Risk of liver dysfunction with ACE inhibitors based on real-world data from the MID-NET® in Japan

Yuki Kinoshita; Takashi Ando; Kazuhiro Kajiyama; Hotaka Maruyama; Mei Kohama; Ayumi Tanaka; Yusuke Matsunaga; Chieko Ishiguro; Takahiro Nonaka; Naoya Horiuchi; Taihei Tanaka; Yoshiaki Uyama

doi:10.1038/s41440-025-02390-x

Risk of liver dysfunction with ACE inhibitors based on real-world data from the MID-NET^® in Japan

Hypertens Res. 2025 Oct 10. doi: 10.1038/s41440-025-02390-x. Online ahead of print.

Authors

Yuki Kinoshita^#^{1

2}, Takashi Ando^#^{1

2}, Kazuhiro Kajiyama^{1

2

3}, Hotaka Maruyama^{1

2}, Mei Kohama^{2

4}, Ayumi Tanaka¹, Yusuke Matsunaga¹, Chieko Ishiguro^{2

5}, Takahiro Nonaka^{2

6}, Naoya Horiuchi¹, Taihei Tanaka¹, Yoshiaki Uyama^{7

8}

Affiliations

¹ Office of Pharmacovigilance I, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
² Office of Medical Informatics and Epidemiology, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
³ Office of Regulatory Science Research, Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
⁴ Office of Pharmacovigilance Ⅱ, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
⁵ Section of Clinical Epidemiology, Department of Data Science, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
⁶ Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Office of Medical Informatics and Epidemiology, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan. uyama-yoshiaki@pmda.go.jp.
⁸ Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan. uyama-yoshiaki@pmda.go.jp.

^# Contributed equally.

PMID: 41073682
DOI: 10.1038/s41440-025-02390-x

Abstract

Warnings about liver dysfunction in Japanese package inserts vary among angiotensin-converting enzyme (ACE) inhibitors, and risk assessment of liver dysfunction with ACE inhibitors has been limited. To evaluate the risk of liver dysfunction among patients prescribed ACE inhibitors available in Japan, we conducted this study based on the real-world data from MID-NET^®. We identified patients who were newly prescribed ACE inhibitors between January 1, 2009 and December 31, 2019 and excluded patients with liver dysfunction before the first prescription of ACE inhibitors. To compare the risk of liver dysfunction between the control group (enalapril maleate) and each exposure group, a pairwise Cox proportional hazards model was employed to estimate the hazard ratio (HR) adjusted by inverse probability weighting based on the high-dimensional propensity score. A total of 29,817 patients were identified for analysis in the cohort. Compared with the control group, the HRs (95% confidence interval) were 1.37(0.79-2.38) for captopril, 0.71(0.33-1.54) for alacepril, 0.72(0.55-0.93) for imidapril hydrochloride, 1.08(0.86-1.34) for perindopril erbumine, and 0.69(0.52-0.91) for lisinopril hydrate. The risk of liver dysfunction with ACE inhibitors is unlikely to be a class-effect. Although continuous safety monitoring is necessary for promoting proper use of ACE inhibitors, the results indicate that no additional safety measures are currently required for ACE inhibitors that do not carry a liver dysfunction-related warning in Japan.

Keywords: Angiotensin-converting enzyme inhibitors; Hypertension; Liver dysfunction; Pharmacoepidemiology; Safety measure.