药学学报

Disease	PPI drug	Mechanism of action	Potential risk	Clinical medication recommendation
Obesity, metabolic syndrome	Rabeprazole, omeprazole	Inhibits appetite hormone and promotes polarization of M2 macrophages	Osteoporosis (long-term high doses)	Avoid conjugating PPI (clopidogrel) with CYP2C19 substrates
T2DM	Pantoprazole, omeprazole	Increased gastrin secretion promotes β-cell proliferation and enhances the effect of metformin	Increased risk of T2DM and CKD	Combination with metformin requires monitoring of blood concentrations
NAFLD, hepatic fibrosis	Esomeprazol, lansoprazole	Inhibiting pro-inflammatory factors and activating the antioxidant pathway Nrf2	Hepatic encephalopathy (intestinal flora imbalance)	Avoid concomitant NSAIDs
Gout, hyperuricemia	Lansoprazole	Gastrointestinal protection	Uric acid excretion disorder	Monitor blood uric acid levels
Osteoporosis	Most PPI	PHOSPHO1 enzyme inhibition, osteoclast activation	Increased risk of fracture	Supplement calcium and vitamin D, and undergo regular bone density screening

Disease	PPI drug	Mechanism of action	Potential risk	Clinical medication recommendation
Obesity, metabolic syndrome	Rabeprazole, omeprazole	Inhibits appetite hormone and promotes polarization of M2 macrophages	Osteoporosis (long-term high doses)	Avoid conjugating PPI (clopidogrel) with CYP2C19 substrates
T2DM	Pantoprazole, omeprazole	Increased gastrin secretion promotes β-cell proliferation and enhances the effect of metformin	Increased risk of T2DM and CKD	Combination with metformin requires monitoring of blood concentrations
NAFLD, hepatic fibrosis	Esomeprazol, lansoprazole	Inhibiting pro-inflammatory factors and activating the antioxidant pathway Nrf2	Hepatic encephalopathy (intestinal flora imbalance)	Avoid concomitant NSAIDs
Gout, hyperuricemia	Lansoprazole	Gastrointestinal protection	Uric acid excretion disorder	Monitor blood uric acid levels
Osteoporosis	Most PPI	PHOSPHO1 enzyme inhibition, osteoclast activation	Increased risk of fracture	Supplement calcium and vitamin D, and undergo regular bone density screening

质子泵抑制剂在代谢性疾病中的最新应用进展

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王雨晴 ¹ , 王国成 ¹^,^* , 王宝莲 ²

药学学报 | 综述 2026,61(2): 349-355

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药学学报 |综述 2026 , 61 (2) : 349 -355

质子泵抑制剂在代谢性疾病中的最新应用进展

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王雨晴¹, 王国成¹^,^*, 王宝莲²

作者信息

¹内蒙古医科大学药学院, 内蒙古呼和浩特 010110

²中国医学科学院北京协和医学院, 药物研究所, 北京 100050

通讯作者:

王国成, E-mail: 8662384@qq.com

作者简介:

作者贡献:

王雨晴进行综述文献的资料搜集及撰写; 王宝莲、王国成提供学术指导。

Recent advances in the use of proton pump inhibitors in metabolic diseases

Yu-qing WANG¹, Guo-cheng WANG¹^,^*, Bao-lian WANG²

Affiliations

¹School of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, China

²Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-0549

文章导航

摘要

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质子泵抑制剂(proton pump inhibitors, PPI) 作为抑制胃酸、治疗消化系统疾病的一线药物, 近年来研究发现其对代谢性疾病的调控具有多途径影响, 在代谢性疾病防治中治疗潜力与风险并存。研究表明, PPI能通过降低食欲相关激素水平、改善胰岛素敏感性、降低肝细胞脂肪堆积和参与纤维化进程等多重调控机制, 参与肥胖、2型糖尿病(type 2 diabetes mellitus, T2DM) 及非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 的病理生理过程。然而长期使用存在电解质紊乱、肠道菌群失调、骨质疏松、骨折风险升高及患心血管疾病风险增加等潜在风险。临床应用需基于患者个体化特征精准制定用药方案, 避免无指征长期用药, 并密切监测相关风险。

