Gastro-Hepatoloy Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Viruses. 2023 Dec 17;15(12):2451. doi: 10.3390/v15122451.
Patients with chronic hepatitis C (CHC) and concomitant type 2 diabetes mellitus (DM) show a higher risk of developing hepatocellular carcinoma (HCC). Successful antiviral therapy has reduced the incidence of post-therapy HCC, but the presence of DM still represents an unfavourable predictive factor even in cured patients. Metformin (MET) is recommended as a first-line therapy for DM, and its use is associated with a significant reduction in HCC among diabetic patients with chronic liver disease of different etiology, but very few studies specifically address this issue in patients with CHC.
the aim of this review is to evaluate whether the use of MET induces a significant decrease in HCC in diabetic patients with CHC, treated or untreated with antiviral therapy.
A search of PubMed, Medline, Web of Sciences and Embase was conducted for publications evaluating the role of MET in reducing the risk of HCC in patients with DM and CHC, with no language and study type restrictions up to 30 June 2023. Only studies fulfilling the following inclusion criteria were considered: (1) data on the incidence of HCC in the follow-up of diabetic patients with CHC only; (2) follow-up ≥24 months; (3) sufficient data to establish the rate of diabetic patients with CHC treated with metformin or other antidiabetic medications; and (4) data on the type of antiviral treatment and the clinical outcome.
Three studies met the inclusion criteria. A prospective cohort study considering only patients with DM and untreated advanced CHC, or non-responders to interferon (IFN) therapy, showed that the use of MET was associated with a significant decrease in HCC incidence, liver-related death and liver transplants. A recent retrospective study focusing on a large-scale nationwide cohort of patients with CHC in Taiwan successfully treated with IFN-based therapy stratified patients into 3 groups: non-MET users, MET users and non-diabetic patients, with 5-year cumulative rates of HCC of 10.9%, 2.6% and 3.0%, respectively, showing a significantly higher HCC risk in non-MET users compared with MET users and with non-diabetic patients, while it was not significantly different between MET users and non-diabetic patients. In a recent Italian cohort study focusing on 7007 patients with CHC treated and cured with direct-acting antiviral agents (DAAs), a combined effect of DM and MET therapy was found, showing a higher incidence of HCC in diabetic patients not taking MET compared with those without DM and those with DM taking MET.
according to the current evidence, the use of MET should be encouraged in diabetic patients with CHC in order to reduce the risk of HCC; however, a well-designed randomized controlled trial is needed to establish the generalizability of the beneficial effects of MET in this particular subset of patients.
患有慢性丙型肝炎（CHC）和 2 型糖尿病（DM）的患者发生肝细胞癌（HCC）的风险更高。成功的抗病毒治疗降低了治疗后 HCC 的发生率，但 DM 的存在即使在已治愈的患者中仍然是一个不利的预测因素。二甲双胍（MET）被推荐作为 DM 的一线治疗药物，其使用与不同病因慢性肝病的糖尿病患者 HCC 发生率的显著降低相关，但很少有研究专门针对 CHC 患者。
本综述的目的是评估 MET 的使用是否会降低接受或未接受抗病毒治疗的 CHC 合并 DM 患者的 HCC 发生率。
对 PubMed、Medline、Web of Sciences 和 Embase 进行了检索，以查找评估 MET 在降低 DM 合并 CHC 患者 HCC 风险中的作用的出版物，截至 2023 年 6 月 30 日，没有语言和研究类型的限制。仅考虑符合以下纳入标准的研究：（1）仅评估 CHC 合并 DM 患者随访期间 HCC 发生率的数据；（2）随访时间≥24 个月；（3）有足够的数据确定接受 MET 或其他抗糖尿病药物治疗的 CHC 合并 DM 患者的比例；（4）有关于抗病毒治疗类型和临床结局的数据。
三项研究符合纳入标准。一项仅考虑 DM 且未接受 ADV 治疗的晚期 CHC 或 IFN 治疗无应答患者的前瞻性队列研究表明，MET 的使用与 HCC 发生率、肝相关死亡和肝移植的显著降低相关。最近一项针对台湾接受 IFN 为基础治疗的大规模全国性 CHC 患者队列的回顾性研究将患者分为 3 组：非 MET 用户、MET 用户和非糖尿病患者，5 年 HCC 累积发生率分别为 10.9%、2.6%和 3.0%，非 MET 用户 HCC 风险显著高于 MET 用户和非糖尿病患者，而 MET 用户与非糖尿病患者之间无显著差异。在最近的一项意大利队列研究中，研究人员关注了 7007 例接受直接作用抗病毒药物（DAAs）治疗并治愈的 CHC 患者，结果发现 DM 和 MET 联合治疗存在协同作用，与无 DM 且不服用 MET 的患者和有 DM 且服用 MET 的患者相比，不服用 MET 的糖尿病患者 HCC 发生率更高。
根据目前的证据，应鼓励 CHC 合并 DM 患者使用 MET，以降低 HCC 风险；然而，需要进行一项精心设计的随机对照试验，以确定 MET 在这一特定患者亚组中的有益效果的普遍性。
