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Observational Study
. 2021 Jan;9(1):e001787.
doi: 10.1136/bmjdrc-2020-001787.

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Kohjiro Ueki  1 , Yukio Tanizawa  2 , Jiro Nakamura  3 , Yuichiro Yamada  4 , Nobuya Inagaki  5 , Hirotaka Watada  6 , Iichiro Shimomura  7 , Rimei Nishimura  8 , Hideaki Miyoshi  9 , Atsuko Abiko  10 , Hideki Katagiri  11 , Michio Hayashi  12 , Akira Shimada  13 , Keiko Naruse  14 , Shimpei Fujimoto  15 , Masazumi Fujiwara  16 , Kenichi Shikata  17 , Yosuke Okada  18 , Eiichi Araki  19 , Tsutomu Yamazaki  20 , Takashi Kadowaki  21   22 ; J-BRAND Registry Group
Collaborators, Affiliations
Observational Study

Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Kohjiro Ueki et al. BMJ Open Diabetes Res Care. 2021 Jan.

Abstract

Introduction: Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.

Research design and methods: We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.

Results: Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.

Conclusions: Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Keywords: diabetes mellitus; dipeptidyl peptidase 4; registries; safety; type 2.

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Conflict of interest statement

Competing interests: KU reports lecture fees from Takeda, Novo Nordisk, Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma, AstraZeneca, MSD, Ono, Sumitomo Dainippon Pharma, Sanofi, and Astellas; research grants from Astellas, Novo Nordisk, Eli Lilly, Nippon Boehringer Ingelheim, Abbott Japan, and MSD; endowments from Takeda, Astellas, Novo Nordisk, Sumitomo Dainippon Pharma, Sanofi, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, and Ono. YT reports lecture fees from Takeda, Astellas, AstraZeneca, MSD, Ono, Kyowa Hakko Kirin, Kissei, Kowa, Sanofi Aventis, from Taisho Pharmaceutical, Taisho Pharma, Mitsubishi Tanabe Pharma, Nippon Shinyaku, Bristol-Myers Squibb, Sumitomo Dainippon Pharma, Chugai, Eli Lilly, Nippon Boehringer Ingelheim, and Novo Nordisk; manuscript fees from Kyowa Hakko Kirin; consulting fees from Terumo; research grants from Daiichi-Sankyo and Novo Nordisk; endowments from Astellas, Takeda, Chugai, Sanwa Kagaku, Daiichi-Sankyo, MSD, Kyowa Hakko Kirin, Eisai, Sumitomo Dainippon Pharma, Shionogi, Eli Lilly, Sanofi Aventis, Mitsubishi Tanabe Pharma, Novo Nordisk, Kissei, Nippon Boehringer Ingelheim, Kowa Pharmaceutical, Teijin Pharma, Pfizer, Nihon Pharmaceutical, and Nippon Shinyaku. JN reports lecture fees from Takeda, Astellas, AstraZeneca, MSD, Ono, Kowa Pharmaceutical, Sanofi, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Terumo, Eli Lilly, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Japan Tobacco Inc., Taisho Pharma, Sumitomo Dainippon Pharma, Sanwa Kagaku, Kissei, Mylan, Arkray, Medtronic Japan, Fukuda Denshi, and Abbott Japan; research grants from Kissei, Nippon Boehringer Ingelheim, and Fukuda Colin; endowments from Takeda, Astellas, MSD, Ono, Daiichi-Sankyo, Taisho Pharma, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Eli Lilly, Novartis, Novo Nordisk, Japan Tobacco Inc., Otsuka Pharmaceutical, Kaken Pharmaceutical, Kissei, Kyowa Hakko Kirin, Kowa Pharmaceutical, Sanwa Kagaku, Shionogi, Nippon Boehringer Ingelheim, Nippon Becton Dickinson, and Pfizer. YY reports lecture fees from MSD, Novo Nordisk, Ono, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Takeda, Sanofi, and Daiichi-Sankyo; endowments from Ono, Takeda, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, and Sanwa Kagaku. NI reports lecture fees from Takeda, Kowa Pharmaceutical, MSD, Arkray, Astellas, Kissei, Sanofi, Novartis, Novo Nordisk, Bayer, Ono, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Eli Lilly, Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Medtronic Japan, Taisho Pharma, Pfizer, Fujifilm Pharma, Saishin Igaku Co., Toyooka Hospital, Terumo, Olympus, Sunstar Foundation, Japan Tabacco Inc., ILSI Japan, University of Occupational and Environmental health, Japan, Japanese Red Cross Wakayama Medical Center, AstraZeneca, Tumura, Chugai, Wakayama Medical University, Hokkaido University, Mainichi Ga Hakken Inc., Boehringer Ingelheim, MSD Life Science Foundation, Taisho Pharmaceutical, and Scohia Pharma; grants from Mitsubishi Tanabe