Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan.
Medical Information and Product Advancement Department, Kowa Pharmaceutical Co., Ltd., Tokyo, Japan.
J Clin Endocrinol Metab. 2019 Sep 1;104(9):3647-3660. doi: 10.1210/jc.2018-02254.
Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known.
To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue.
An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs).
Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m2; estimated glomerular filtration rate, 83.9 mL/min/1.73m2; 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (-3.6 mmol/L·pmol/L and -6.2 mmol/L·pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52.
The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.
尽管钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2is）长期治疗可导致尿葡萄糖排泄增加而导致热量损失，但 SGLT2is 导致体重减轻的机制尚不清楚。
检查长期使用 SGLT2i，托格列净治疗时体重减轻减弱的机制，重点研究胰岛素对脂肪组织的抗脂解作用。
对两项为期 52 周托格列净给药的 3 期研究的数据进行综合分析。通过空腹胰岛素（f-IRI）和空腹游离脂肪酸（f-FFA）水平的乘积计算脂肪组织胰岛素抵抗（Adipo-IR）来评估抗脂解作用。
分析了 774 例 2 型糖尿病患者（平均年龄 58.5 岁；糖化血红蛋白 8.1%；体重指数 25.6 kg/m2；估算肾小球滤过率 83.9 mL/min/1.73m2；66%为男性）的数据。体重在第 24 周到第 52 周之间逐渐稳定下降。从基线到第 24 周，f-IRI 水平显著下降，并且这种下降一直持续到第 52 周。f-FFA 水平显著升高，在第 24 周达到峰值，然后从第 24 周到第 52 周下降。Adipo-IR 水平在整个 52 周内逐渐下降（第 24 周和第 52 周分别为-3.6 mmol/L·pmol/L 和-6.2 mmol/L·pmol/L；P<0.001 基线与第 24 周和第 52 周以及第 24 周与第 52 周相比）。较高的基线 Adipo-IR 水平与第 52 周时体重减轻更大独立相关。
脂肪组织中抗脂解作用的改善可能会减弱脂肪的渐进性分解，从而减轻 2 型糖尿病患者中 SGLT2i 诱导的未来体重减轻。
