Background

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.

Methods

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.

Findings

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

Interpretation

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.

Funding

AstraZeneca KK, Ono Pharmaceutical Co., Ltd.

Informations de copyright

© 2023 The Author(s).

Déclaration de conflit d'intérêts

FY reports grants and personal fees from AstraZeneca K.K. and Ono Pharmaceutical Co., LTD., during the conduct of the study. FY also has received grants from the Japanese government (KAKENHIPROJECT-17K09002, 20K07819, 23K09616) and personal fees from Daiichi Sankyo, National Agricultural Insurance Association, AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Teijin, Otsuka, Sumitomo Dainippon, Terumo, Novartis, Akahata, Tanabe Mitsubishi, Boehringer Ingelheim, and Sumitomo, outside the submitted work. MI has nothing to disclose. IS 3) reports grants and personal fees from the National Cerebral and Cardiovascular Centre during the conduct of the study. IS 3) also received grants from Ryukyu University, Soiken Co., Res. Inst. for Production Development and Nexis Co., and personal fees from Daiichi Sankyo, Kowa, AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Nipro, Otsuka, Sumitomo Dainippon, Eisai, Novartis, Glaxo Smith Kline, Toa Eiyo, Boehringer Ingelheim, Novo Nordisk, Bristol Myers Squibb, and Sanwa Kagaku, outside the submitted work. YH received grants from the Japanese government (AMED JP20ek0210152, and JP22ek21065) from the National Centre for Global Health and Medicine (21A1001, 21A2004, 21A2007, and 23A1019) and personal fees from AstraZeneca, Daiichi Sankyo, Bayer, Otsuka, Novartis, Tanabe Mitsubishi, Roche, Novo Nordisk, Mochida, Viatris, Kowa, Chugai, MSD, Boehringer Ingelheim, Takeda, Eisai, and Edwards Lifesciences outside the submitted work. HH reports grants and personal fees from AstraZeneca Plc. and Ono Pharmaceutical Co., LTD., during the conduct of the study. HH also received personal fees from Daiichi Sankyo, AstraZeneca, Bayer, and Terumo outside the submitted work. OO has nothing to disclose. CI 6) author, has nothing to disclose. CI 7) author reports grants from the Japanese government (KAKENHIPROJECT-22K08118), AMED (22ek0109539h0002, and 23ek0109629h0001), Daiichi Sankyo, Cannon Medical Systems, Teijin, Pfizer, Idorsia Pharmaceuticals Japan, LSI Medience and Shin Nippon PPD as well as personal fees from Daiichi Sankyo, Edwards Lifesciences, AstraZeneca, Cannon Medical Systems, Bayer, Astellas, Mochida, Teijin, Otsuka, Sumitomo Dainippon, Pfizer, Novartis, Bristol-Myers Squibb, Tanabe Mitsubishi, Boehringer Ingelheim, Tsumura, and MSD outside the submitted work. TN received grants from the Japanese government (KAKENHIPROJECT-22K08223, 22H03191, 21K08044, 20K08483, 20H03681, and 19K08571) and the Japan Agency for Medical Research and Development (AMED: 23811571, 20314990, 21453332, 21472516, and 17930494). TN received personal fees from AstraZeneca, Kyowa-Kirin, Bayer, Astellas, Mochida, Takeda, Otsuka, Sumitomo Dainippon, Boston-Scientific, Novartis, Daiichi Sankyo, Tanabe Mitsubishi, Boehringer Ingelheim, Kowa, Toaeiyo, Bristol Myers Squibb, Gwangju International Interventional Cardiology Symposium (GICS 2023), and Gwangju International Interventional Cardiology Symposium (GICS 2022) outside the submitted work. TS has nothing to disclose. NN has nothing to disclose. KF has nothing to disclose. KI reports honoraria from AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sumitomo Pharma, Amgen, Kowa Company, Bayer, Kyowa-Kirin, Daiichi Sankyo, Astellas, Mochida, Otsuka Pharmaceutical, Novartis, and Tanabe Mitsubishi, and support for attending meetings and travel from Novo Nordisk A/S. OT has nothing to disclose. KK receives personal fees from Otsuka, AstraZeneca, Kyowa-Kirin, Novartis, Amgen, and Abbott. MT received honoraria for lectures from AstraZeneca, Ono Pharmaceutical Co., Kyowa-Kirin, Kowa Company Limited, Sanofi K.K., Daiichi Sankyo, TAISHO PHARMACEUTICAL, Takeda Pharmaceutical, Tanabe Mitsubishi, Boehringer Ingelheim, Novo Nordisk Pharma, Sumitomo Dainippon, MSD, Astellas, Eli Lilly, KISSEI PHARMACEUTICAL, Teijin, Novartis, Mochida, Otsuka, SANWA KAGAKU KENKYUSHO, Sumitomo Pharma, NIPRO CORPORATION, and Bayer. KY received personal fees from Mochida Pharmaceutical Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical, Sanofi, Boston Scientific, Abbott Diagnostics Medical Co., Ltd., Bristol Myers Squibb, DAIICHI SANKYO COMPANY, LIMITED, Nippon Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Kowa Company, Limited, Amgen K.K., Novartis Pharma K.K., AstraZeneca K.K., Edwards Lifesciences, and Mitsubishi Tanabe Pharma Corporation. HT receives personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Mochida, Nippon Shinyaku, Novartis, Omron, Otsuka, PDRadiopharma, and Sumitomo Dainippon outside the submitted work. TH 16) has nothing to disclose. IS 17) reports honoraria from Kyowa-Kirin Terumo, Sumitomo, Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim Sanofi, Otsuka, and MSD. TM receives grants from the Japanese government (KAKENHIPROJECT 18K15864, and 21K16068) and personal fees from Daiichi Sankyo, AstraZeneca, Bayer, Astellas, Mochida, Otsuka, Novartis, and Boehringer Ingelheim outside the submitted work. KW reports consulting fees from Terumo, Gadelius Medical, and ITI Co., LTD., during the conduct of the study. KW also received personal fees from OrbusNeich, Japan Medtronic, Ono Pharmaceutical Co., Daiichi-Sankyo, Dainihon Sumitomo, Amgen, Kowa, Japan Lifeline, Novartis, Toaeiyo, Otsuka Pharma, Mochida, Sumitomo Pharma, Fuji Yakuhin, and AstraZeneca outside the submitted work. KS has nothing to disclose. TH 21) has nothing to disclose. SA has nothing to disclose. SH receives personal fees from Daiichi Sankyo, AstraZeneca, Novartis, Nippon Boehringer Ingelheim, Kowa, Viatris, Actelion, Bayer, Amgen, Bristol Myers, Takeda, Termo, Ono, Janssen, Novo Nordisk, Tanabe, Otsuka, Astellas, and Edwards Lifesciences outside the submitted work. MA received grants from Daiichi Sankyo, Otsuka, Boehringer Ingelheim, and personal fees from AstraZeneca, Tanabe Mitsubishi, Daiichi Sankyo, Novartis, Byer, Boehringer Ingelheim, Nippon Shinyaku, Viatris, Janssen, Astellas, Eli Lilly, and Otsuka outside the submitted work. TK receives Grants-in-Aid for Scientific Research (KAKENHI 22K10547). KO receives personal fees from Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. SI reports a grant from the Japan Society for the Promotion of Science outside the submitted work. MK reports grants from the Japanese government, grants from the Japan Heart Foundation, grants from the Japan Cardiovascular Research Foundation, personal fees from Daiichi-Sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-Mitsubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-Ingelheim, grants from Kowa, and personal fees from Otsuka, and personal fees from Eli Lilly outside the submitted work.