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C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study

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Abstract

Purpose

Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events.

Methods

This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality.

Results

Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint.

Conclusion

Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment.

Trial Registration

ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749

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Data Availability

The data underlying this article cannot be shared publicly because the privacy of the individuals who participated in the study must be protected. The data will be shared upon reasonable request to the corresponding author.

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Acknowledgements

We acknowledge the support and assistance of all participating hospitals and patients. We also thank Maki Takami for secretarial assistance.

Funding

The FREED was funded by a grant from Teijin Pharma Ltd. to the Kumamoto Circulation Society according to a support contract. The sponsor was not involved in the planning, implementation, analysis, or interpretation of study results. The first author, corresponding author, and academic statistician had full access to the trial databases and generated trial analyses, prepared the first draft of the manuscript, and decided to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Sakurajyuji Yatsushiro Rehabilitation Hospital, 2-4-33 Honmachi, Yatsushiro, 866-0861, Japan

    Sunao Kojima

  2. Uchiyama Clinic, 1161-1 Shita-machi, Yoshikawa-ku, Joetsu, 949-3443, Japan

    Kazuaki Uchiyama

  3. Yokota Naika, 642-1 Komuta, Miyazaki, Hanagashima-cho, 880-0036, Japan

    Naoto Yokota

  4. Tokutake Iin, 2-28-1 Asahi, Kawaguchi, 332-0001, Japan

    Eiichi Tokutake

  5. Wakasa Medical Clinic, 3-16-25 Sainen, Kanazawa, 920-0024, Japan

    Yutaka Wakasa

  6. Hiramitsu Heart Clinic, 2-35 Shiroshita-cho, Minami-ku, Nagoya, 457-0047, Japan

    Shinya Hiramitsu

  7. Shizuoka City Shizuoka Hospital, 10-93 Ote-machi, Shizuoka, Aoi-ku, 420-8630, Japan

    Masako Waki

  8. Jinnouchi Hospital Diabetes Care Center, 6-2-3 Kuhonji, Kumamoto, Chuo-ku, 862-0976, Japan

    Hideaki Jinnouchi

  9. Kakuda Iin, Na 15-1, Takamatsu, Kahoku, 929-1215, Japan

    Hirokazu Kakuda

  10. Hayashi Medical Clinic, 5-22 Nakamozu-cho, Sakai, Kita-ku, 591-8023, Japan

    Takahiro Hayashi

  11. Kawai Naika Clinic, 4-32 Kanazono-cho, Gifu, 500-8113, Japan

    Naoki Kawai

  12. Sugawara Clinic, 3-9-16 Shakujii-machi, Nerima-ku, 177-0041, Japan

    Masahiro Sugawara

  13. Fuji Health Promotion Center, 392-5 Yunoki, Fuji, 416-0908, Japan

    Hisao Mori

  14. Department of Cardiovascular Medicine, Kumamoto University, 1-1-1 Honjo, Kumamoto, Chuo-ku, 860-8556, Japan

    Kenichi Tsujita

  15. Department of Family, Community, and General Medicine, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, Chuo-ku, 860-8556, Japan

    Kunihiko Matsui

  16. Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, 86 Nishi-machi, Yonago, 683-8503, Japan

    Ichiro Hisatome

  17. Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine 207 Uehara, Okinawa, Nishihara-cho, 903-0215, Japan

    Yusuke Ohya

  18. Division of Cardiology, Yokohama City University Medical Center, 4-57 Urafune-cho, Yokohama, Minami-ku, 232-0024, Japan

    Kazuo Kimura

  19. Department of Cardiovascular Medicine, Nara Medical University, 840 Shijyo-cho, Kashihara, 634-8522, Japan

    Yoshihiko Saito

  20. Kumamoto University, 2-39-1 Kurokami, Kumamoto, Chuo-ku, 860-8555, Japan

    Hisao Ogawa

Authors
  1. Sunao Kojima
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  2. Kazuaki Uchiyama
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  3. Naoto Yokota
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  4. Eiichi Tokutake
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  5. Yutaka Wakasa
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  6. Shinya Hiramitsu
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  7. Masako Waki
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  8. Hideaki Jinnouchi
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  9. Hirokazu Kakuda
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  10. Takahiro Hayashi
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  11. Naoki Kawai
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  12. Masahiro Sugawara
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  13. Hisao Mori
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  14. Kenichi Tsujita
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  15. Kunihiko Matsui
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  16. Ichiro Hisatome
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  17. Yusuke Ohya
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  18. Kazuo Kimura
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  19. Yoshihiko Saito
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  20. Hisao Ogawa
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Consortia

on behalf of the Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) investigators

Contributions

Conceptualization, data curation, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing–original draft, writing–review, and editing: S.K.

