Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 20201, USA.
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 20201, USA.
medRxiv. 2023 Jun 12:2023.03.07.23286875. doi: 10.1101/2023.03.07.23286875.
SGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes - including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.
Canagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including drug-induced increases in urinary excretion of glucose, sodium, and uric acid.
This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6x10), serum creatinine (+0.05 mg/dL; p=8×10 ), and serum uric acid (-0.90 mg/dL; p=5×10 ). The effects of sex on glucosuria depended upon how data were normalized. Whereas males' responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m .
Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study ( NCT02891954 ) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function.
NCT02462421 ( clinicaltrials.gov ).
Research grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.
SGLT2 抑制剂为 2 型糖尿病患者带来多种获益，包括改善血糖控制和降低心肾疾病风险。由于个体对药物的反应存在差异，我们开始进行研究以确定与药物反应幅度相关的遗传变异。
给 30 名健康志愿者单次服用卡格列净（300mg）。测量了多个终点以评估临床相关反应，包括药物引起的尿葡萄糖、钠和尿酸排泄增加。
这项初步研究证实，卡格列净（300mg）可引发多种生物标志物的急性变化：空腹血糖降低（-4.1mg/dL；p=6x10），血清肌酐升高（+0.05mg/dL；p=8x10），血清尿酸降低（-0.90mg/dL；p=5x10）。在对数据进行归一化时，性别对糖尿的影响取决于数据归一化的方式。当数据按照体表面积进行归一化时，男性的反应约为女性的 60%，而当按照尿糖/肌酐比值进行归一化时，男女的反应相似。在这些估算肾小球滤过率（eGFR）>60mL/min/1.73m 的健康非糖尿病个体中，糖尿的幅度与空腹血糖、估算的肾小球滤过率或年龄均无显著相关性。
相对于肌酐排泄进行数据归一化将有助于在单一分析中纳入男性和女性的数据。此外，由于我们正在进行的药物基因组学研究（NCT02891954）是在健康个体中进行的，这将有助于发现遗传关联，同时限制年龄和肾功能等其他因素的混杂影响。
NCT02462421（clinicaltrials.gov）。
美国国立糖尿病、消化和肾脏疾病研究所的研究资助：R21DK105401、R01DK108942、T32DK098107 和 P30DK072488。
