Effect of Multifactorial Intervention on Diabetic Kidney Disease in Patients with Type 2 Diabetes

BACKGROUND: A randomized control trial conducted to assess the effects of intensified multifactorial intervention (intensive therapy) compared with the guideline-based standard care (conventional therapy) on diabetic complications and all-cause mortality, the J-DOIT3 showed a nonsignificant reduction in the primary outcome. The study was intended to determine the effect of intensive therapy on the pre-specified renal outcome as a secondary outcome measure. METHODS: A total of 2540 eligible patients were randomly assigned to intensive therapy (n = 1269) and conventional therapy (n = 1271) and treated for a median of 8.5 years. The renal outcome measure was a composite of the onset or progression of nephropathy defined as progression from normoalbuminuria (urinary albumin < 30 mg/g·creatinine) to microalbuminuria (urinary albumin ≥30 mg/g·creatinine, < 300 mg/g·creatinine); progression from normoalbuminuria to macroalbuminuria (urinary albumin ≥ 300 mg/g·creatinine), progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by 2-fold or more compared to baseline, or end-stage renal failure (permanent dialysis initiated or renal transplant performed). The primary analysis was carried out on the intention-to-treat (ITT) population. Changes in the estimated glomerular filtration rate (eGFR) and albuminuria were also analyzed RESULTS: A total of 438 renal events occurred (181 in the intensive therapy group and 257 in the conventional therapy group), and intensive therapy was associated with a significant 32% reduction in renal events compared to conventional therapy (HR, 0.68; 95% CI, 0.56 to 0.82; P < 0.0001) and was associated with a decrease in HbA1c at 1 year from study initiation. CONCLUSIONS: The pre-specified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to the currently recommended care. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00300976 FUNDING STATEMENT: This trial was supported by Ministry of Health, Labour and Welfare, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical. DECLARATION OF INTERESTS: K. U. reports a funded research department from MSD, Nippon Boehringer Ingelheim, and Novo Nordisk; lecture fees from Astellas, AstraZeneca, Daiichi Sankyo, Eli Lilly, Kissei, Kowa, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Shionogi, Sumitomo Dainippon, Taisho Toyama Pharmaceutical Co., Ltd., and Takeda; grants and endowments from Astellas, AstraZeneca, Daiichi Sankyo, Eli Lilly, Kowa, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Ono, Sanofi, Sanwa Kagaku, Sumitomo Dainippon, Taisho Toyama, and Takeda. T. S. reports lecture fees from Kissei, Mitsubishi Tanabe, and Takeda. Y. O. reports lecture fees from Nippon Boehringer Ingelheim, and Takeda. S. O. reports lecture fees from AstraZeneca, Eli Lilly, and Mitsubishi Tanabe. H. K. reports lecture fees from Eli Lilly, Mitsubishi Tanabe, Novo Nordisk, and Ono. M. H. reports lecture fees from AstraZeneca, Kissei, and Mitsubishi Tanabe. A. Morita reports lecture fees from Nippon Boehringer Ingelheim. K. O. reports lecture fees from Abbott Japan Co., Ltd., ASKA Pharmaceutical Co. Ltd., Astellas, AstraZeneca, Daiichi Sankyo, Eli Lilly, Johnson & Johnson K. K., Kao Corporation, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novo Nordisk, Ono, Sanofi K. K., and Takeda. K. H. reports consulting fees from Kissei and Takeda; research support from Novartis. A. Morise reports lecture fees from Nippon Boehringer Ingelheim. Y. O. reports lecture fees from Eli Lilly, Novo Nordisk, Sanofi, and Takeda; consulting fees from Astellas, Chugai Pharmaceutical Co., Ltd., and Kowa; being the chairman of the board of directors, and owning stock in Statcom Co., Ltd. M. N. reports lecture fees from AbbVie G. K., Astellas, Daiichi Sankyo, Eli Lilly, Kissei, Kowa, Kyowa Hakko Kirin, Meiji Seika Pharma Co., Ltd., Mitsubishi Tanabe, MSD, Novo Nordisk, Sanofi, Ono, Taisho Toyama, and Takeda; grants and endowments from AstraZeneca, Daiichi Sankyo, Kowa, Kyowa Hakko Kirin, Mitsubishi Tanabe, Mochida Pharmaceutical Co., Ltd., Sanwa Kagaku, and Takeda. T. K. reports funded research departments from MSD, Nippon Boehringer Ingelheim, Novartis, and Novo Nordisk; lecture fees from Astellas, AstraZeneca, Eli Lilly, Kissei, Kowa, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Novo Nordisk, Ono, Sumitomo Dainippon, and Takeda; manuscript fees from Eli Lilly; grants and endowments from Daiichi Sankyo, Mitsubishi Tanabe, Sumitomo Dainippon, and Takeda; funds for contracted research from Daiichi Sankyo, Sanwa Kagaku, and Takeda; funds for collaborative research from Daiichi Sankyo and Novartis. No other potential conflicts of interest relevant to this work are reported. The authors and the participating investigators of the J-DOIT3 Study Group declared duality of interest also to his/her healthcare institution. ETHICS APPROVAL STATEMENT: The study protocol was approved by the ethics committee of each participating institution. All patients provided written informed consent.