Metformin in patients with chronic kidney disease: strengths and weaknesses

Abstract

A wide array of benefits has been attributed to metformin. These include attenuation of abnormal glucose metabolism (diabetes treatment and prevention), weight neutrality or weight loss, improvement in the pathophysiologic components of metabolic syndrome (insulin resistance, subclinical inflammation, and endothelial dysfunction), lipid-lowering properties, cardiovascular protection, and antineoplastic potential. Metformin itself is not a nephrotoxic drug. Initially appointed as the safest hypoglycemic agent in chronic kidney disease, its use has been limited in these patients because of the perceived risk of lactic acidosis. A fear perpetuated by numerous case reports in which it is implicated. Current guidelines stipulate that it must be used with caution in estimated glomerular filtration rates (eGFRs) of less than 60 mL/minute and not at all in eGFRs of less than 30 mL/minute. Identified risk factors for metformin-associated lactic acidosis include acute kidney injury, hypoxemia, sepsis, alcohol abuse, liver failure, myocardial infarction, and shock. Treatment may include supportive care and dialysis techniques. On the other hand, it is likely that the use of metformin would be beneficial in many with chronic kidney disease according to the advantages associated with attenuation of metabolic syndrome and cardiovascular protection. The reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment raises the question of limitation of its use in these patients.

Metformin revisited: A critical review of the benefit–risk balance in at-risk patients with type 2 diabetes

“…However, the risk of lactic acidosis should not be neglected [9,89,92] and the drug should be immediately stopped in presence of unstable RI, any acute event (high fever for instance), gastrointestinal disorders (diarrhea, vomiting), dehydration, ..., all conditions that can rapidly deteriorate renal function [9,92]. Last but not least, the use of nephrotoxic agents (nonsteroidal anti-inflammatory drugs, … ) should also be avoided in any patient with renal dysfunction, especially in those of stage 3 CKD on metformin therapy.…”

Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin

“…11,12) Reported predisposing factors include acute kidney injury, history of lactic acidosis, hypovolemia, seizure, liver disease, alcohol abuse, acute heart failure, myocardial infarction, and shock. [13][14][15] Although lactic acidosis during metformin use has better prognosis than other types of severe lactic acidosis, 16) the mortality rate of lactic acidosis is reported to be as high as 25-50%. 3,5,9) A decreased glomerular filtration rate may increase the risk of lactic acidosis during metformin use, because unmetabolized metformin is eliminated by the kidneys.…”

Study of Prevalence of Metformin Associated Lactic Acidosis (MALA) In Patients with Creatinine Clearance More Than 20ml/Min/Per 1.73m2

“…2 [6] .In contrast,the Canadian diabetes association practice guidelines are now based solely on eGFR,recommending caution with eGFR <60ml/min per 1.73m 2 and contraindicating its use with eGFR <30ml/min per1.73 m 2 . The Australian Diabetes Society practice guidelines similarly recommend against metformin with eGFR <30ml/min per 1.73m 2 and caution with eGFR 30-45ml/min per 1.73m 2 [6] .Thus ,although there is clear recognition that renal failure may be a risk factor for adverse events with metformin use there is significant divergence inopinion across the globe regarding the optimal definition of safety.…”

“…The Australian Diabetes Society practice guidelines similarly recommend against metformin with eGFR <30ml/min per 1.73m 2 and caution with eGFR 30-45ml/min per 1.73m 2 [6] .Thus ,although there is clear recognition that renal failure may be a risk factor for adverse events with metformin use there is significant divergence inopinion across the globe regarding the optimal definition of safety. [5] Given the current contraindications,we might consider it a challenge to conduct a new clinical trial to evaluate the use of metformin in individuals with various degrees of impaired renal function,taking into account new criteria for assessing glomerular filtration,attempting to translate creatinine into corresponding eGFR cut points in the context of metformin therapy.…”

“…An evidence based approach to prescribing metformin in this group appears warranted taking into account the current pervasive use of eGFR in clinical care. [6] At present the exact glomerular filtrationrate cutoff threshold for the safe use of metformin is controversial.…”