862-P: Reduced Metformin Clearance Is Associated with Increased Metformin-Related Side Effects in Older Adults with Type 2 Diabetes (T2D)

Abstract

The safe use of metformin in the elderly population and in patients with impaired renal function has not been clearly defined. Metformin has side effects that limit use particularly in vulnerable populations. In this pilot study, we aimed to investigate the interplay between metformin pharmacokinetics, pharmacogenetics of metformin transporters and metformin-related side effects. Participants were recruited based on age ≥ 65 years or eGFR=30-59 mL/min. Two sample PK sampling was performed; lactic acid, vitamin B12 and creatinine levels were measured. Participants completed a survey on GI side effects. Metformin clearance (Cl) and area under the curve (AUC) were calculated using previously described limited sampling strategy by Chen et al. Participants were genotyped for variants in the following transporters affecting metformin clearance: OCT1, OCT2, OCT3, OCTN1, MATE1, MATE2-K and PMAT. Nineteen participants with T2D and mean age 72y (range: 56-86y) completed the study. Mean eGFR was 79±27mL/min and median morning dose of metformin was 1000mg (range: 500-1500mg). Mean metformin Cl was 302 ±227ml/min, consistent with previous reports based on age and renal function. Those with GI side effects had lower Cl (389ml/min vs 191ml/min, P = 0.03). There was a positive correlation between metformin AUC and baseline lactic acid levels (R2 = 0.46, P <0.01). There was no relationship between metformin Cl or AUC and vitamin B12 levels. Individuals homozygous for rs272893 in OCTN1 had lower metformin Cl based on a univariate generalized linear model (β: -181 per allele, SE=62, P = 0.003) We confirm that metformin Cl is lower in older adults with T2D and show that lower Cl is associated with increased GI side effects. Genetic variation in metformin transporter OCTN1 was associated with reduced Cl. Larger studies are needed to examine the impact of metformin dose modification in patients with reduced clearance based on pharmacogenetics to minimize side effects. Disclosure K.Yen: None. S.Srinivasan: None. L.A.Dapkus: None. B.Tamraz: Advisory Panel; Codex Genetics. U.Masharani: Research Support; Clementia Pharmaceuticals. S.E.Mccabe: None. L.Kroon: None.