |  |  | 
| Adverse events and safety variables (e.g. hypoglycaemia, haemoglobin, white blood cell count, cobalamine and folate). |  |  |