68-LB: Early Pharmacological Intervention (EPIC) to Preserve Beta-Cell Function in Prediabetes (PreDM)

Beta cell failure is the key pathophysiologic determinant in progression from PreDM to type 2 diabetes (T2D). Lifestyle modifications frequently are insufficient to prevent T2D onset and drugs that modify disease progression by targeting pathophysiologic defects in PreDM may be required.

Methods: EPIC seeks to answer whether a specific drug provides greater benefit to prevent PreDM progression and to assess the effect of two years of treatment with antidiabetic drugs in 200 individuals with IFG and/or IGT on insulin sensitivity (IS) and beta cell function (BCF). At baseline, participants received 2h-OGTT and two-step hyperglycemic clamp (HC) (+125 and +400 mg/dl) with GLP-1RA infusion. Subjects then were randomized to metformin (MET), pioglitazone (PIO), saxagliptin (SAXA) or dapagliflozin (DAPA). 55 participants have completed the intervention (35F/20M; age = 51 ± 3 ys) Matsuda Index of IS was quantitated from OGTT. Beta Cell Function (BCF) was quantitated: (i) from OGTT as (ΔC-Pep/ΔG) x (Matsuda) and (ii) from HC as ΔC-Pep (First Phase, AIR x Matsuda; ΔC-Pep (Second Phase, +400 mg/dL x Matsuda; and (Second Phase + Exenatide) x Matsuda.

Results: A1c did not change significantly in any group, while FPG (106 ±4 to 100 ± 3 mg/dl) and 2h PG (150 ±8 to 141 ± 11) decreased significantly in all groups (p<0.05 for PIO > SAXA). Matsuda Index increased in all groups (p<0.01 for PIO vs all other groups). Weight increased significantly in PIO (+2.5kg p<0.05), did not change with SAXA, decreased with DAPA and MET (both p = NS). BCF during OGTT tended to increase in all groups (p<0.10 for trend). No significant changes in AIR, second phase (+400 mg/dl), and second phase (+400) + Exenatide were seen for MET, SAXA, DAPA, but significantly increased with PIO (AIR 7.1 to 22.8; 2^ND STEP 10 to 45.4; 2^nd STEP + Exenatide 19 to 79 (all p <0.01).

Conclusion: Early drug intervention in prediabetes with pioglitazone preserves beta cell function and improves insulin sensitivity better than MET, SAXA, and DAPA.