Aims: Urinary glucose excretion (UGE) induced by SGLT2 inhibitors (SGLT2i) varies considerably by individual, and is influenced by blood glucose level and glomerular filtration rate (GFR). It is however unknown what other factors are involved in this process. We have now investigated the relation between various physiological parameters and UGE in patients treated with an SGLT2i.
Methods: To minimize the influence of glycemic variability, we analyzed SGLT2i-induced UGE during a hyperinsulinemic-euglycemic clamp. OGTT and a 120 min-hyperinsulinemic-euglycemic clamp, during which plasma glucose (PG) were maintained at 90 mg/dl, were performed with type 2 diabetes subjects (n=45) within 6 days after the start of dapagliflozin (5mg/day). Relationships between UGE during the clamp and various indexes for insulin secretion/sensitivity were analyzed. Disposition index (DI) was calculated as the product of insulinogenic index (II) and insulin sensitivity index (ISI) determined by the clamp.
Results: During the clamp, UGE considerably varied from 28.2 to 176.9 (mean ± SD, 87.1 ± 32.8) mg/kg/120min. In univariate analysis, UGE was not correlated with PG before the clamp, mean PG during the clamp or any indexes for insulin secretion/sensitivity determined by OGTT or the clamp (HOMA-β, II, OGTT AUCIRI/AUCPG, HOMA-IR, composite index, QUICKI and ISI). However, UGE was correlated with log-transformed DI (r = -0.338, p = 0.023) as was eGFR (r = 0.418, p = 0.004). Multivariate analysis revealed that eGFR and log-transformed DI were independent predictors of UGE (R2 = 0.267, β = 0.332, p = 0.045, and β = -0.315, p = 0.031, respectively).
Conclusion: Even in euglycemic conditions, SGLT2i-induced UGE considerably varied by individuals and was correlated with DI, which represents individual capacity of glucose disposal. The present results thus suggest that SGLT2i-induced UGE is regulated by an unidentified physiological process that is related to glucose tolerance in living body.
K. Sakaguchi: Other Relationship; Self; AstraZeneca, Novartis AG, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. A. So: None. J. Ito: None. A. Kaneko: None. Y. Morita: None. T. Yamada: None. H. Miura: None. N. Otowa-Suematsu: None. T. Nakamura: None. H. Komada: None. Y. Okada: None. Y. Hirota: Other Relationship; Self; Sanofi. Y. Tamori: None. W. Ogawa: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharma GmbH & Co.KG, Eli Lilly Japan K.K., Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.