A spotlight on using HIF-PH inhibitors in renal anemia

ABSTRACT

Introduction

Erythropoiesis-stimulating agents (ESAs) together with iron supplementation had been the standard treatment for anemia in chronic kidney disease (CKD) for the past decades. Recently, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have attracted attention as a novel treatment option.

Areas covered

This review summarizes the effectiveness and the safety of HIF-PHIs based on previous clinical trials and discusses points to consider for their clinical use.

Expert opinion

The results from clinical trials demonstrate that HIF-PHIs are non-inferior to ESAs in terms of the efficacy to maintain or improve blood hemoglobin levels. However, concerns about adverse events including cardiovascular outcomes, thrombotic events, and tumor progression have prevented HIF-PHIs from being widely approved for clinical use. Also, long-term safety has not been demonstrated yet. Practically, HIF-PHIs should be used with caution in patients with a history of thrombosis or active malignancy. Patients without them may be preferable for HIF-PHIs if those are bothered with regular injections of ESAs or are hyporesponsive to ESAs without obvious reasons, provided that the drugs were approved in the country. Even so, clinicians must take caution for signs of adverse events such as heart failure after prescribing the drugs.

KEYWORDS:

• Hypoxia-inducible factor-prolyl hydroxylase inhibitors
• erythropoiesis-stimulating agents
• chronic kidney disease
• anemia
• dialysis

Article highlights

• The efficacy of HIF-PHIs in the treatment of anemia has been demonstrated in many clinical trials.

• Some safety concerns regarding HIF-PHIs including increased risk of cardiovascular and thromboembolic events as well as long-term adverse effects remain.

• Approval of HIF-PHIs has been controversial among nations, especially for patients not on dialysis.

• It is generally recommended that patients with a history of malignancy or thrombotic events avoid the use of HIF-PHIs or be prescribed with extreme caution.

• Patients without the abovementioned history and with good adherence may benefit from HIF-PHIs due to its oral administration route, or those who are hyporesponsive to ESAs despite appropriate dose and evaluation for the cause.

Declaration of interest

H Nishi received honoraria from Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly and Company, Kowa, Kyowa Kirin, MSD, Ono, Tanabe Mitsubishi, and Torii and research grant from Bayer, Boehringer Ingelheim, Kyowa Kirin, Novo Nordisk, and Tanabe Mitsubishi. M Nangaku received honoraria and advisory fees from Kyowa-Kirin, Astellas, Astra Zeneca, GSK, Daiichi-Sankyo, Tanabe-Mitsubishi, Chugai, Torii, Japan Tobacco, Novo Nordisk, Boehringer Ingelheim and research funding from Kyowa-Kirin, Daiichi-Sankyo, Astellas, Ono, Tanabe-Mitsubishi, Japan Tobacco, Chugai, Bayer, Torii, Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed being a former consultant and on the speakers bureau for roxadustat and daprodustat. They are a current consultant for vadadustat. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.