GLP-1药物先驱，权威期刊全面总结司美格鲁肽等药物减重降糖外的健康益处

Core Viewpoint - GLP-1 drugs, initially developed for blood sugar and weight control, have shown potential in treating various chronic diseases, including cardiovascular diseases, chronic kidney disease, fatty liver, arthritis, and sleep apnea, with benefits stemming from their anti-inflammatory and metabolic regulatory mechanisms, some of which are independent of weight loss [2]. Group 1: Multiple Efficacies of Modern GLP-1 Drugs - Modern GLP-1 receptor agonists, such as liraglutide, dulaglutide, semaglutide, and dual agonists like tirzepatide, were initially used for type 2 diabetes (T2D) treatment, promoting insulin secretion and appetite suppression [3]. - Liraglutide, semaglutide, and tirzepatide are now approved for treating obesity or overweight individuals with at least one related disease [3]. Group 2: Broad Benefits Beyond Glycemic Control and Weight Loss - GLP-1 drugs significantly reduce the risk of chronic kidney disease (CKD), myocardial infarction, stroke, and cardiovascular mortality, particularly in patients with obesity and/or T2D [5]. Group 3: Cardiovascular and Renal Protective Effects - In 2024, semaglutide became the first FDA-approved drug for weight loss that also reduces cardiovascular event risks in non-T2D patients with obesity or overweight and cardiovascular disease risk [6]. - The SELECT trial showed that semaglutide reduced the incidence of major adverse cardiovascular events (MACE) by 20%, independent of weight loss [6]. - The FLOW trial indicated that semaglutide reduced significant adverse events related to kidney function deterioration by 24% over 3.4 years in T2D and CKD patients [6]. Group 4: Efficacy Against Metabolic Fatty Liver Disease - A 240-week phase 3 trial showed that 63% of patients with moderate to severe liver fibrosis achieved fatty liver inflammation resolution after 72 weeks of semaglutide treatment, with significant improvement in fibrosis compared to placebo [10]. Group 5: Improvements in Arthritis and Sleep Apnea - The STEP 9 trial demonstrated significant improvement in joint pain scores among participants with moderate knee osteoarthritis after 68 weeks of semaglutide treatment, with a weight loss of 13.7% [11]. - Tirzepatide was approved for treating moderate to severe obstructive sleep apnea (OSA) in 2024, showing significant reductions in apnea/hypopnea events [11]. Group 6: Efficacy in Peripheral Artery Disease - The STRIDE trial evaluated semaglutide's efficacy in T2D patients with intermittent claudication, showing significant improvement in maximum walking distance compared to placebo [12]. Group 7: Neuroprotective Potential and Inflammatory Mechanisms - Large clinical trials have found that GLP-1 drugs can reduce stroke risk, potentially through improved metabolism, central inflammation regulation, and enhanced vascular function [13]. - Ongoing trials are investigating the effects of oral semaglutide on early Alzheimer's disease, with results expected in 2025 [14]. Group 8: Potential Independent of Weight Loss - The therapeutic effects of GLP-1 drugs in various chronic diseases may not solely depend on weight loss, as they can significantly lower inflammatory markers independent of weight reduction [15]. - The anti-inflammatory mechanisms of GLP-1 drugs may involve direct action on GLP-1 receptor-positive cells and immune cells, indirect improvement of inflammation through weight loss and blood sugar control, and activation of specific neuronal populations in the central nervous system [15]. Group 9: Outlook and Future Directions - The benefits of GLP-1 drugs have expanded beyond glycemic control and weight loss to include multiple systemic diseases, with ongoing research exploring their effects on addiction, mental health, and neurodegenerative diseases [16]. - Future research should focus on ideal dosing in non-obese populations, potential use of lower doses in non-metabolic diseases, and identifying signaling pathways independent of weight loss [16].