GLP-1受体激动剂与代谢功能障碍相关脂肪肝疾病患者发展为肝硬化及相关并发症的风险

代谢功能障碍相关脂肪肝疾病（MASLD）正逐渐成为肝硬化的主要原因。胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1 RAs）在改善MASLD患者的肝脏炎症方面显示出有效性。旨在确定使用GLP-1 RAs是否与降低MASLD患者发展为肝硬化及其并发症（包括失代偿和肝细胞癌，HCC）的风险相关。本回顾性队列研究采用主动比较、新启动者设计，利用国家退伍军人健康管理局企业数据仓库及中央癌症登记处的数据。纳入对象为2006年1月1日至2022年6月30日期间在130个退伍军人医疗中心及相关门诊诊所就诊、同时启动GLP-1 RAs或二肽酰肽酶-4抑制剂（DPP-4i）的糖尿病伴MASLD患者。从基线开始追踪，直至出现研究结局或研究截止（2022年12月31日），以先到者为准。每位GLP-1 RAs新用户采用倾向评分匹配1:1，与同期启动DPP-4i的患者匹配。在未患肝硬化与已患肝硬化的患者中分别进行分析。未患肝硬化者的主要结局为发展为肝硬化（由验证的诊断编码或非侵入性肝纤维化标志物定义），次要结局包括肝硬化相关并发症（总体及具体，包括失代偿、HCC或肝移植）和全因死亡。肝硬化患者的主要结局为肝硬化并发症的复合指标，次要结局为失代偿、HCC及全因死亡。共有16,058名患者启动GLP-1 RAs，其中14,606名未患肝硬化（平均年龄60.56±10.31岁；男性89.1%），1452名患肝硬化（平均年龄66.99±7.09岁；男性93.7%），均与相应数量启动DPP-4i的患者匹配。在未患肝硬化者中，GLP-1 RAs的使用与较低的肝硬化风险相关（每千人年事件数：9.98 vs 11.10；风险比[HR]为0.86，95% CI：0.75-0.98）。次要结局亦显示类似趋势。GLP-1 RAs的使用与较低的肝硬化并发症（1.89 vs 2.55）及死亡风险（21.77 vs 24.43）相关（HR=0.78和0.89，95% CI：0.59-1.04和0.81-0.98）。在已患肝硬化者中未观察到明显关联。本研究发现，GLP-1 RAs在糖尿病伴MASLD患者中，与肝硬化进展及死亡风险降低相关，该保护作用在已有肝硬化的患者中不明显，强调了早期治疗的重要性。

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective in improving liver inflammation in patients with MASLD.To determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD.This retrospective cohort study with an active comparator, new-user design used data from the national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry. Patients with MASLD and diabetes who were seen at 130 Veterans Health Administration hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between January 1, 2006, and June 30, 2022, were included. Patients were followed up from baseline until one of the study outcomes or the end of the study period (December 31, 2022), whichever came first.Each GLP-1 RA new user was propensity score matched in 1:1 ratio to a patient who initiated a DPP-4i during the same month. Separate analyses were conducted among patients without and with cirrhosis at baseline.For patients without cirrhosis, the primary outcome was progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, and secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality.Of 16 058 patients who initiated GLP-1 RAs, 14 606 did not have cirrhosis (mean [SD] age, 60.56 [10.31] years; 13 015 [89.1%] male), and 1452 had cirrhosis (mean [SD] age, 66.99 [7.09] years; 1360 [93.7%] male) at baseline. These patients were matched to an equal number of patients who initiated a DPP-4i. In patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). Similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of the composite outcome of cirrhosis complications (1.89 vs 2.55 events per 1000 person-years; HR, 0.78; 95% CI, 0.59-1.04) and mortality (21.77 vs 24.43 events per 1000 person-years; HR, 0.89; 95% CI, 0.81-0.98). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis.In this cohort study, GLP-1 RA use was associated with a lower risk of progression to cirrhosis and mortality among patients with MASLD and diabetes. The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.