Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) improve hard renal outcomes in type 2 diabetes (T2D) patients. An acute and reversible drop in eGFR that stabilizes over time, as with RAS inhibitors, suggests involvement of a beneficial renal hemodynamic mechanism. In hyperfiltering T1D patients, SGLT2i lowered GFR by increasing afferent arteriolar resistance, possibly by activating tubuloglomerular feedback. We studied the renal hemodynamic effects of SGLT2i dapagliflozin in T2D patients like those included in recent outcome trials. Methods: Forty-four T2D patients on metformin monotherapy, (62.9±7.0 years, HbA1c 7.38±0.63%, GFR 113±19 mL/min) were randomized to 12 weeks dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD to achieve glycemic equipoise. At baseline and week 12, GFR and renal plasma flow (RPF) were measured by gold-standard inulin and para-aminohippurate clearances. The measurements were performed 1) in the fasting state, 2) during clamped euglycemia (90 mg/dL) and 3) hyperglycemia (270 mg/dL). Renal vascular resistance (RVR) and filtration fraction (FF) were calculated using GFR, RPF, Ht and MAP. Afferent and efferent arteriolar resistances were estimated by Gomez’ equations. Results: HbA1C decreased similarly (0.47% with DAPA and 0.65% with GLIC; p=ns), while only DAPA significantly reduced MAP by approximately 6 mmHg. DAPA reduced GFR during all three conditions by 8.9 (p<0.01), 9.0 (p=0.01) and 13.4 mL/min (p<0.001), respectively, without altering RPF, thus also reducing FF. Importantly, DAPA lowered RVR and efferent arteriolar resistance. GLIC did not alter any renal hemodynamic variables. Conclusion: We confirm that SGLT2i induces beneficial renal hemodynamic changes in T2D beyond glycemic control that are characterized by reduced GFR and FF. However, in contrast to standing opinion, this is mediated by efferent arteriolar dilation rather than afferent arteriolar constriction. Disclosure E.J. van Bommel: None. M.A. 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. J.A. Joles: None. 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. Funding AstraZeneca Nederland BV
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. Disclosure 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. Funding AstraZeneca Nederland BV
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