关键词

质子泵抑制剂 / 代谢性疾病 / 肥胖 / 2型糖尿病 / 非酒精性脂肪性肝病 / 应用及风险

Abstract

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As first-line drugs for inhibiting gastric acid and treating digestive system diseases, proton pump inhibitors (PPI) have been found in recent studies to have multi-pathway effects on the regulation of metabolic diseases. There are both therapeutic potentials and risks in the prevention and treatment of metabolic diseases. Studies have indicated that PPI participate in the pathophysiological processes of obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) through multiple regulatory mechanisms, including reducing levels of appetite-related hormones, improving insulin sensitivity, decreasing hepatic fat accumulation, and modulating fibrotic progression. However, long-term use of PPI has potential risks, including electrolyte disorders, intestinal flora imbalance, osteoporosis, increased risk of fractures, and increased risk of cardiovascular diseases. In clinical application, the medication regimen should be precisely formulated based on the individual characteristics of patients, long-term use without indications should be avoided, and relevant risks should be closely monitored.

Key words

proton pump inhibitor / metabolic disease / obesity / type 2 diabetes mellitus / non-alcoholic fatty liver disease / application and risk

引用本文

王雨晴, 王国成, 王宝莲. 质子泵抑制剂在代谢性疾病中的最新应用进展. 药学学报, 2026 , 61 (2) : 349 -355 . DOI: 10.16438/j.0513-4870.2025-0549

Yu-qing WANG, Guo-cheng WANG, Bao-lian WANG. Recent advances in the use of proton pump inhibitors in metabolic diseases[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 349 -355 . DOI: 10.16438/j.0513-4870.2025-0549

正文

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质子泵抑制剂(proton pump inhibitors, PPI) 是通过选择性抑制H⁺/K⁺-ATP酶活性来减少胃酸分泌的药物, 自20世纪80年代上市以来, 就已成为胃食管反流病、消化性溃疡、根除幽门螺旋杆菌等消化系统疾病治疗的一线药物, 其代表药物有奥美拉唑、兰索拉唑、泮托拉唑和雷贝拉唑等^[1]。因其显著的抑酸效果及良好的安全性, 在全球范围内广泛使用。然而, 随着PPI在临床的广泛使用, 其长期使用存在的潜在风险引发关注, 包括骨折、肠道菌群失调和艰难梭菌感染等^{[2, 3]}。

代谢性疾病是由代谢紊乱引起的一种疾病, 包括肥胖、2型糖尿病(type 2 diabetes mellitus, T2DM)、非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 和高血压等, 具有高发病率和高死亡率的特点。近年来, 肥胖、T2DM和NAFLD的患病率逐年升高, 不仅严重威胁公众健康, 也带来沉重的经济负担^[4]。尽管胰高血糖素样肽-1 (glucagon-like peptide-1, GLP-1) 受体激动剂、钠-葡萄糖协同转运蛋白2 (sodium-dependent glucose transporters 2, SGLT-2) 抑制剂等药物在部分代谢性疾病的治疗中显示出一定疗效, 但仍存在个体治疗反应差异大、心血管并发症风险未完全消除等问题^[5]。因此, 面对这一系列的代谢性疾病相关问题, 寻找安全有效的药物和手段进行预防和治疗已成为当前代谢性疾病防治领域的研究热点。

值得关注的是, PPI除抑酸作用外, 其对代谢调控的影响被逐渐揭示。越来越多的研究表明, PPI可能通过降低食欲相关激素水平、改善胰岛素敏感性、调控脂肪细胞分化及肝纤维化进程等多途径, 参与肥胖、T2DM及NAFLD等代谢性疾病的病理生理过程。

1　PPI概述

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临床常用PPI如奥美拉唑、兰索拉唑、泮托拉唑等核心化学结构均为苯并咪唑环, 可穿过壁细胞胞膜, 蓄积于强酸性分泌小管中, 转化为次磺酰胺类化合物, 与H⁺/K⁺-ATP酶α亚基半胱氨酸残基的巯基形成共价二硫键, 使该酶失活, 从而抑制胃酸分泌^[6]。PPI是一种药物前体, 它的代谢需要经过肝脏进行生物转化, 其主要由CYP2C19和CYP3A4介导, 每种PPI的代谢在特定细胞色素450同工酶的特征和程度方面不同。不同PPI的代谢特征存在差异: 苯并咪唑类如奥美拉唑和兰索拉唑, 主要经CYP2C19代谢, 个体差异显著, 快代谢型患者疗效减弱, 且CYP2C19变异对其代谢的影响为奥美拉唑和埃索美拉唑 > 泮托拉唑 > 兰索拉唑 > 雷贝拉唑^{[7, 8]}; 其次是吡啶类, 主要经CYP3A4酶代谢, 药物相互作用较少, 如泮托拉唑在临床上适用于合并用药的患者^[9]; 最后是亚砜类, 主要以非酶代谢途径为主, 起效快且作用持久, 如雷贝拉唑是肝硬化患者的首选药物^[10]。

