貧血是慢性腎臟病常見且影響住院和死亡率的共病，發生主因為紅血球生成素 (erythropoietin, EPO) 不足，過去治療除了輸血外，亦會補充紅血球生成刺激劑(erythropoiesis stimulating agent, ESA)，ESA 屬基因重組的紅血球生成素，需要注射給予，且使用ESA 仍存在風險，包括增加死亡和心血管事件發生率。但相較於輸血，施打ESA 帶來的疾病社會負擔較小。西元2019 年，諾貝爾生理醫學獎得主發現缺氧誘導因子 (hypoxia-inducible factor, HIF) 影響基因轉錄的分子理論，使得EPO 不足的貧血治療有了新轉機，缺氧誘導因子脯氨醯羥化酶抑制劑 (hypoxia-inducible factor prolyl hydroxylase inhibitor, HIF-PHI) 可穩定HIF 活性，使得人體在沒有缺氧情況，也可促進紅血球生成、抑制鐵調素分泌及增加鐵質運用，以藥理學角度，此機轉可改善EPO 不足的貧血。本文回顧6 個目前已有三期臨床試驗的HIF-PHI，含desidustat, daprodustat, molidustat, enarodustat, vadadustat 和roxadustat，各自療效和安全性有不同特點，根據網絡統合分析，desidustat 在透析和非透析患者中皆顯示有最佳的血紅素改變量。但目前文獻大多屬臨床試驗，無可避免的篩選和執行偏差可能會使藥品上市後的療效和安全性不如預期，長期副作用亦需更多觀察性研究來驗證。慢性腎臟病及透析在國人中盛行率較高，共病帶來的負擔需加以重視。新藥上市或許能為病患帶來福祉，但也需謹慎評估風險和長期效果，以確保整體社會經濟的效益。
Anemia is a common comorbidity in chronic kidney disease (CKD) and significantly affects hospitalization rates and mortality. The primary cause is insufficient erythropoietin (EPO) production. In the past, treatment options included blood transfusions and the administration of erythropoiesis-stimulating agents (ESA), which are recombinant forms of EPO. However, ESA use carries risks, including increased mortality and cardiovascular events. Nonetheless, compared to blood transfusions, the societal burden of ESA treatment is lower. In 2019, the Nobel Prize in Physiology or Medicine recognized the discovery of the molecular mechanism of hypoxiainducible factor (HIF), which regulates gene transcription. This discovery has paved the way for new approaches to treating EPO-deficient anemia. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) can stabilize HIF activity, promoting erythropoiesis, suppressing hepcidin secretion, and enhancing iron utilization, even under non-hypoxic conditions. From a pharmacological perspective, this mechanism has the potential to address anemia causes by insufficient EPO. This review discusses six HIF-PHIs that have completed phase III clinical trials: desidustat, daprodustat, molidustat, enarodustat, vadadustat, and roxadustat, each with distinct efficacy and safety profiles. According to network meta-analyses, desidustat demonstrated the most significant improvement in hemoglobin levels in both dialysis and non-dialysis patients. However, as most of the current data are from clinical trials, inevitable selection and performance biases may lead to real-world outcome differing from clinical expectations. Long-term side effects also require further observational studies for validation. With CKD and dialysis being highly prevalent in Taiwanese population, the burden of comorbidities shouldn’t be overlooked. While the introduction of new drugs may benefit patients, a cautious assessment of their risks and long-term effects is essential to ensure overall socioeconomic benefits.
Submitted for publication: 2023.12.26; Accepted for publication: 2024.6.25
