Prevalence of metformin use and the associated risk of metabolic acidosis in US diabetic adults with CKD: A national cross-sectional study

The use of metformin in chronic kidney disease (CKD) population has been intensely debated with conflicting evidence. Large population studies are needed to inform risk assessment and therapeutic decision-making. We evaluated the associations among metformin, metabolic acidosis, and CKD in a 10-year nationally representative noninstitutionalized civilian population in the United States. In this cross-sectional study, a total of 2279 diabetic adults aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2012 were included and had measurements of serum bicarbonate, sodium, potassium, and chloride. The exposure was metformin use. The outcome was subclinical and severe metabolic acidosis defined by serum bicarbonate <23 mEq/L and anion gap > 16mEq/L and by serum bicarbonate < 20 mEq/L, respectively. The prevalence of metformin use decreased from 67.2% among CKD-1 and-2, 40.6% among CKD-3, to 1.3% among advanced CKD-4 and-5. Across CKD stages up to CKD-3b, we observed a tendency of lower levels of serum bicarbonate that was significant in metformin users with CKD-2 and CKD-3a and marginally significant with CKD-3b compared to nonmetformin users. The corresponding tendency of higher anion gap in metformin users with the estimated glomerular filtration rate >60 mL/min/1.73m² was also observed. In multiple linear regression analysis, metformin was significantly associated with decreased serum bicarbonate levels (β1/4-0.45, 95% CI:-0.73,-0.17) and increased serum anion gap levels (β1/40.40, 95% CI: 0.19, 0.61). The adjusted odds ratio of subclinical high anion gap and severe metabolic acidosis for metformin users was 1.68 (95% CI: 1.11, 2.55) and 1.31 (0.49, 3.47), respectively. The association between metformin and serum bicarbonate was significantly modified by CKD status. No interaction was found between metformin and CKD stages for serum anion gap and acidosis. Metformin is associated with subclinical metabolic acidosis but not with severe metabolic acidosis. The propensity of serum bicarbonatelowering effect was intensified in advanced CKD; however, such tendency was not associated with the risk of clinically defined acidosis. Our findings highlight a potential of cautious expansion of metformin use among CKD-3b patients with diabetes meriting further investigations.