Investigation, review, and editing: K.U., N.Y., E.T., Y.W., S.H., M.W., H.J., H.K., T.H., N.K., M.S., and H.M.

Project administration, resources, writing (review and editing): K.T.

Conceptualization, formal analysis, methodology, software, validation, review, and editing: K.M.

Conceptualization, investigation, supervision, validation, visualization, reviewing, and editing: I.H., Y.O., K.K., and Y.S.

Conceptualization, funding acquisition, investigation, methodology, supervision, validation, visualization, review, and editing: H.O.

Corresponding author

Correspondence to Sunao Kojima.

Ethics declarations

Ethical Approval

FREED was a multicenter, prospective, randomized, open-label, blinded endpoint, two-arm parallel treatment group study conducted as an investigator-initiated study following the principles of the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour, and Welfare in Japan. The FREED protocol was reviewed by the central institutional review board before approval by the institutional review board of each participating study site, and all the patients registered with the FREED provided written informed consent. The FREED is registered at ClinicalTrial.gov (identification number: NCT01984749).

Consent to Participate

All the patients registered with the FREED provided written informed consent. In this post-hoc analysis, 1070 patients from the FREED were analyzed, and the requirement for informed consent was waived.

Conflicts of Interest

S.K. reports personal fees from Teijin Healthcare, limited, personal fees from Teijin Pharma and Otsuka Pharmaceutical Co., Ltd., personal fees from Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Novartis K.K., and grants from Grants-in-Aid for Scientific Research (21K07356) of the Japan Society for the Promotion of Science outside the submitted work. K.T. reports and has received remuneration for lectures at Amgen K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc., trust research/joint research funds from AMI Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., and Mochida Pharmaceutical Co., Ltd., scholarship funds from AMI Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd., and affiliations with endowed departments from Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., Nipro Corporation, Terumo Co., Ltd., Abbott Medical Co., Ltd., Boston Scientific Japan K.K., Cardinal Health Japan, Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., and Medtronic Japan Co., Ltd. outside the submitted work. I.H. reports grants and personal fees from Sanwa Kagaku Kenkyusho Co., Ltd., Fuji Yakuhin Co., Ltd., personal fees from Pfizer Co., Ltd., and grants from Dainippon Sumitomo Pharma Co., Ltd., and Teijin Pharma outside the submitted work. K.K. reports grants from Teijin Pharma and personal fees from Tanabe Mitsubishi outside the submitted work. Y.S. reports grants from MEXT KAKENHI (grant number JP19155855), Health Labour Sciences Research (grant number 19189094), Health Labour Sciences Research (grant number 17933459), AMED (grant numbers JP19ek0210080, JP19ek0210118, JP19ek0210121, JP19ek0210115, JP19ek0109367, JP19ek0109406, and JP19km0405009), Takeda Pharmaceutical Co., Ltd., Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics Co., Ltd., and Fuji Yakuhin Co., Ltd. during the study, grants and personal fees from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Kowa Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and Pfizer Japan Inc., grants, personal fees, and other from Novartis Pharma K.K. and Bayer Yakuhin, Ltd., other from Amgen Astellas BioPharma K.K., Actelion Pharmaceuticals Japan Ltd., and Roche Diagnostics K.K., personal fees from Alnylam Japan K.K., AstraZeneca K.K., Tsumura & Co., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Mochida Pharmaceutical Co., Ltd. outside the submitted work. H.O. reports personal fees from Towa Pharmaceutical and Novartis Pharma outside the submitted work.

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Kojima, S., Uchiyama, K., Yokota, N. et al. C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study. Cardiovasc Drugs Ther 37, 965–974 (2023). https://doi.org/10.1007/s10557-022-07347-7

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