General Poster Session 2
Dissociation Between Metformin Plasma Exposure and its Glucose-Lowering Effect: A Novel Gut-Mediated Mechanism of Action
, JOHN B. BUSE, TERRI KIM, SHARON SKARE, ALAIN BARON, MARK FINEMAN,
We designed a delayed release (DR) metformin (Met) tablet that targets the lower bowel to reduce Met bioavailability and test whether Met plasma exposure is required for its glucose-lowering effects. Met DR was compared to commercially available immediate release (IR) Met in a randomized, double-blind, crossover study. Subjects with type 2 diabetes (N=24, age 51 y, BMI 33 kg/m
) were withdrawn from oral diabetes therapy for 2 wks, then received each treatment orally twice daily (BID) for 5 days, separated by a 9—12 day washout: 1000mg IR, 1000mg DR, 500mg DR. Plasma Met, glucose, insulin, GLP-1 and PYY were measured from 7am—5pm (7am breakfast; 12pm lunch) at baseline (BL) and day 5. Compared to 1000mg IR, Met exposure was reduced by 45 and 57% with 1000mg and 500mg DR (N=19, both p<0.0001). The reduction in fasting plasma glucose from BL (197—200 mg/dl) was similar for all treatments (LSmean±SE: 22.5±6.8 mg/dl, 1000mg IR; -19.9±5.0 mg/dl, 1000mg DR; 16.4±3.8 mg/dl, 500mg DR; all p<0.01 vs. BL). The 10h glucose AUC was similarly reduced in all treatments by 8—14% (all p<0.0001 vs. BL). Insulin AUC was unchanged from BL. All treatments increased fasting and postprandial PYY and GLP-1 (all p<0.05 vs. BL). The GLP-1 AUC increased by 87, 62 and 69% and PYY AUC increased by 55, 38, and 46% for 1000mg IR, 1000mg DR and 500mg DR (all p<0.0001 vs. BL). Nausea (9%) and vomiting (9%) occurred with Met IR but not Met DR. Diarrhea (10—15%) occurred in all treatments. Despite substantial reductions in exposure, a Met DR formulation that targets the lower bowel was as effective as Met IR with better tolerability. Met IR and DR similarly increased plasma gut peptide levels. This evidence indicates that the glucose-lowering effects of Met are in a large part due to Met actions on gut enteroendocrine cells. By directly targeting the lower bowel, Met DR may provide maximum efficacy with improved tolerability at lower doses (≤1000mg total daily) than typically used with currently available formulations.
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