Introduction: Disease progression in type 2 diabetes (T2D) is due to a continuous loss of β-cell function, partly driven by chronic secretory stress on remaining islets caused by hyperglycemia. Beta-cell loss may be further enhanced by insulin secretagogues such as sulfonylureas. In contrast, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may improve beta-cell function by reducing β-cell afterload by lowering blood glucose levels through glucosuria.
Methods: Forty-four T2D patients treated with metformin (age 63 ± 7 years; HbA1c 7.3 ± 0.6%; GFR 113±19 mL/min) were randomized to dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD. At baseline and week 12, whole-body insulin sensitivity (M-value) and β-cell function were quantified by gold-standard hyperinsulinemic-euglycemic and hyperglycemic clamp with additional arginine stimulation. First-phase glucose-stimulated and arginine-stimulated incremental area under the C-peptide curves (iAUCCP) were calculated. iAUCCP multiplied by M-value rendered disposition indices (1st phase and ARG-DI; nmol.min/L.mg/kg.min).
Results: HbA1C decreased similarly (-0.47% with DAPA and -0.65% with GLIC; p=ns). DAPA, but not GLIC, decreased fasting hyperinsulinemia (-18.4 pmol/l vs. +2.7 pmol/l, p=0.01). Neither treatment improved insulin sensitivity. GLIC significantly increased 1st phase DI from 0.75 ± 1.21 to 2.89 ± 3.25 (p<0.01), while DAPA did not (1.51 ± 2.81 to 2.15 ± 2.27, p=0.29). ARG-DI increased from 42.4 ± 12.1 to 45.2 ± 15.6 (p=0.03) with DAPA but was not improved by GLIC (52.3 ± 9.9 to 63.7 ± 8.6; p=0.28).
Conclusion: In contrast to the secretagogue GLIC, DAPA lowered fasting insulin levels and did not further enhance C-peptide secretion in response to hyperglycemia. However, it did improve ARG-DI, which may reflect β-cell total secretory capacity. Thus, by lowering beta-cell afterload, DAPA may confer long-term β-cell benefit versus GLIC.
E.J.M. van Bommel: None. M.H. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi.
AstraZeneca Nederland BV