超越疗效：肠促胰岛素和多受体激动剂的治疗生命周期

文献信息

中文摘要

肠促胰岛素和多受体激动剂疗法在一代人中提供了任何药理学类别中最广泛的心血管代谢获益，在肥胖、2型糖尿病、心血管和肾脏结局、射血分数保留的心力衰竭、阻塞性睡眠呼吸暂停以及代谢功能障碍相关脂肪性肝炎方面均有 documented 获益。相当一部分心血管获益独立于体重。关键试验证据现已成熟，并扩展至专门的替尔泊肽心血管结局项目。然而，决定长期心血管和代谢获益的临床和系统层面过程，在很大程度上超出了这些试验所测量的疗效范围。在非糖尿病肥胖中，真实世界12个月持续用药率约为三分之一。停药主要由费用而非治疗失败主导。突然停止治疗后，体重和心血管代谢获益在数月内回落至基线。在停药后重新开始治疗的成人中，周期性使用已成为常见的真实世界模式。我们的综述提出了一个生命周期框架，将证据沿着患者旅程组织，从起始治疗到剂量滴定、治疗中轨迹、不良事件全景、持续用药、停药和重新开始治疗。替尔泊肽作为分析的重心；选择性GLP-1受体激动剂文献作为成熟的对照。提出了七个分析立场，并指定了五项具体试验设计作为该领域所需的研究议程，其中四项仍未得到解决。未来的工作是将试验、处方路径和准入系统与该类药物作为慢性药物治疗的现实相协调。

英文摘要

Incretin and multi-receptor agonist therapies have delivered the widest range of cardiometabolic benefit of any pharmacological class in a generation, with documented benefit across obesity, type 2 diabetes, cardiovascular and renal outcomes, heart failure with preserved ejection fraction, obstructive sleep apnea, and metabolic-dysfunction-associated steatohepatitis. A substantial fraction of the cardiovascular benefit is weight independent. The pivotal trial evidence is now mature, extending to the dedicated tirzepatide cardiovascular outcome program. The clinical and system-level processes that govern long-term cardiovascular and metabolic benefit, however, lie largely outside the efficacy envelope that these trials measure. Real-world persistence is approximately one-third at 12 months in non-diabetic obesity. Discontinuation is dominated by cost rather than therapeutic failure. Weight and cardiometabolic gains revert toward baseline within months of abrupt cessation. Cyclical use has emerged as a common real-world pattern among adults who discontinue and then restart therapy. Our review proposes a lifecycle framework that organizes the evidence along the patient journey from initiation through titration, on-treatment trajectory, adverse-event landscape, persistence, discontinuation, and reinitiation. Tirzepatide serves as the analytical center of gravity; the selective GLP-1 receptor agonist literature serves as the mature comparator. Seven analytical positions are advanced, and five specific trial designs are named as the research agenda the field requires, four of which remain unaddressed. The work ahead is to align trials, prescribing pathways, and access systems with the chronic-pharmacotherapy reality of the class.