Metformin Challenges in Advanced Chronic Kidney Disease: A Promising Therapeutic Strategy

Background: Metformin is the first-line treatment in type 2 diabetes mellitus because the beneficial effects respect to other antidiabetic drugs on hypoglycemia, obesity, dyslipidemia and cardiovascular morbidity and mortality and even on renal cancer incidence. However, the accumulation of metformin in cases of impaired renal function may lead to a type B lactic acidosis, which has led to its contraindication in patients with chronic kidney disease (CKD), initially to glomerular filtration less than 60 ml/min and subsequently less than 30 ml/min. The dosedependent toxicity, the low rate of onset of metforminassociated lactic acidosis (MALA) and lack of knowledge of pharmacokinetics in CKD, have motivated the development of studies which could support metformin use in advanced stages of CKD.

Methods: We did a literature review compiling recent, more relevant and impact articles, to conclude about the current situation of metformin safety in advanced stages of CKD as well as try to offer a concise future perspective. The analysis has been structured about pharmacokinetics and pharmacodynamics studies, mortality, rate of metabolic acidosis and potential benefits.

Findings: Several studies have demonstrated to provide accurate pharmacokinetics and pharmacodynamics of metformin in advanced CKD stages allowing us to predict a possible behavior. It has been necessary to perform plasma levels and adjustments due to high variability concentrations in hemodiafiltration. MALA has a high mortality rate but incidence rate remains very low, clearly dose dependent among other modifiable factors.

Conclusions: We believe in the need to reconsider the current contraindications of metformin in CKD, especially in stage 4. A single dose of 500 mg per day with some recommendations it seems appropriate. Clinical trials are urgently needed having a possible impact on diabetic nephropathy progression. More data are necessary to validate its use on stage 5 of CKD, which gain in complexity and seems prohibitive.

Author(s): M. Fidalgo Díaz*, R. Alonso Valente, V. Becerra Mosquera, I. Abuward, S. Puello Martínez, N. Ardha, M. Durán Beloso, D. Novoa García, T. Cordal Martínez, D. Güimil Carbajal, C. Díaz Rodríguez

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