Presentation Abstract

Session: Late Breaking Abstracts
Abstract Number: 75-LB
Title: Delayed-Release Metformin may be Suitable for Use in Diabetes Patients with Renal Impairment that are Contraindicated for Currently Available Metformin Formulations
Authors: RALPH A. DEFRONZO, JOHN BUSE, JON MONTELEONE, TERRI KIM, SHARON SKARE, ALAIN BARON, MARK FINEMAN, San Antonio, TX, Chapel Hill, NC, Cary, NC, San Diego, CA.
Abstract: We recently uncovered that metformin’s (Met) glucose-lowering effects are predominantly due to actions on enteroendocrine L-cells which are more densely populated in the lower bowel and that plasma Met exposure is not required for efficacy (ADA 2013, #1087-P). Met is contraindicated in patients with renal impairment due to Met accumulation and associated risk of lactic acidosis. By targeting a daily dose of 1000 mg delayed-release metformin (Met DR) directly to the lower bowel of patients with type 2 diabetes, Met exposure was reduced by 68% relative to a daily dose of 2000 mg immediate release Met (Met IR). Despite lower Met exposure, Met DR produced a similar glucose lowering effect as Met IR and increased fasting and postprandial GLP-1 and PYY. We hypothesized that Met DR may be a viable treatment for diabetic patients with renal impairment. We used a population PK model based on data from 2 clinical studies (N=44) of Met DR, Met IR, and Met extended-release (Met XR) to predict Met exposure (AUC0-48) following administration of each formulation in normal subjects and those with varying degrees of renal impairment (mild to severe). The median predicted AUCs (ng*h/mL) for 1000 mg daily Met DR in patients with normal, mild, moderate and severe renal impairment were 4669, 4984, 5524, and 6527. Predicted AUCs (ng*h/mL) were significantly higher for 2000 mg daily Met IR and Met XR (22659 and 20607 with normal renal function and 31606 and 29074 with severe renal impairment). Thus, in patients with severe renal impairment, 1000 mg daily Met DR is predicted to result in lower Met exposure than 2000 mg daily Met IR or Met XR in patients with normal renal function, while maintaining comparable glucose-lowering efficacy. Met DR may provide a method to treat renally impaired type 2 diabetic patients with metformin without increasing the risk of Met associated lactic acidosis.





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