Pharma, Daiichi-Sankyo, AstraZeneca, Sumitomo Dainippon Pharma, Novartis, Novo Nordisk, Astellas, Sanofi, Terumo, Kyowa Hakko Kirin, Taisho Pharma, and Ono; endowments from Takeda, Kissei, Taisho Pharma, Sanofi, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Japan Tabacco Inc., Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Astellas, MSD, Ono, Sanwa Kagaku, Eli Lilly, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Teijin Pharma, Shionogi, and The Japan China Medical Association. HW reports lecture fees from Takeda, Astellas, Sanofi, Mitsubishi Tanabe Pharma, Novo Nordisk, Kowa Pharmaceutical, AstraZeneca, Novartis, Nippon Boehringer Ingelheim, MSD, Sumitomo Dainippon Pharma, Eli Lilly, Sanwa Kagaku, Ono, Kissei, and Fujifilm Pharma; grants from Kowa Pharmaceutical, Novartis, Sanwa Kagaku, and Eli Lilly; endowments from Takeda, Astellas, Sanofi, Mitsubishi Tanabe Pharma, Novo Nordisk, AstraZeneca, Novartis, Nippon Boehringer Ingelheim, MSD, Sumitomo Dainippon Pharma, Kowa Pharmaceutical, Ono, Kyowa Hakko Kirin, Daiichi-Sankyo, Terumo, Pfizer, Mochida Pharmaceutical, Taisho Pharma, Johnson & Johnson, Sanwa Kagaku, and Kowa. IS reports personal fees from Lotte, Kowa Life Science Foundation, Sunstar Foundation, MSD Life Science Foundation, Kanae Foundation, Senri Life Science Foundation, Fuji Foundation for Protein Research, Japan Cardiovascular Research Foundation, Japan Foundation for Applied Enzymology, Japan Society for the Promotion of Science, NPO Hormon Station, and Kawanishi medical association; lecture fees from Takeda, Japan Pharmacy Laboratory, Asia-Pacific Diabetes and Obesity Study Group, MSD, Astellas, AstraZeneca, Ono, Kyowa Hakko Kirin, Covidien Japan, Kowa Pharmaceutical, Sanofi, The Japan Society of Internal Medicine, Daiichi-Sankyo, Taisho Pharma, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Teijin Pharma, Eli Lilly, Nippon Boehringer Ingelheim, Japanese Society for Surgical Metabolism and Nutrition, Novartis, Novo Nordisk, Mochida Pharmaceutical, Rohto Pharmaceutical, Sanwa Kagaku, and Astellas Amgen BioPharma; fees of speakers bureaus from Fuji Foundation for Protein Research; manuscript fees from Iji Publishing, AstraZeneca, Ono, Kyowa Hakko Kirin, Sanwa Kagaku, Eli Lilly, Saishin Igaku-sha, Sentan Igaku-sha, and Medical Review-sha; consulting fees from Takeda, AstraZeneca, MSD, Ono, Kowa Pharmaceutical, Novartis, Novo Nordisk, Sanwa Kagaku, Nippon Boehringer Ingelheim, and Taisho Pharmaceutical; grants from AMED (Japan Agency for Medical Research and Development), National Center for Global Health and Medicine, Fukushima Medical University, Chiba University, Juntendo University, Kowa Pharmaceutical, Rohto Pharmaceutical, Otsuka Pharmaceutical, Sanwa Kagaku, and Immuno-Biological Laboratories; endowments from Takeda, MSD, Astellas, Nippon Becton Dickinson, Sumitomo Dainippon Pharma, Kyowa Hakko Kirin, Terumo, Mitsubishi Tanabe Pharma, Teijin Pharma, Shionogi, Kaken Pharmaceutical, Ono, Novartis, AstraZeneca, Sanofi, Eli Lilly, Daiichi-Sankyo, Kowa Pharmaceutical, Novo Nordisk, The Japan Diabetes Society, Midori Health Management Center, Japan Foundation for Applied Enzymology, MSD Life Science Foundation, Kowa Life Science Foundation, Suzuken Memorial Foundation, Japan Diabetes Foundation, Japan Heart Foundation, Gout Research Foundation, The Uehara Memorial Foundation, Takahashi Industrial and Economic Research Foundation, Soiken Holdings Inc., and Fukumoto Naika Clinic. RN reports lecture fees from Takeda, Sanofi, Medtronic Japan, Nippon Boehringer Ingelheim, Kissei, Novartis, Eli Lilly, Novo Nordisk, MSD, and Astellas; endowments from Japan Diabetes Foundation and Nippon Boehringer Ingelheim. HM reports lecture fees from Takeda, Novo Nordisk, Eli Lilly, Sanofi, Astellas, MSD, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Novartis, Ono, Kowa Pharmaceutical, Nippon Boehringer Ingelheim, AstraZeneca, Daiichi-Sankyo, Taisho Pharmaceutical, Teijin Pharma, and Sanwa Kagaku; grants from Astellas and Taisho Pharma; endowments from Takeda, Novo Nordisk, Eli Lilly, Nippon Boehringer Ingelheim, Daiichi-Sankyo, Ono, Sumitomo Dainippon Pharma, Astellas, MSD, Kowa Pharmaceutical, Taisho Pharmaceutical, Teijin Pharma, Sanwa Kagaku, and Kyowa Hakko Kirin. AA reports lecture fees from Takeda, Sanofi, Novo Nordisk, Eli