Yoshihara Fumiki, Imazu Miki, Sakuma Ichiro, Hiroi Yukio, Hara Hisao, Okazaki Osamu, Ishiguro Chizuru, Izumi Chisato, Noguchi Teruo, Shiraiwa Toshihiko, Nishioka Norio, Fujii Kenshi, Iwakura Katsuomi, Tomonaga Osamu, Kobayashi Koichi, Takihata Masahiro, Yumoto Kazuhiko, Takase Hiroyuki, Himi Toshiharu, Shimizu Ikki, Murakami Tsutomu, Wagatsuma Kenji, Sato Katsuhiko, Hiramatsu Takeyuki, Akabame Satoshi, Hata Shiro, Asakura Masanori, Kawabata Takanori, Omae Katsuhiro, Ito Shin, Kitakaze Masafumi
Division of Nephrology and Hypertension, National Cerebral and Cardiovascular Centre, Suita, Osaka, Japan.
Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Centre, Suita, Osaka, Japan.
EClinicalMedicine. 2023 Nov 27;66:102334. doi: 10.1016/j.eclinm.2023.102334. eCollection 2023 Dec.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D.
DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135.
Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group.
Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling.
AstraZeneca KK, Ono Pharmaceutical Co., Ltd.
钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可降低存在或不存在心力衰竭（HF）或2型糖尿病（T2D）的蛋白尿水平升高患者的尿白蛋白与肌酐比值（UACR）。然而，在同时存在HF和T2D的情况下，这些作用尚未见报道。缺乏这方面的证据促使我们开展一项关于达格列净对HF和T2D患者UACR影响的临床试验。
DAPPER是一项多中心、随机、开放标签、平行组、标准治疗对照试验，在日本18个医疗机构招募患者。年龄在20至85岁之间、同时患有HF和T2D的符合条件参与者被随机分配到达格列净组或对照组（SGLT2抑制剂以外的抗糖尿病药物），分配比例为1:1。主要结局是两年观察期后UACR相对于基线的变化，次要终点是心血管（CV）事件以及与HF相关的参数。该试验已在UMIN-CTR注册中心注册，注册号为UMIN000025102，在日本临床试验注册中心注册，注册号为jRCTs051180135。
在2017年5月12日至2020年3月31日期间，294例患者被随机分配到达格列净组（n = 146）或对照组（n = 148）。患者的平均年龄为72.1岁，29%为女性。达格列净组糖化血红蛋白平均值为6.9%，NT-proBNP平均值为429.1 pg/mL，估计肾小球滤过率平均值为65.7 mL/min/1.73 m²，UACR中位数为25.0（8.8 - 74.6）mg/g Cr；对照组糖化血红蛋白平均值为6.9%，NT-proBNP平均值为429.1 pg/mL，估计肾小球滤过率平均值为65.7 mL/min/1.73 m²，UACR中位数为25.6（8.2 - 95.0）mg/g Cr。在达格列净组的146例患者中，122例完成了研究，在观察期结束时，107例（87.7%）患者每天服用5 mg达格列净。达格列净组和对照组的主要结局无显著差异。在次要终点中，作为超声心动图参数之一的左心室舒张末期内径的平均减小幅度，达格列净组大于对照组。复合终点定义为CV死亡或因CV事件住院、因HF事件住院、因各种原因住院以及在两年观察期内心力衰竭处方的额外变化，达格列净组比对照组更少见。
尽管每日5 mg剂量的达格列净未使HF和T2D患者的尿白蛋白排泄量低于对照组，但我们的研究结果表明，达格列净可减少CV事件并抑制左心室重构。
阿斯利康株式会社、小野制药株式会社
