Abstract：
Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
摘要：
代谢功能障碍相关的脂肪变性肝病（MASLD）与肥胖和2型糖尿病密切相关。通过改善组织学结果和降低合并症的风险，生活方式干预和减肥手术旨在大幅减轻体重是MASLD治疗的基石。最初是作为抗高血糖药物开发的，肠促胰岛素（co-）激动剂和SGLT2抑制剂也可以减少脂肪变性和心血管事件。某些肠促胰岛素激动剂可有效改善MASLD的组织学特征，但不是纤维化。值得注意的是，对MASLD的有益效果不一定需要减肥。尽管体重增加适度，在事后分析中,一种PPARγ激动剂改善脂肪组织和MASLD,对纤维化有一定益处.同样，由于MASLD和纤维化的显著改善,第一种THRβ激动剂最近获得临时批准.我们在这里讨论不同的MASLD治疗诱导的肝脏相关和代谢作用及其与体重减轻的关联。因此,我们比较了通过减肥作用的药物的临床试验结果(肠促胰岛素(共)激动剂，SGLT2抑制剂）与那些没有体重减轻的人（吡格列酮；雷美替罗姆）。此外，其他正在开发中的直接靶向肝脂质代谢的药物(脂肪生成抑制剂，FGF21类似物）。尽管THRβ激动作用可有效改善肝脏预后，MASLD治疗概念应考虑所有心脏代谢危险因素，以有效降低受影响人群的发病率和死亡率。