Lilly, Ono, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Sanwa Kagaku, Mitsubishi Tanabe Pharma, Astellas, AstraZeneca, MSD, Taisho Pharma, Daiichi-Sankyo, Novartis, Kowa Pharmaceutical, Bayer, Shionogi, Sumitomo Dainippon Pharma, and Fujifilm Pharma; consulting fees from Sanofi and Novo Nordisk; grants from Novo Nordisk and Taisho Pharma. HK reports lecture fees from Takeda, MSD, Novo Nordisk, Daiichi-Sankyo, Astellas, AstraZeneca, Ono, Kyowa Hakko Kirin, Kowa Pharmaceutical, Sanofi, Eli Lilly, Sanwa Kagaku, Taisho Pharma, Sumitomo Dainippon Pharma, Novartis, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Bayer, Medtronic Japan, and Alcon Japan; grants from Otsuka Pharmaceutical; endowments from MSD, Eli Lilly, Novo Nordisk, Takeda, Daiichi-Sankyo, Astellas, Sanofi, Novartis, Mitsubishi Tanabe Pharma, Ono, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Taisho Pharma, Fujifilm Pharma, Kissei, Nippon Becton Dickinson. MH reports lecture fees from Takeda, Astellas, MSD, Ono, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Kowa, Eli Lilly, Novo Nordisk, and Sanofi. AS reports lecture fees from MSD, Eli Lilly, Novo Nordisk, Sanofi, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Astellas, Ono, and Terumo; endowments from Takeda, MSD, Astellas, Novo Nordisk, Nippon Boehringer Ingelheim, Ono, and Daiichi-Sankyo. KN reports none. SF reports lecture fees from Takeda, Ono, AstraZeneca, Novo Nordisk, MSD, Daiichi-Sankyo, Kyowa Hakko Kirin, Eli Lilly, Kowa, Astellas, Sumitomo Dainippon Pharma, Asahi Kasei Pharma, and Nippon Boehringer Ingelheim; endowments from Takeda, Sanofi, Sumitomo Dainippon Pharma, MSD, Ono, Mitsubishi Tanabe Pharma, Eli Lilly, Novo Nordisk, Shionogi, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Taisho Pharma, and Daiichi-Sankyo. MF reports none. KS reports lecture fees from Ono, Novartis, MSD, Astellas, Mitsubishi Tanabe Pharma, AstraZeneca, Sanofi Aventis, Novo Nordisk, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Daiichi-Sankyo, and Eli Lilly; manuscript fees from Johnson & Johnson and Kyowa Hakko Kirin; consulting fees from Daiichi-Sankyo; grants from Eli Lilly and Mitsubishi Tanabe Pharma; endowments from Takeda, Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, MSD, Astellas, Novartis, Ono, Sanofi Aventis, and Chugai. YO reports lecture fees from Takeda, MSD, Eli Lilly, Novartis, Sumitomo Dainippon Pharma, Sanofi, Daiichi-Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk, Kissei, Boehringer Ingelheim, AstraZeneca, Astellas, Mitsubishi Tanabe Pharma, Kowa, Bayer, and Ono; grants from Mitsubishi Tanabe Pharma and Kowa. EA reports lecture fees from Takeda, Arkray, Astellas, AstraZeneca, Abbott Japan, Alcon, MSD, Ono, Kyowa Kikaku, Kyowa Hakko Kirin, Kissei, Kowa, Kowa Pharmaceutical, Sanofi, Sanwa Kagaku, Shionogi, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Taisho Pharmaceutical, Sumitomo Dainippon Pharma, Chugai, Terumo, Eli Lilly, Fujifilm Pharma, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, Bayer, Pfizer, Medical Review, Medtronic Japan, and MedScape; manuscript fees from Yodosha, Fuji Medical Publishing, and Life science Co; endowments from Takeda, Astellas, MSD, Ono, Kissei, Kyowa Hakko Kirin, Kowa, Sanofi, Shionogi, Taisho Pharmaceutical, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Terumo, Eli Lilly, Nippon Boehringer Ingelheim, Novartis, Novo Nordisk, and Mochida. TY reports lecture fees from Takeda, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, AstraZeneca, Shionogi, and Sumitomo Dainippon Pharma. TK reports lecture fees from Takeda, Astellas, AstraZeneca, MSD, Ono, Eli Lilly, Nippon Boehringer Ingelheim, Novo Nordisk, Mitsubishi Tanabe Pharma, Sanofi, Novartis, Sanwa Kagaku Kenkyusho, Medtronic Japan, Sumitomo Dainippon Pharma, Kyowa Hakko Kirin, Abbott Japan, MedScape Education, Daiichi-Sankyo, and Taisho Pharmaceutical; manuscript fees from Takeda; grants from Takeda, Daiichi-Sankyo, AstraZeneca, Nippon Boehringer Ingelheim, and Eli Lilly; endowments from Takeda, Sumitomo Dainippon Pharma, Astellas, Taisho Pharma, Kyowa Hakko Kirin, Kissei, Novo Nordisk, Sanofi, Ono, Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Kowa Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Terumo, and Asahi Mutual Life Insurance Company.

