Introduction and Objective: Antidiabetic agents differ in their mechanisms of action and can exert distinct long-term effects on β-cell function (BCF). Hyperglycemic clamp studies (HC) enable detailed assessment of first- and second-phase insulin secretion (ISecr), yet comparative longitudinal data across drug classes among individuals with PreDM remains limited.Methods: Sixty PreDM subjects were studied and treated with either metformin (MET n=15), pioglitazone (PIO n=15), saxagliptin (SAXA n=15), or dapagliflozin (DAPA n=15) for 2 years. All groups were matched for age and BMI. HC (+125 mg/dL) were performed before and after treatment. ISecr was calculated as the incremental AUC of insulin from 0-15 min (first phase) and during the 15-120 min (second phase) of the HC. Insulin sensitivity was estimated as glucose infusion rate during the steady state (GIR 90-120) of the HC.Results: As a whole (n=60), FPG decreased from 107 to 104 mg/dL (p < 0.05), with no significant change in HbA1c. First-phase ISecr increased from baseline to follow-up (949 vs 1174 µU/ml, p<0.001), with no change in second-phase ISecr, while GIR 90-120 improved (from 6.1 to 7.2 mg/kg.min, p<0.05). In treatment-specific analyses, MET, SAXA and PIO increased first-phase ISecr at 2 years (p < 0.05). GIR 90-120 improved with MET (p<0.05), DAPA (p < 0.05) and PIO (p = 0.05). Second-phase ISecr and disposition index (ISecr x GIR) remained unchanged across all four individual treatment groups. MET led to a net weight loss (p<0.005), whereas PIO led to weight gain (p<0.001).Conclusion: Treatment with antidiabetic agents for two years improved first phase ISecr and maintained second phase ISecr in individuals with PreDM, which carries a ~10% annual risk of progression to type 2 diabetes. Intervening early with pharmacological treatment can improve beta-cell function and modify the natural course toward progression to diabetes.
H. Zaitoon: None. A. Merovci: None. P. Mahapol: None. A.A. Hansis-Diarte: None. E. Cersosimo: None. J.M. Adams: None. C.L. Puckett: None. M. Abdul-Ghani: None. R. Belfort DeAguiar: None. R.A. DeFronzo: Advisory Panel; Ended; AstraZeneca. Research Support; Current; AstraZeneca. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Corcept Therapeutics. Speaker’s Bureau; Current; Corcept Therapeutics. Consultant; Current; Alnylam Pharmaceuticals, Inc. Advisory Panel; Current; Regeneron Pharmaceuticals Inc., Aardvark. A.O. Chavez-Velazquez: Advisory Panel; Ended; Crinetics Pharmaceuticals, Inc.
Astra Zeneca (ISSDAPA0002), National Institute of Health (R01 DK024092-37)
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