Hospitalization for Lactic Acidosis Among Patients With Reduced Kidney Function Treated With Metformin or Sulfonylureas

Abstract

To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function. RESEARCH DESIGN AND METHODS This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 or serum creatinine ‡1.4 mg/dL [female] or 1.5 mg/dL [male]) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. Lactic acidosis hospitalization was defined as a composite of primary discharge diagnosis or laboratory-confirmed lactic acidosis (lactic acid ‡2.5 mmol/L and either arterial blood pH <7.35 or serum bicarbonate £19 mmol/L within 24 h of admission). We report the cause-specific hazard of lactic acidosis hospitalization between metformin and sulfonylureas from a propensity score-matched weighted cohort and conduct an additional competing risks analysis to account for treatment change and death. RESULTS The weighted cohort included 24,542 metformin users and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m 2). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70]). CONCLUSIONS Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued sulfonylureas. Metformin is considered first-line pharmacologic treatment for type 2 diabetes partly on the basis of the publication of the UK Prospective Diabetes Study (UKPDS) in 1998 (1,2). In addition to reducing glycated hemoglobin (HbA 1c) and microvascular complications, metformin users experience weight loss, enhanced insulin sensitivity,

Metformin Protects against Podocyte Injury in Diabetic Kidney Disease

“…No conclusive evidence for an increase in lactic acidosis due to metformin was observed when analyzing the reported cases of lactic acidosis in the U.S. Food and Drug Administration´s Adverse Event reporting System, restricting the analysis to U.S. cases [ 150 ]. Support for this finding is provided by other studies [ 143 , 151 , 152 ]. Another research found; however that the use of metformin is associated with an increased risk of lactic acidosis in individuals with eGFR < 30 mL/min/1.73 m 2 [ 153 ].…”

KDOQI US Commentary on the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD

“…130,131 Additional more recent large studies showing a lack of risk for lactic acidosis above this eGFR cutoff now support this recommendation. 45,127,130 While the FDA does not explicitly state that dose adjustments are required above an eGFR of 30 mL/min/1.73 m 2 , we agree with the KDIGO guideline, which offers a practice point to halve the dose for an eGFR <45 mL/min/1.73 m 2 . Not mentioned by KDIGO is the FDA recommendation that metformin not be initiated in people with an eGFR <45 mL/min/1.73 m 2 , based upon the notion that these patients are likely to progress to an eGFR <30 mL/min/1.73 m 2 , wherein metformin would be contraindicated.…”

“…44 Another significant barrier is low patient awareness. 45 The net result of poor CKD awareness, limited education, as well as personal, financial, and institutional barriers, is the low understanding of the health risks associated with CKD, poor prioritization of CKD management, and reduced adherence to recommended care. 46,47 The use of "high points" and condensed versions of lengthy practice recommendations tailored for busy clinicians may improve their dissemination, acceptance, and implementation.…”

Management of type 2 diabetes in chronic kidney disease

“…29 An analogous study using data from the Veteran's Health Administration found no difference in lactic acidosis hospitalizations between metformin and sulfonylurea users who developed reduced kidney function. 30 In a cohort study using national-level data from Sweden, metformin demonstrated less risk of a composite endpoint of acidosis, serious infection, and all-cause mortality compared with insulin and other oral antihyperglycemic agents in the subgroup of patients with eGFR of 45-60 mL/min/1.73 m 2 . 31 It is recommended to continue metformin in those with eGFR of ≥45 mL/min/1.73 m 2 , titrate cautiously or halve the dose with eGFR of 30-44 mL/min/1.73 m 2 , and to discontinue with eGFR of <30 mL/min/1.73 m 2 and the dialysis population.…”