The use of metformin in patients with chronic kidney disease (CKD) has been a debatable issue since many years. A major concern associated with metformin therapy is risk of lactic acidosis due to accumulation of this drug in patients with renal impairment. However, growing literature has added new perspectives. Lalau and colleagues conducted 3 complementary studies on the use of metformin in patients with CKD stages 3A, 3B or 4-a dose-finding study, a chronic metformin treatment study and a pharmacokinetic study. They analyzed adjusted dosage regimens based on the level of CKD. Although a link was reported between metformin levels and estimated glomerular filtration rate (GFR), there was no relation between metformin levels and plasma lactate. Besides, as long as the dose of metformin was adjusted to the level of chronic kidney disease, pharmacokinetics remained stable.¹ The study indicates that metformin treatment seems to be safe and pharmacologically effective in patients with moderate-to-severe CKD, when the dose is adjusted for the degree of renal failure.²

Until early 2016, the United States Food and Drug Administration(FDA) guidelines contradicted the use of metformin with a serum creatinine (Cr) >1.5 mg/dL and 1.4 mg/dL in males and females, respectively. As it is well known that serum Cr measurements do not reflect GFRsaccurately, the FDA is finally requiring labelling changes for metformin. It is recommending measuring GFR instead of serum Cr, before initiating metformin therapy. In established patients, it allows the use of metformin up to a GFR of 30 mL/min/1.73 m^2.3 Different organizations around the world have made recommendations on the cautious use of metformin in patients with CKD.¹ The joint position statement of the American Diabetes Association and European Association for the Study of Diabetes agrees that it is reasonable to use metformin down to a GFR of 30 mL/min/1.73 m², with further dose reduction at a GFR of 45 mL/min/1.73 m². However, GFR should be monitored often in such cases, and the drug should be discontinued in cases of worsening clinical condition, dehydration and hypoxemia. Moreover, the European Medicines Agency and the advisory board of European Renal Best Practice have also suggested the use of metformin in patients with a GFR as low as 30 mL/min/1.73 m², with dose alterations based on renal function. In Australia, National Evidence Based Guidelines for blood glucose control in type 2 diabetes mellitus have suggested that metformin, although contraindicated if GFR is <30 mL/min/1.73 m², can be used with caution in those with a GFR of 30–45 mL/min/1.73 m^2.3

Furthermore, in an open cohort study comprising 4,69,688 patients with type 2 diabetes mellitus, association between antidiabetic therapy and various complications was assessed. The results demonstrated that in comparison to non-users, users of metformin had a remarkably lower risk of severe kidney failure, while insulin and sulfonylureas increased the risk. In another systematic review involving 17 observational studies, metformin use appeared to be associated with reduced all-cause mortality in patients with CKD, congestive heart failure, and chronic liver disease.²

Therefore, metformin is likely to exhibiter no protective properties along with its glucose-lowering actions in patients with type 2 diabetes and CKD.^1-3

References

1. MacCallum L, SeniorPA. Safe Use of Metformin in Adults With Type 2 Diabetes and Chronic Kidney Disease: Lower Dosages and Sick-Day Education Are Essential. Can J Diabetes. 2019 Feb;43(1):76-80.
2. Corremans R, Vervaet BA, DHaese PC, et al. Metformin: A Candidate Drug for Renal Diseases. Int J Mol Sci. 2018;20(1):42.
3. Imam TH. Changes in metformin use in chronic kidney disease. Clin Kidney J. 2017;10(3):301-304.