Zahn Laura A, Budine Taylor D, Shirey-Rice Jana K, Joly Meghan M, Wallis Robert S, Bernard Gordon R, Holroyd Kenneth J, Pulley Jill M, Jerome Rebecca N
Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States.
Aurum Institute, Johannesburg, South Africa.
Front Pharmacol. 2025 Aug 13;16:1562587. doi: 10.3389/fphar.2025.1562587. eCollection 2025.
There are many diseases prevalent around the globe that lack accessible and safe treatment options. Through Vanderbilt University Medical Center's and Repurposing Essential Medicines Internationally program (Project Remedi), we aim to identify novel therapeutic uses for medications already approved and on the World Health Organization's (WHO) Essential Medicines List (EML). We explored additional uses for simvastatin, an oral 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that is on the EML and may have additional therapeutic use outside of hypercholesterolemia.
We conducted a phenome wide association study (PheWAS) of a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene single nucleotide polymorphism (SNP) Ile638Val in 35,000 patient samples to identify novel uses for simvastatin. We then assessed biologic rationale and existing clinical evidence base related to novel phenotypes for simvastatin use for key PheWAS results.
PheWAS of HMGCR variants identified a novel signal related to ovarian disease, in addition to a validating signal related to lipid dysfunction. Review of the literature substantiated involvement of HMG-CoA reductase signaling in hormone synthesis and posited involvement of dysfunction in this pathway in the development of polycystic ovary syndrome (PCOS). Synthesis of the literature regarding use of statins supported the role of these agents in improvement of symptoms and quality of life in women affected by PCOS who are not pregnant or trying to conceive, with a safety profile similar to this agent's use in hyperlipidemia.
Given the evidence supporting safety and efficacy of simvastatin for PCOS management, the widespread availability on the EML and affordability worldwide, simvastatin is a promising therapeutic avenue for PCOS. A large-scale efficacy trial would be valuable in further substantiating this use. Repurposing simvastatin, a widely available medicine, can provide clinicians and patients with an additional strategy for PCOS, especially in areas where medical care is limited.
全球有许多流行疾病缺乏可及且安全的治疗选择。通过范德比尔特大学医学中心和国际基本药物重新利用项目（Remedi项目），我们旨在确定已获批准且列入世界卫生组织（WHO）基本药物清单（EML）的药物的新治疗用途。我们探索了辛伐他汀的其他用途，辛伐他汀是一种口服的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，已列入EML，可能在高胆固醇血症之外还有其他治疗用途。
我们对35000份患者样本中的3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）基因单核苷酸多态性（SNP）Ile638Val进行了全表型关联研究（PheWAS），以确定辛伐他汀的新用途。然后，我们评估了与辛伐他汀用于关键PheWAS结果的新表型相关的生物学原理和现有临床证据基础。
HMGCR变体的PheWAS除了发现一个与脂质功能障碍相关的验证信号外，还发现了一个与卵巢疾病相关的新信号。文献综述证实HMG-CoA还原酶信号传导参与激素合成，并推测该途径功能障碍参与多囊卵巢综合征（PCOS）的发展。关于他汀类药物使用的文献综合表明，这些药物在改善未怀孕或未试图怀孕的PCOS女性的症状和生活质量方面发挥作用，其安全性与该药物用于高脂血症时相似。
鉴于有证据支持辛伐他汀用于管理PCOS的安全性和有效性，其在EML上广泛可得且在全球范围内价格可承受，辛伐他汀是治疗PCOS的一个有前景的治疗途径。大规模疗效试验对于进一步证实这种用途将很有价值。重新利用广泛可得的药物辛伐他汀可为临床医生和患者提供治疗PCOS的额外策略，尤其是在医疗资源有限的地区。
