持续低剂量司美格鲁肽或替尔泊肽患者的心脏代谢获益与耐受性比较

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中文摘要

司美格鲁肽和替尔泊肽通常通过剂量递增进行评估，但常规诊疗中的许多患者由于耐受性、可及性、费用、供应或个体化目标而未能达到推荐维持剂量。在此，我们使用仅重复0.25 mg司美格鲁肽和仅2.5 mg替尔泊肽的处方记录，作为持续使用最低批准剂量的真实世界替代指标，这种处方模式可能与有意微量给药重叠，但并不能确立有意微量给药。我们分析了来自覆盖2900万患者的联邦系统的去标识化电子健康记录（EHR）。在490 072例接受司美格鲁肽治疗的患者中，814例符合严格的持续低剂量标准，即至少有3张不同的0.25 mg处方，且从首张至末张合格处方跨度至少6个月；在322 442例接受替尔泊肽治疗的患者中，1016例符合类似标准，即至少有3张不同的2.5 mg处方且跨度至少6个月。在借助AI辅助临床笔记整理进行的匹配头对头比较中，持续低剂量替尔泊肽在24个月时显示出高于持续低剂量司美格鲁肽的不良事件发生率（P < .05），包括便秘（32.6% vs. 22.4%）、急性肾损伤（2.7% vs. 0.4%）、肌肉痉挛（8.3% vs. 4%）、腰椎间盘疾病（3.3% vs. 0.3%）、劳力性呼吸困难（9.6% vs. 6.8%）、雀斑样痣（4.7% vs. 0.8%）和光化性角化病（3.3% vs. 0.6%）；而持续低剂量司美格鲁肽（相对于替尔泊肽）的耳炎（5.6% vs. 2.1%）、多汗（5.5% vs. 3.2%）和踝部肿胀（6.9% vs. 3.7%）发生率更高。持续低剂量替尔泊肽与比司美格鲁肽更大的体重下降相关（12个月平均体重变化百分比 -5.5% vs. -2.2%；所有时间点P < .05）。处方模式分析支持了临床笔记的发现。例如，低剂量替尔泊肽后肾脏支持治疗和高钾血症治疗增加（12个月时从5.6%增至9.5%，P = .016），而低剂量司美格鲁肽后未增加（8.2%至6.6%，P = .382）。总之，这些观察性关联提示需要开展前瞻性研究，以更好地描述持续起始剂量司美格鲁肽或替尔泊肽的结局和药理学，以及相关的微量给药研究。

英文摘要

Semaglutide and tirzepatide are typically evaluated through dose escalation, yet many patients in routine care do not reach a recommended maintenance dose due to tolerability, access, cost, supply, or individualized goals. Here, we used repeated 0.25 mg only semaglutide and 2.5 mg only tirzepatide prescription records as real-world proxies for sustained treatment at the lowest approved dose, a prescribing pattern that may overlap with, but does not establish, intentional microdosing. We analyzed de-identified electronic health records (EHRs) from a federated system of 29 million patients. Among 490 072 semaglutide-treated patients, 814 met the stringent sustained low-dose criterion of at least three distinct 0.25-mg prescriptions spanning at least 6 months from the first to the last qualifying prescription and among 322 442 tirzepatide-treated patients, 1016 met the analogous criterion of at least three distinct 2.5-mg prescriptions spanning at least 6 months. In a matched head-to-head comparison aided by AI-enabled curation of clinical notes, sustained low-dose tirzepatide showed higher 24-month adverse event rates (P < .05) than sustained low-dose semaglutide for constipation (32.6% vs. 22.4%), acute kidney injury (2.7% vs. 0.4%), muscle cramps (8.3% vs. 4%), lumbar disc disease (3.3% vs. 0.3%), dyspnea on exertion (9.6% vs. 6.8%), lentigo (4.7% vs. 0.8%), and actinic keratosis (3.3% vs. 0.6%), whereas sustained low-dose semaglutide (vs. tirzepatide) had higher rates of including otitis (5.6% vs. 2.1%), diaphoresis (5.5% vs. 3.2%), and ankle swelling (6.9% vs. 3.7%). Sustained low-dose tirzepatide was associated with greater weight loss than semaglutide (mean 12-month percent weight change -5.5% vs. -2.2%; P < .05 at all timepoints). Analyses of prescription patterns supported the findings from clinical notes. For example, renal-supportive and hyperkalemia therapies increased after low-dose tirzepatide (5.6% to 9.5% at 12 months, P = .016) but not after low-dose semaglutide (8.2% to 6.6%, P = .382). Taken together, these observational associations motivate prospective studies to better characterize the outcomes and pharmacology of sustained initiation-dose semaglutide or tirzepatide, and related microdosing studies.