Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas.
Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas.
JAMA Intern Med. 2024 Nov 1;184(11):1314-1323. doi: 10.1001/jamainternmed.2024.4661.
IMPORTANCE: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.
重要性:代谢功能相关脂肪性肝病(MASLD)是肝硬化的一个日益增加的原因。胰高血糖素样肽 1 受体激动剂(GLP-1 RAs)在改善 MASLD 患者的肝脏炎症方面非常有效。 目的:确定 GLP-1 RAs 的使用是否与 MASLD 患者发生肝硬化及其并发症(包括失代偿和肝细胞癌[HCC])的风险降低相关,这些并发症包括代偿失调和肝细胞癌。 设计、地点和参与者:这是一项回顾性队列研究,采用了活性对照物的新使用者设计,使用了来自国家退伍军人健康管理局公司数据仓库和中央癌症登记处的数据。纳入了在 130 家退伍军人健康管理局医院及其附属门诊就诊的 MASLD 和糖尿病患者,这些患者在 2006 年 1 月 1 日至 2022 年 6 月 30 日期间开始使用 GLP-1 RA 或二肽基肽酶 4 抑制剂(DPP-4i)。从基线开始随访,直到出现研究结果之一或研究期间结束(2022 年 12 月 31 日),以先发生者为准。 暴露:每个 GLP-1 RA 新使用者都按比例与同月开始使用 DPP-4i 的患者进行 1:1 匹配。在基线时没有和有肝硬化的患者中分别进行了单独的分析。 主要结果和测量:对于没有肝硬化的患者,主要结局是通过验证性诊断代码或非侵入性肝纤维化标志物定义的进展为肝硬化,次要结局是肝硬化并发症的复合和个别并发症,包括失代偿、HCC 或肝移植,以及全因死亡率。对于有肝硬化的患者,主要结局是肝硬化并发症的复合结局,次要结局是失代偿、HCC 和全因死亡率。 结果:在 16058 名开始使用 GLP-1 RAs 的患者中,有 14606 名患者没有肝硬化(平均[标准差]年龄,60.56[10.31]岁;13015[89.1%]名男性),1452 名患者有肝硬化(平均[标准差]年龄,66.99[7.09]岁;1360[93.7%]名男性)。这些患者与同等数量的开始使用 DPP-4i 的患者进行了匹配。在没有肝硬化的患者中,与使用 DPP-4i 相比,GLP-1 RA 的使用与较低的肝硬化风险相关(每 1000 人年 9.98 与 11.10 例;风险比[HR],0.86;95%CI,0.75-0.98)。次要结局也出现了类似的结果。与使用 DPP-4i 相比,GLP-1 RA 的使用与肝硬化并发症的复合结局(每 1000 人年 1.89 与 2.55 例;HR,0.78;95%CI,0.59-1.04)和死亡率(每 1000 人年 21.77 与 24.43 例;HR,0.89;95%CI,0.81-0.98)的风险降低相关。在有肝硬化的患者中,GLP-1 RA 的使用与结局之间没有关联。 结论和相关性:在这项队列研究中,GLP-1 RA 的使用与 MASLD 和糖尿病患者发生肝硬化和死亡率降低相关。在存在肝硬化的患者中没有观察到这种保护作用,这突出了在疾病早期进行治疗的重要性。
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