2　PPI在代谢性疾病中的研究应用

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2.1　肥胖与代谢综合征

代谢综合征是多种代谢异常情况在个体内聚集的一种临床症候群, 主要涉及中心性肥胖、血糖异常、血压升高、血脂紊乱等。代谢综合征能增加多种代谢性疾病的发病风险, 如心血管疾病、T2DM等慢性病。肥胖作为核心病理因素, 通过诱导代谢失调促使多种代谢性疾病发生^[11]。

PPI在肥胖和代谢综合征的治疗中展现出多途径调节潜力。奥美拉唑与GLP-1受体激动剂联合应用, 能降低胃促生长素和瘦素等食欲相关激素水平, 进而抑制食欲并减少能量的摄入, 同时能减少恶心等不良反应的发生^{[12, 13]}; 兰索拉唑对于脂肪细胞的分化呈浓度依赖性, 低浓度促进健康脂肪细胞增殖, 改善胰岛素敏感性, 高浓度抑制其分化^{[7, 9]}; 雷贝拉唑能减少脂肪组织中的M1型巨噬细胞浸润, 增加M2型比例, 改善葡萄糖耐量和胰岛素敏感性, 减轻肝脏脂肪堆积和炎症损伤, 对肥胖相关代谢紊乱的保护作用^[10], 因其代谢稳定、药物相互作用少, 成为肥胖患者尤其是合并代谢综合征或需长期用药者的首选^[14]; 腹腔镜袖状胃切除术后, 奥美拉唑持续微泵输注能显著提升胃内pH值, 缩短胃肠道症状的持续时间, 适用于需长期控制胃酸分泌的肥胖术后患者^{[15, 16]}。潜在风险方面, 长期高剂量使用依赖CYP2C19代谢的PPI可能会增加感染和骨质疏松的风险^{[12, 14]}; 泮托拉唑在孕期暴露, 可能通过内分泌干扰机制诱导胎儿脂肪细胞发育异常, 增加成年后肥胖易感性^[17]。综上, PPI在肥胖及代谢综合征治疗中具多途径协同潜力, 但要注意用药方案, 以平衡疗效与安全性。

2.2　T2DM

T2DM是胰岛素抵抗、胰腺β细胞功能逐渐丧失及代谢异常所导致的一种疾病。目前用于治疗T2DM的药物有双胍类、磺脲类、胰岛素、GLP-1受体激动剂、DPP-4抑制剂和PPAR-γ受体激动剂等^{[18, 19]}。研究发现, PPI对糖尿病也有一定影响, 且与糖尿病的影响呈双向作用, 既有潜在的治疗效果, 也存在一定的风险。

在治疗方面, PPI通过抑制胃酸分泌升高胃泌素的水平, 胃泌素通过激活CCK-B受体, 诱导胰腺导管细胞向β细胞分化, 促进胰岛素分泌。如泮托拉唑可通过此方式增强胰岛素的分泌, 改善血糖控制^[20]; 奥美拉唑与GLP-1激动剂联合治疗可能通过胃泌素介导的β细胞修复或新生, 增加胰岛素储备, 并通过提升葡萄糖激酶活性, 优化β细胞对葡萄糖的响应能力, 从而改善胰岛素分泌和血糖稳态^{[13, 21]}。PPI还可通过增强胰岛素的敏感性而维持血糖的稳态。雷贝拉唑能减少小鼠体内脂肪和肝脏中促炎反应的M1型巨噬细胞, 促进抗炎反应的M2型巨噬细胞极化, 减轻炎症, 改善葡萄糖耐量和胰岛素敏感性^[10]。大多数的PPI (奥美拉唑、泮托拉唑、兰索拉唑、雷贝拉唑) 对于二甲双胍的降糖作用具有促进作用, 通过抑制有机阳离子转运蛋白, 减少二甲双胍在肝脏和肾脏的排泄, 使其血药浓度升高, 增强其降糖效果, 同时具有改善脂质代谢、抑制氧化应激等器官保护作用^[22]。在潜在风险方面, 长期高剂量使用PPI与T2DM的风险呈剂量相关性^[23]; 系统评价和荟萃分析显示PPI的使用显著增加患有T2DM的风险^[24]; 在糖尿病患者中, 高剂量的PPI使慢性肾病(chronic kidney disease, CKD) 风险增加, 尤其是埃索美拉唑和兰索拉唑, 可能与电解质紊乱、急性肾损伤、间质肾炎等机制有关^[25-27]。其作用机制主要涉及胃泌素介导的β细胞保护、抗炎抗氧化反应, 以及胆汁酸代谢紊乱和肠道菌群失调等。

