Metformin use in diabetics w/ mild to moderate CKD not associated with lactic acidosis

Drug still safe up to eGFRs of 30 to 45 mL/min/1.73 m2

METFORMIN is a popularly used first-line drug in the treatment of diabetes mellitus. Its safety and cardiovascular benefits have been shown in landmark clinical trials. However, because of its potential risk to cause lactic acidosis in patients with impaired renal function, its use has been limited or considered contraindicated in diabetic patients in whom renal function is already suspect, as suggested by a borderline or slightly increased serum creatinine level.

Most drug regulatory authorities restrict the use of metformin in patients with essentially any level of chronic kidney disease (CKD) because of the fear that its renal clearance is already compromised in CKD which may cause lactic acidosis. But experts note that these restrictions, released since metformin’s introduction 20 years ago, were mainly based on pharmacokinetic studies which subsequent clinical and postmarketing data did not validate or support.

Inzucchi SE et al. conducted a systematic review of metformin in patients with type 2 diabetes and kidney disease, which was published in the December 2014 issue of JAMA.

The systematic review covered 65 studies, mostly case series and observational postmarketing surveillance studies, that addressed risk for lactic acidosis in patients with type 2 diabetes; and the researchers reported the following:

• 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.
• Moderate 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).

Commenting on the study in Journal Watch, Thomas Schwenk, MD, noted that in Canada and the United Kingdom, metformin use is allowed by their regulatory authorities in patients with mildly impaired renal function, with specific dosage and monitoring guidelines.

Based on this systematic review, the authors recommend still considering metformin use up to dosages of =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 should be discontinued with any further deterioration in renal function. It is to be emphasized though that their recommended dosage limits have not been evaluated in clinical trials. Dr. Reuben Ricallo w/JAMA and Journal Watch reports

Vital Signs Issue 71 Vol. 4, January 1-31 2015