Figures

Figure 1
Figure 1
Patient disposition. #Patients were excluded if no visits post-baseline. DPP, dipeptidyl peptidase; GLP-1, glucagon-like peptide-1.
Figure 2
Figure 2
Kaplan-Meier analysis of major adverse events. (A) Symptomatic hypoglycemia, (B) skin disorders of non-extrinsic origin, (C) severe infections, and (D) cancer. Between-group comparisons were performed by log-rank test. Numbers (N) under each time point denote patients at risk.
Figure 3
Figure 3
Over-time changes of efficacy endpoints. HbA1c (A), fasting glucose (B), fasting insulin (C), and urinary albumin (D) were determined at baseline and following visits. Changes of these parameters from baseline (mean±SD) were plotted against each visit. Note the patients were excluded from the analysis if they received insulin products and/or GLP-1 or related formulations (group A), and received insulin products, GLP-1 or related formulations, and/or DPP-4 inhibitors (group B). Between-group difference was examined at each visit by two-sample t-test, giving significant p values only for HbA1c as ***p<0.001, ***p<0.001, ***p<0.001, **p=0.001, *p=0.026, and *p=0.027, respectively. Also note that mean HbA1c was 7.58% in group A patients and 7.86% in group B patients at baseline with significant difference (p<0.001 by 2-sample t-test; table 1). DPP, dipeptidyl peptidase; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c.
See this image and copyright information in PMC

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