2.3　代谢性肝脏疾病

代谢性肝脏疾病由代谢紊乱直接或间接引起的肝脏结构和功能损害, 代谢性肝病的自然病程通常分为以下阶段: 肝细胞内脂肪沉积引起单纯性脂肪变性, 又称脂肪肝; 脂肪堆积基础上出现炎性浸润、肝细胞损伤的脂肪性肝炎; 持续炎症激活肝星状细胞, 细胞外基质沉积, 形成纤维间隔导致肝纤维化; 广泛纤维化导致肝结构结节样重塑, 功能丧失形成肝硬化, 可能还会引发肝衰竭、肝性脑病等并发症; 肝硬化、持续炎症及遗传变异最终导致肝癌^[28]。

PPI与肝脏疾病的关系同样兼具治疗潜力与潜在风险。在治疗方面, 埃索美拉唑能通过清除自由基、抑制炎性级联反应、抑制肝细胞凋亡、促进肝组织修复调控纤维化进程, 显著改善大鼠肝纤维化, 效果与经典的保肝药物水飞蓟素效果相当^[29]; 奥美拉唑通过抑制SREBP-1c减少肝内脂肪的合成, 下调促炎、促凋亡因子, 上调抗凋亡因子, 抑制肝星状细胞活化和细胞外基质沉积, 与螺旋藻联合应用在改善大鼠非酒精性脂肪性肝炎展现协同作用^[30]; 兰索拉唑能通过上调Nrf2蛋白的表达, 下调TGF-β、IL-6等因子表达, 显著延缓大鼠肝纤维化进展^[7], 且发现兰索拉唑对于脂肪细胞的分化具有双向调节依赖浓度, 高浓度抑制脂肪细胞分化, 减少脂肪堆积^[9]; 雷贝拉唑可通过激活ATP6V1A依赖的巨胞饮作用, 促进细胞外囊泡(extracellular vesicles, EVs) 内化, 减少致病性EVs的远端效应, 同时增强治疗性EVs的递送效率, 减轻肝损伤和代谢紊乱^[31]。在潜在风险方面, 长期使用PPI会导致口腔来源菌群富集和固有肠道菌群减少, 促进细菌易位和内毒素血症^[32], 增加肝硬化患者患肝性脑病和自发性细菌性腹膜炎风险^[33]; 全国性队列研究表明, PPI的使用剂量与患脂肪肝的风险呈剂量依赖性, 可能通过肠-肝轴促进肝脏脂肪堆积和炎症^[34]; 与非甾体抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs) 联合应用会协同加重肠道菌群失调和肠道通透性损伤, 进一步诱导肝脏氧化应激和纤维化, 加重NAFLD^[35]。

2.4　痛风和高尿酸血症

痛风和高尿酸血症也是常见的代谢性疾病, 尿酸代谢紊乱导致血尿酸水平升高是其核心的病理机制。目前, 临床对于痛风和高尿酸血症治疗的主要药物有黄嘌呤氧化酶抑制剂、尿酸排泄促进剂、NSAIDs和糖皮质激素等, 但上述药物均存在不同程度的不良反应^[36]。尤其NSAIDs会有胃肠道的不良反应, PPI在该治疗领域主要发挥胃肠道保护功能, 其临床应用呈现双向作用的特征。

一位78岁男性因痛风服用吲哚美辛后, 食管裂孔疝合并Cameron病变出现上消化道大出血, 治疗中使用PPI来抑制胃酸, 最终缓解出血。因此, 当痛风患者合并消化性溃疡出血或存在胃肠道高风险时, PPI与NSAIDs或糖皮质激素的联合使用可显著提升治疗安全性^[37]。此外, PPI药物可能通过肾脏H⁺-K⁺-ATP酶抑制尿酸排泄通路, 导致肾小管尿酸重吸收增加^[38]; 通过诱导胰岛素抵抗影响嘌呤代谢关键酶活性; 还可能通过干扰胃黏膜ATP代谢间接引发尿酸生成底物的异常堆积。基于以上研究证据, 对于需长期使用PPI的高尿酸血症或痛风患者, 优先选择兰索拉唑; 对于存在代谢综合征、胰岛素抵抗或糖脂代谢异常的患者, 应避免长期使用奥美拉唑、泮托拉唑等PPI药物, 可能会加剧代谢紊乱。用药期间需定期监测血尿酸水平及肾功能, 以评估PPI使用的必要性^{[39, 40]}。

