Objective: SGLT2 inhibitors including ipragliflozin have been used as adjunctive to insulin therapy for the treatment of type 1 diabetes (T1D) in Japan. Previous studies showed glucagon levels increased after initiating SGLT2 inhibitors, however, the effects of increased glucagon on glycemic control and ketogenesis in T1D remains unclear.

Methods: Twenty-five patients with T1D with HbA1c >7.5% were administered ipragliflozin 50 mg as an add-on to insulin therapy. The patients underwent a mixed-meal tolerance test (MMTT) twice before (1st-MMTT) and 12 weeks after administration of ipragliflozin (2nd-MMTT) to evaluate glucagon responses and its associations with glycemic parameters including CGM data.

Results: The values of area under the curve from fasting to 120 min (AUC0-120min, pg/mL) of plasma glucagon in 2nd-MMTT were significantly increased than 1st-MMTT (75±37 vs. 66±37, p=0.044), but fasting glucagon levels were not changed. The levels of fasting β-OHBA and AUC0-120min of β-OHBA were significantly elevated in 2nd-MMTT compared to 1st-MMTT, but there were no correlations between glucagon and β-OHBA levels. In CGM analyses, the values of glycemic variability (SD, CV% and MAGE) significantly ameliorated and the percentage of time in range (70-180 mg/dL) significantly increased from baseline to 12 weeks (46±14% vs. 54±20%, p=0.005) without an increase of the time below range (TBR, <70 mg/dL). A negative correlation between TBR% and fasting glucagon levels (r=-0.45, p=0.048) was found at 12 weeks but not at baseline. No severe adverse events including ketoacidosis developed in the participants during the study.

Conclusion: Adjunctive treatment of ipragliflozin was found to increase postprandial glucagon secretion and might contribute to prevention of hypoglycemia via mitigating glycemic variability in T1D.

Disclosure

Y.Nakamura: Research Support; Astellas Pharma Inc. Y.Maeda: None. M.Minami: None. T.Matsui: None. A.Kawakami: Research Support; Astellas Pharma Inc. I.Horie: Research Support; Astellas Pharma Inc. N.Abiru: None. T.Kitamura: None. Y.Kusunoki: None. K.Nishida: None. A.Yamamoto: None. Y.Hirota: Other Relationship; Lilly, Sanofi K.K., Terumo Corporation, Sumitomo Dainippon Pharma Co., Ltd., Research Support; Sumitomo Dainippon Pharma Co., Ltd. T.Fukui: None.

Funding

Astellas Pharma Inc.

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