Extending Metformin Use in Diabetic Kidney Disease: A Pharmacokinetic Study in Stage 4 Diabetic Nephropathy

Abstract

IntroductionMetformin use in advanced chronic kidney disease is controversial. This study sought to examine the pharmacokinetics, safety, and efficacy of low-dose metformin in patients with type 2 diabetes and stage 4 chronic kidney disease.MethodsIn this open-label, phase I trial, 3 consecutive cohorts (1, 2, and 3) of 6 patients each were recruited to receive 250-, 500-, or 1000-mg once-daily doses of metformin, respectively. All patients underwent a first-dose pharmacokinetic profile and weekly trough metformin concentrations for the duration of 4 weeks of daily therapy. Prespecified clinical and biochemical safety endpoints of serum bicarbonate, venous pH, and serum lactate were assessed weekly. Efficacy was assessed by pre- and post-HbA1c and 72-hour capillary glucose monitoring.ResultsThere was no evidence of accumulation of metformin in any cohort. There were no episodes of hyperlactatemia or metabolic acidosis and no significant change in any biochemical safety measures. Median (interquartile range) observed trough concentrations of metformin in cohorts 1, 2, and 3 were 0.083 (0.121) mg/l, 0.239 (0.603) mg/l, and 1.930 (3.110) mg/l, respectively. Average capillary glucose concentrations and mean HbA1c decreased in all cohorts.DiscussionIn our patient cohorts with diabetes and stage 4 chronic kidney disease, treatment with 4 weeks of low-dose metformin was not associated with adverse safety outcomes and revealed stable pharmacokinetics. Our study supports the liberalization of metformin use in this population and supports the use of metformin assays for more individualized dosing.

Pharmacokinetics of metformin in patients with chronic kidney disease stage 4 and metformin‐naïve type 2 diabetes

“…All post–baseline measurements were above the minimum quantifiable amount. Maximum observed concentrations, AUC 0‐∞ , and time to maxima are reported elsewhere …”

“…Note that the C max and t max values reported in Dissanayake et al (Table ) are empirical medians, whereas the values in Table in this article are estimates (with confidence intervals) from the compartment model.…”

“…Mean concentrations estimated from the fixed effects component are shown in Dissanayake et al (Figure 3A) along with observed concentrations. A clear dose‐proportional response is evident in the fitted concentrations and the dose‐specific parameter estimates C max and AUC 0‐∞ .…”

“…Eighteen patients completed the study. Baseline values for demographic and clinical variables are summarized in Dissanayake et al Briefly, these were as follows for the entire study cohort expressed as median followed by interquartile range (IQR) in parentheses: age 66.0 (6.54) years; body mass index 38.0 (9.87) kg/m 2 ; duration of diabetes 15.0 (7.75) years; eGFR 21.0 (8.0) mL/min/1.73 m 2 ; HbA1c 67.5 (25.75) mmol/mol (8.3% IQR: 4.5%); venous pH 7.3 (0.05); serum lactate 1.05 (0.58) mmol/L; and CrCl 30.2 (8.6) mL/min. Two patients in the 250 mg group and 2 in the 1000 mg group were females the remainder were males.…”

“…The primary safety outcome of the trial was the development of acidosis assessed via fasting levels of venous lactate, bicarbonate, and pH. This was reported on in Dissanayake et al . In this study we assess additional outcomes, namely, single‐ and repeat‐dose fasting serum metformin concentrations.…”