胰高血糖素样肽-1受体激动剂可减少酒精摄入量，但二肽基肽酶-4抑制剂则不能。
Glucagon-like peptide-1 receptor agonists, but not dipeptidyl peptidase-4 inhibitors, reduce alcohol intake.
作者信息
Farokhnia Mehdi, Tazare John, Pince Claire L, Bruns Nicolaus, Gray Joshua C, Lo Re Vincent, Fiellin David A, Kranzler Henry R, Koob George F, Justice Amy C, Vendruscolo Leandro F, Rentsch Christopher T, Leggio Lorenzo
机构信息
Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
出版信息
J Clin Invest. 2025 Mar 6;135(9). doi: 10.1172/JCI188314. eCollection 2025 May 1.
BACKGROUNDDespite growing preclinical evidence that glucagon-like peptide1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown.METHODSWe conducted a large cohort study using 2008-2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score-matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of 2 DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake.RESULTSGLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 0.68,1.33], P < 0.0001). There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSIONConvergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDINGThis work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.
背景
尽管临床前证据越来越多地表明胰高血糖素样肽1受体激动剂（GLP-1RAs）可用于治疗酒精使用障碍（AUD），但临床证据却很少。此外，二肽基肽酶-4抑制剂（DPP-4Is）对酒精摄入量的潜在影响在很大程度上尚不清楚。
方法
我们利用美国退伍军人事务部2008 - 2023年的电子健康记录数据进行了一项大型队列研究。在倾向得分匹配的GLP-1RA接受者、DPP-4I接受者和未暴露的对照者之间比较了酒精使用障碍识别测试-消费量（AUDIT-C）评分的变化。我们进一步测试了两种DPP-4Is（利格列汀和奥格列汀）对小鼠暴饮样饮酒以及对酒精依赖大鼠操作性口服酒精自我给药的影响，之前曾用这些模型证明GLP-1RA司美格鲁肽在减少酒精摄入量方面有显著效果。
结果
GLP-1RA接受者报告的AUDIT-C评分下降幅度大于未暴露个体（差异差值[DiD]：0.09[95%置信区间：0.03, 0.14]，P = 0.0025）和DPP-4I接受者（DiD：0.11[95%置信区间：0.05, 0.17]，P = 0.0002）。在基线患有AUD的个体中饮酒量的减少更为明显（GLP-1RA与未暴露个体相比：0.51[95%置信区间：0.29, 0.72]，P < 0.0001；GLP-1RA与DPP-4I相比：0.65[95%置信区间：0.43, 0.88]，P < 0.0001）以及基线有危险饮酒行为的个体中（GLP-1RA与未暴露个体相比：1.38[95%置信区间：1.07, 1.69]，P < 0.0001；GLP-1RA与DPP-4I相比：1.00[95%置信区间：0.68, 1.33]，P < 0.0001）。DPP-4I接受者和未暴露个体之间没有差异。后一结果通过反向转化方法得到了证实。具体而言，利格列汀和奥格列汀均未减少小鼠或大鼠的酒精摄入量。啮齿动物实验也证实了靶点参与，因为两种DPP-4Is均降低了血糖水平。
结论
在人类、小鼠和大鼠中得出的一致结果表明，GLP-1RAs可减少酒精消费，而DPP-4Is则不能，并且GLP-1RAs可能对治疗AUD有效。
资助
这项工作得到了美国国立卫生研究院内部研究项目（ZIA DA000635、ZIA DA000644、ZIA DA000602）、国立酒精滥用与酒精中毒研究所外部资助（R01 AA030041、P01 AA029545、U01 AA026224、U24 AA020794、U01 AA020790、U10 AA013566）、美国退伍军人事务部（I01BX004820）以及阿尔克姆斯通路研究奖的支持。
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