Metformin in Moderate and Severe Renal Failure (CKD 3-4): A Follow-up Study

Study Overview
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Brief Summary
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To validate on the mid-term in moderate and severe renal failure (CKD 3-4) a nomogram to adapt a fixed metformin daily posology according to renal function on the basis of the first short-term study made by the investigators.

Detailed Description
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A first open-label pilot study at different stages of CKD (1-5) (concerning whether or not metformin use is safe provided a dose adjustment is used) has evaluated (i) metformin levels in plasma and in erythrocytes according to an increasing metformin dosage and CKD severity (1-5) and (ii) the prevalence of lactate levels ≥2.5 mmol/L in CKD 3-5. All patients underwent 3 one-week- blocks of metformin treatment at an increasing dosage, each of which followed by a one week-wash- out period: 500 mg/day in the evening (E) in phase 1; 1,000 mg/day (500 mg morning (M) and E) in phase 2; 2,000 mg/day (1,000 mg M and E) in phase 3. Steady-state trough blood levels were assayed 12 hours after the last dose of metformin. In this study a progressive dose-related increase of the trough metformin levels were observed and in particular in severe CKD stages. No case of severe hyperlactatemia was reported in this study. In continue, the investigators thought to conduct a new study to evaluate safety of metformin in mid-term period of time. For this purpose, metformin will be given at a fixed dose during 4 months: 1) 1,500 mg/day (500 mg M and 1,000 mg E) in stage 3a; 2) 1,000 mg/day (500 mg M and E) in stage 3b; and 3) 500 mg/day (M) in stage 4. Metformin levels in plasma and in erythrocytes, venous lactate, and HbA1c levels will be measured at 1, 2, 3 and 4 months for assessment of safety.

Official Title
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Metformin in Moderate and Severe Renal Failure (CKD 3-4): A Follow-up Study

Conditions
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Renal Insufficiency, Chronic

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes patients with stable CKD stages 3A, 3B and 4 aged between 18 and 80 years requiring metformin (and any other antidiabetic treatment) Exclusion Criteria: Hyperlactatemia (> 2.5 mmol/L) No creatinine levels available since 3 months Severe hepatic insufficiency No liver function parameters available Need of investigation with iodized contrast media Hypersensitivity to metformin

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: moderate impairment, CKD stage 3a<br>(12 subjects): GFR 59-45 (moderate impairment, CKD stage 3a) Metformin : 1500mg/day | Drug: Metformin<br> <br> * Other names: Glucophage;|
| Experimental: moderate impairment, CKD stage 3a)<br>(12subjects): GFR 44-30 (moderate impairment, CKD stage 3b) Metformin : 1000mg/day | Drug: Metformin<br> <br> * Other names: Glucophage;|
| Experimental: severe impairment<br>(12 subjects): GFR 29-15 (severe impairment, CKD stage 4) Metformin : 500mg/day | Drug: Metformin<br> <br> * Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monitoring of blood metformin plasma levels with a fixed dose of metformin |  | 4 months | 
| Monitoring of blood metformin erythrocytes levels with a fixed dose of metformin |  | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, moderate renal failure, severe renal failure, chronic kidney disease, hyperlactatemia, lactic acidosis