Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function

Abstract

IMPORTANCE Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kidney disease. OBJECTIVE To quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate (eGFR), accounting for change in eGFR stage over time. DESIGN, SETTING, AND PARTICIPANTS Community-based cohort of 75 413 patients with diabetes in Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, sourced from 350 private US health systems. EXPOSURES Metformin use. MAIN OUTCOMES AND MEASURES Hospitalization with acidosis (International Classification of Diseases, Ninth Revision, Clinical Modification code of 276.2). RESULTS In the primary cohort (n = 75 413), mean (SD) patient age was 60.4 (15.5) years, and 51% (n = 38 480) of the participants were female. There were 2335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m 2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/min/1.73 m 2 (adjusted HR, 1.09; 95% CI, 0.83-1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m 2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). Results were consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.71; 95% CI, 0.45-1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.86; 95% CI, 0.37-2.01). CONCLUSIONS AND RELEVANCE In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m 2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m 2 .

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

“…The incidence rates of acidosis in people with CKD stage 2 (eGFR 60–89 mL/min/1.73m 2 ), 3A (eGFR 45–59 mL/min/1.73m 2 ), 3B (eGFR 30–44 mL/min/1.73m 2 ), and 4–5 (eGFR ≤ 30 mL/min/1.73m 2 ) were 4, 7, 10, and 24 per 1000 person‐years, respectively. These results were reproducible when new metformin users were compared with new sulfonylurea users, in propensity score‐matched cohort, and in the replication cohort of 82 017 people from a nationwide database . Similarly, a Taiwanese population‐based, observational cohort study demonstrated that metformin use was associated with a 35% higher risk of all‐cause mortality in people with type 2 diabetes and serum creatinine concentrations greater than 530 μmol/L (equivalent to end‐stage kidney disease) .…”

“…The data on the safety of metformin in mild to moderate renal impairment (eGFR 30–60 mL/min/1.73m) have been limited until recently and sometimes conflicting, despite increased laxity in prescribing guidelines. Recent studies provide further evidence that metformin does not appear to increase the risk of lactic acidosis in mild to moderate renal impairment . However, prescribing metformin in people with moderate to severe renal impairment remains a controversial issue and this is reflected in the conflicting advice in the different international prescribing guidelines (Box 1), with some authorities providing more conservative advice.…”

Nephro Update Europe 2018

“…Another study published in July 2018 looked at metformin use in a real-world setting [14]. It had a community-based cohort of 75,000 diabetic patients within the Geisinger Health System in the USA.…”

Evidence of safety of metformin in people with kidney disease

“…1 In 2016, the USA Food and Drug Administration (FDA) changed the recommendations for metformin for diabetes to expand its use in certain patients with reduced kidney function. 2 However, despite this and other changes to metformin labelling, it was thought that many people may be missing out on the possible benefits of treatment with metformin because of persisting concerns over drug accumulation and lactic acidosis.…”

“…1 It included 75,413 people with diabetes registered with a primary healthcare organisation in Pennsylvania USA, with assessment of eGFR from January 2004 until January 2017. The authors also used data on 67,578 new metformin users and 14,439 new sulfonylurea users from 350 private USA health systems, to replicate the results.…”