ADA: Diabetes Journals: Published June 2023

Diabetes mellitus (DM) is one of the most important causes of CKD. Moreover, both DM and CKD are important risk factors for cardiovascular disease (CVD). 

Metformin is still the first-line drug for DM management. The concern, of course, is an increased risk of metformin-associated lactic acidosis (MALA) at low eGFR.

Traditionally, metformin use has not been recommended for patients with CKD because of the risk of lactic acidosis. However, several clinical trials and observational studies have reported that the risk of fatal and nonfatal lactic acidosis did not increase with metformin use, even in patients with advanced CKD

Metformin can be used in patients with chronic kidney disease (CKD) up to estimated glomerular filtration rate [eGFR] ≥30 ml/min/1.73m². However, surveys suggested its continuing use in some patients with eGFR<30 ml/min/1.73m² in real world practice although the risk-benefit ratios remain uncertain.

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The aim of the study is to estimate the hazard ratio (HR) of death, major-adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD) in continued versus discontinued-metformin users.

Of 36,940 metformin users with new-onset eGFR<30 ml/min/1.73m², 8400 discontinued metformin within 6 months whereas 28,540 continued with metformin.

The median metformin daily dose was 1000 mg in continued-metformin users. During a median follow-up of 3.5 years, 15.3%, 16.6%, and 28.1% had incident MACE, heart failure, and ESKD respectively, and 41.5% died.

Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (95%), heart failure, ESKD, and death. Results were consistent in patients with and without established cardiovascular diseases (CVD).

Conclusions:

Discontinuation of metformin was associated with an increased risk of cardiovascular-renal events, regardless CVD status. Continuation of metformin below eGFR 30ml/min/1.73m² may be associated with cardio-renal and mortality benefits that needs to be weighed against the risks of lactic acidosis.

The data suggest that in a clinic setting, metformin can be continued with dose adjustment in patients with advanced chronic kidney disease to sustain glycemic control and for organ protection.

Continuation of metformin below an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73m² may be associated with cardio-renal and mortality benefits, regardless of cardiovascular disease status, according to the study.