Metformin: time to review its role and safety in chronic kidney disease

Abstract

Summary ■Metformin is recommended as first‐line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) — a condition that commonly coexists with diabetes — due to concerns over drug accumulation and metformin‐associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all‐cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin‐associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present‐day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–60 mL/min/1.73m2). However, prescribing metformin in people with severe renal impairment (eGFR < 30 mL/min/1.73m2) remains a controversial issue. Due to observed increased risk of lactic acidosis and all‐cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration.

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

“…[14]. This might explain the mixed opinions regarding metformin use in clinical guidelines [8]. Our ndings suggest that a higher dose of metformin is associated with a higher risk of LA, in line with other ndings that have shown an increased risk with high daily exposure to metformin in patients with CKD (adjusted HR: 13.0, 95% CI: 2.36-72.0) [7].…”

“…It is noteworthy that, prior to the aforementioned regulatory authorities' guidelines, observational studies had already shown an increased incidence of LA in patients exposed to metformin in parallel to the degree of impairment of renal function [6], as well as an increased risk of LA in patients with eGFR <60 mL/min, mainly due to the higher risk in patients with eGFR <45 mL/min [7].Prescribing metformin for people with renal impairment continues to be a matter of debate today, especially in patients with severely reduced kidney function. As a consequence, there is still considerable variation between the different international prescribing guidelines for metformin [8]. The aim of this case-control study (ALIMAR-C2 [Riesgo de Acidosis Láctica asociado al uso de MetforminA en pacientes diabéticos tipo 2 con enfermedad Renal crónica moderada-severa: estudio de Casos y Controles]), using electronic health records from hospitals linked to their corresponding primary healthcare regions, was therefore to assess the association between metformin and LA in Spanish patients with DM2 and reduced kidney function.…”

Lactic acidosis associated with metformin in diabetic patients with chronic kidney disease: a multicentre case-control study using electronic health records

“…A channelling bias may be the consequence of the restricted use of metformin with patients at CKD stage 3 or 4, whereas patients with reduced eGFR may have been more likely to receive metformin therapy, if they were healthier [13]. This might explain the mixed opinions regarding metformin use in clinical guidelines [14]. Our ndings suggest that a higher dose of metformin is associated with a higher risk of LA, in line with other ndings that have shown an increased risk with high daily exposure to metformin in patients with CKD (adjusted HR: 13.0, 95% CI: 2.36-72.0) [7].…”

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

“…Metformin itself is perceived as the safest antidiabetic agent in chronic kidney disease. In addition, independent of its hypoglycemic effect, it reduces the risk of myocardial infarction, stroke and mortality in patients with T2DM and chronic kidney disease (CKD) [100]. However, its use has been limited in severe renal impairment patients because of a higher risk of lactic acidosis [100,101].…”