Metformin and Chronic Renal Disease: Proposal for a “Territorial” Therapeutic Diagnostic Path

Abstract

Although Metformin (MT) is a first-line therapy for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of MALA (metformin-associated lactic acidosis), an exceptionally rare but fatal adverse event. Then, the drug is contraindicated in many individuals with impaired kidney function because of concerns of MALA. MT, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma MT concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupt lactate production or clearance (e.g., acute illness in diabetic patients where cardiac, hepatic, pulmonary, or renal function are compromised), are typically necessary to cause MALA. As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, MT has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic MT levels and MALA. However, the reported incidence of MALA in clinical practice has proved to be very low. Several groups have suggested that current renal function cutoffs for MT are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of MT therapy. In keeping with these data the FDA and the EMA recently revised the warning regarding MT. Considering these new recommendations the authors propose a territorial diagnostic and therapeutic path on the use of MT in the Chronic Kidney Disease.