Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4
Jean-Daniel Lalau, Farshad Kajbaf, Youssef Bennis, Anne-Sophie Hurtel-Lemaire, Frans Belpaire, Marc E. De Broe
2018
Diabetes Care
OBJECTIVE This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS Three complementary studies were performed: 1) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations
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... evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA 1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA 1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD. The biguanide drug metformin is not metabolized, does not bind to proteins, and is rapidly eliminated by the kidneys (1). Consequently, most guidelines and reviews discourage the use of metformin in patients with moderate-to-severe chronic kidney disease (CKD) because of the fear of lactic acidosis attributed to metformin accumulation (2). Although metformin is linked to lactate metabolism in several ways, including the inhibition of lactate conversion via gluconeogenesis, the strength of the link between metformin and lactic acidosis has been greatly overstated (3,4). In 2016, the European Medicines Agency (5) and the U.S. Food and Drug Administration (FDA) (6) removed the contraindication on the use of metformin in CKD stages 3A and 3B (glomerular filtration rate [GFR] for CKD stages 1, 2, 3A, 3B, 4, and 5: 120-90,
doi:10.2337/dc17-2231
pmid:29305402
fatcat:mc7huz3yvrgnbmivjornebcruu