Restricting Metformin in CKD: Continued Caution Warranted

To the Editor

Given the low observed incidence of metformin-associated lactic acidosis (MALA) in a systematic review of diabetic patients with and without CKD,¹ a commentary by Stanton² recommends liberalizing metformin use in CKD, namely, continuation at a reduced dose over an eGFR range of 30-60 mL/min/1.73 m². The FDA black box warning and NKF-KDOQI recommendations advise against metformin with Scr levels ≥ 1.4 mg/dL and ≥ 1.5 mg/dL in men and women, respectively (Table 1).^3,4 We are concerned about relaxing restrictions for 3 primary reasons.

Table 1. Clinical Practice Guidelines Regarding Metformin Use and Kidney Function.

Clinical Practice Guideline (Year)	Recommendations
US Food and Drug Administration (1994)	Metformin use contraindicated at Scr ≥ 1.4 mg/dL in men and ≥1.5 mg/dL in women
NKF-KDOQI (2012)	Metformin use contraindicated at Scr ≥ 1.4 mg/dL in men and ≥1.5 mg/dL in women
American Diabetes Association and European Association for Study of Diabetes (2012)	Metformin dose reduction if eGFR < 45 mL/min/1.73 m2 Metformin use contraindicated if eGFR < 30 mL/min/1.73 m2
KDIGO (2012)	Metformin use reviewed if eGFR of 30-44 mL/min/1.73 m2 Metformin use contraindicated if eGFR < 30 mL/min/1.73 m2 Metformin temporarily discontinued if eGFR < 60 mL/min/1.73 m2 with a concurrent serious illness increasing the risk for AKI
National Institute for Health and Clinical Excellence (2009)	Metformin use reviewed if Scr > 1.5 mg/dL or eGFR < 45 mL/min/1.73 m2 Metformin use contraindicated if Scr > 1.7 mg/dL or eGFR < 30 mL/min/1.73 m2
Canadian Diabetes Association (2013)	Metformin use cautioned if eGFR < 60 mL/min/1.73 m2 Metformin use contraindicated if eGFR < 30 mL/min/1.73 m2
Royal Australian College of General Practitioners (2014-2015)	Metformin use cautioned and dose reduction advised if eGFR 30-45 mL/min/1.73 m2 Metformin use contraindicated if eGFR < 30 mL/min/1.73 m2
Japanese Society of Nephrology (2012)	Metformin use re-evaluated if eGFR < 45 mL/min/1.73 m2 Metformin use contraindicated if eGFR < 30 mL/min/1.73 m2

Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; NKF-KDOQI, National Kidney Foundation–Kidney Disease Outcomes Quality Initiative; Scr, serum creatinine.

First, MALA fatality is high (45%-48%).^5,6 The multitude of alternative diabetic pharmacotherapies calls into question whether a small risk for death justifies any benefit of metformin.^7,8

Second, MALA incidence may be underestimated. Randomized trials of metformin are not generalizable to real-life scenarios given their strict inclusion/exclusion criteria and monitoring. While large observational studies may better reflect real-life practices, MALA event capture may be poor.

Third, patients with CKD are susceptible to AKI.⁹ The metformin package insert advises against use in conditions leading to AKI, including “cardiovascular collapse (shock), acute myocardial infarction, and septicemia.” Such complications are common in CKD, substantially increasing MALA risk.⁹

No trials have evaluated the safety and effectiveness of metformin specifically in CKD. New data show that metformin users had higher mortality compared with nonusers among patients with Scr > 6 mg/dL in Taiwan, where until recently there were no metformin restrictions in CKD.¹⁰ While studies are needed to granularly determine the eGFR threshold above which metformin is safe, we recommend a conservative approach: metformin use should be reviewed with eGFRs of 45 to 60 mL/min/1.73 m² and discontinued with eGFRs < 45 mL/min/1.73 m², and treatment should be interrupted with any illness heightening AKI risk regardless of eGFR.