January 8, 2015
Metformin Use in Diabetic Patients with Mild-to-Moderate Chronic Kidney Disease Is Not Associated with Lactic Acidosis.Thomas L. Schwenk, MD reviewing Inzucchi SE et al. JAMA 2014 Dec 24/31.
Use could be liberalized in these patients with appropriate dosage and monitoring guidelines.
Using metformin in patients with type 2 diabetes is endorsed widely because of metformin's safety and cardiovascular benefits. However, the FDA restricts use of metformin in patients with essentially any level of chronic kidney disease (CKD) because of its renal clearance characteristics and its presumed predilection for causing lactic acidosis. These restrictions, in place since metformin's introduction 20 years ago, arose mostly from pharmacokinetic studies; however, subsequent clinical and postmarketing data and outcomes from unrestricted use outside the U.S. do not support this constraint.
In this systemic review, researchers identified 65 studies, mostly case series and observational postmarketing surveillance studies, that addressed risk for lactic acidosis in patients with type 2 diabetes. The major findings are:
Patients with mild-to-moderate CKD who use metformin have slightly elevated but not clinically worrisome lactic acid levels (unlike the pharmacokinetics associated with another biguanide, phenformin, which was subsequently removed from the market).
Among all patients with type 2 diabetes, observational studies showed no excess risk for lactic acidosis in patients who took metformin.
M
oderate CKD (estimated glomerular filtration rate [eGFR], 30–60 mL/minute/1.73 m2) reduces metformin clearance, but metformin levels remained within the safe range.Some, but not all, population-based observational studies showed modest excess risk for lactic acidosis (roughly 2- to 4-fold) in diabetic patients with moderate CKD, but baseline risk was low (≈10 lactic acidosis cases/100,000 person-years).
Very limited data suggest more substantial excess risk (6- to 7-fold) for diabetic patients with severe CKD (eGFR, <30 mL/minute/1.73 m2).COMMENT
Canada and the U.K. permit metformin use in patients with mildly impaired renal function, with specific dosage and monitoring guidelines. The authors recommend a possible approach to metformin use that includes dosages ≤2000 mg/day in patients with stable renal function and eGFRs of 45 to 60 mL/minute/1.73 m2 and ≤1000 mg/day in patients with eGFRs of 30 to 45 mL/minute/1.73 m2; metformin use should cease with any deterioration in renal function. However, they note that their recommended dosage limits have not been evaluated in clinical trials.
CITATION(S):
Inzucchi SE et al.
Metformin in patients with type 2 diabetes and kidney disease: A systematic review. JAMA 2014 Dec 24/31; 312:2668. (Δεν είναι ορατοί οι σύνδεσμοι (links).
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