644-P: Effect of PharmacologIC (EPIC) Therapy on Insulin Sensitivity and Beta-Cell Function in Prediabetes (PreDM)

Abstract

Treating PreDM with medications that target specific pathophysiologic defects can slow/prevent the progression to type 2 diabetes mellitus (T2DM) . While the preventive effects of Pioglitazone (PIO) and Metformin (MET) previously have been described in PreDM, the benefit of newer antidiabetic agents in preventing PreDM progression to T2DM is less well established. OBJECTIVE: To examine the effect of one year of pharmacologic therapy on insulin sensitivity (Matsuda Index) , beta cell function (Disposition Index) , and adipose tissue insulin resistance (fasting FFA x FPI; Adipo IR) . METHODS: EPIC recruited 175 prediabetes subjects (FPG = 100-125 and/or 2-h PG = 140-199 mg/dl; OGTT) of whom 34 have completed 1-year of follow-up. Pre-DM subjects (21F/13M) received OGTT at baseline (BL) and were randomized to treatment with metformin (MET) (n= 7, age = 52 ± 4, BMI= 33 ± 3, A1c= 5.7 ± 0.01) ; PIO (n= 8, age= 49±3, BMI= 30 ± 2, A1c= 5.7 ± 0.08) ; saxagliptin (SAXA) (n= 8 Age= 48 ± 4 BMI= 31 ± 2, A1c= 5.8 ±0.1) ; or dapagliflozin (DAPA) (n= 11, Age= 55 ± 3 BMI= 31 ± 1, A1c=) for 12 months. RESULTS: FPG (p<0.for MET) and 2h-PG (p<0.for MET and PIO) decreased in all groups; A1c did not significantly change in any group. Weight decreased with MET (-4.4kg) and DAPA (-3.4kg) , increased with PIO (+2.1 kg) and remained unchanged with saxagliptin (-0.2 kg) . A nonsignificant increase in Matsuda Index was observed in all 4 groups. Disposition Index increased significantly for MET (3.0 to 5.6, p<0.05) and PIO (3.1 to 5.1, p<0.05) . %FFA suppression during OGTT improved only with PIO (54±8 to 71±5 %, p<0.01) . Adipo IR decreased in all groups (MET: 7.4 to 6.5; PIO: 7.2 to 4.5; DAPA: 8.5 to 6.8; SAXA: 9.2 to 6.9, all p<0.05) . CONCLUSION: Early pharmacological treatment of prediabetes improves whole body insulin sensitivity, beta cell function and Adipo IR. The superiority of one drug over another and their mechanism of action in preventing progression of prediabetes to T2DM will be determined by EPIC. Disclosure A.O.Chavez velazquez: None. E.Ali: None. A.Merovci: None. C.Agyin: None. T.Terasawa: None. M.Abdul-ghani: None. C.L.Triplitt: Consultant; Bayer AG, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. E.Cersosimo: Research Support; AstraZeneca. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. Funding NIH R01-DK024092-34Astra-Zeneca ISSDAPA0002