2.5　其他代谢相关影响

PPI在代谢性疾病治疗中具有明确的临床价值。短期内使用PPI可通过调节肠道菌群、改善胰岛素敏感性等机制产生显著代谢获益。然而其长期用药安全也值得关注, 长期用药可导致电解质紊乱、维生素缺乏等代谢异常, 甚至诱发骨质疏松和心血管疾病等与代谢紊乱密切相关的疾病, 不仅可能影响其初始的治疗效果, 还可能因为代谢紊乱而加剧原有的代谢性疾病^[6]。

2.5.1　电解质与营养失衡

PPI通过抑制胃壁细胞H⁺/K⁺-ATP酶活性减少胃酸的分泌, 长期用药可能会损伤胃黏膜, 导致多种电解质和维生素吸收障碍造成紊乱。胃肠内pH升高会降低钙、镁离子的溶解度, 影响其吸收^[41]; 同时, PPI诱导的肠道微生物群改变也可能减少利于钙、镁离子吸收的酸性环境^[42]。病例报告结果显示, 长期使用PPI的患者出现反复低镁血症, 停药之后患者体内镁水平恢复正常^[43]。低镁血症会抑制肾小管钾通道, 导致钾排泄增加, 引发顽固性低血钾^[44]。

维生素B₁₂吸收主要依赖于胃酸、内因子(intrinsic factor, IF) 和小肠功能, 食物中的维生素B₁₂主要与蛋白质结合, 而胃蛋白酶原被胃酸转化为胃蛋白酶, 从而从食物蛋白质中释放维生素B₁₂, 游离的维生素B₁₂与胃壁细胞分泌的IF结合形成稳定的复合物在回肠末端被吸收^[45]。PPI通过抑制胃壁细胞H⁺/K⁺-ATP酶, 减少胃酸分泌, 阻碍胃蛋白酶释放食物蛋白结合的维生素B₁₂, 导致其无法与IF结合, 最终影响回肠吸收。不仅如此, 长期使用PPI会诱发或加重胃黏膜萎缩, 进一步损伤胃壁细胞减少IF的分泌^[46], 加剧维生素B₁₂的吸收障碍, 尤其在幽门螺旋杆菌患者中更显著^[47]。低胃酸环境诱导的肠道微生物群改变, 还可能减少促进营养物质吸收的微生物代谢产物、损伤肠黏膜的细胞功能, 进一步影响电解质和维生素的摄取^[48]。

荟萃分析及回顾性研究均表明, PPI能使体内铁离子、镁离子水平降低, 同时对于使用PPI的心律失常患者, PPI可能通过降低血清镁离子水平, 增加尖端扭转型心律失常的发生风险。建议医师在用药前先评估患者是否合并其他疾病或状态, 再决定PPI的使用剂量及使用时长^[49-51]。

2.5.2　骨质疏松与骨折风险

长期使用PPI会对骨骼造成一定的损伤, 尤其在长期使用和高剂量使用的人群中, 脊柱、髋部和手腕等部位的骨折风险会显著升高^[42]。针对肝硬化老年患者的研究显示, 骨折的风险与PPI呈剂量依赖性, 且老年患者长期使用PPI可能会延缓骨折修复^[52]。

PPI药物会抑制骨骼特异性磷酸酶PHOSPHO1的活性, 该酶抑制后会导致骨矿化缺陷, 降低骨机械强度, 其中以奥美拉唑抑制作用较显著, 提示PPI的使用可能会抑制PHOSPHO1的活性, 从而导致易骨折, 基于此临床上可选用对PHOSPHO1活性抑制作用最小的PPI药物作为脆性骨折风险高的患者的首选药^[53]。此外, 奥美拉唑还能通过上调破骨基因的表达促进破骨细胞活化和促进钙释放到循环中来增加骨吸收, 从而导致骨密度下降, 严重会引发骨质疏松等疾病^[54]。兰索拉唑则通过IP3R/SOCE通路诱导成骨细胞钙过载, 导致内质网应激和细胞凋亡, 减少成骨细胞数量而导致骨质疏松症^[55]。长期使用PPI会导致胃泌素水平升高, 胃泌素可刺激破骨细胞的分化; 同时, 药物诱导的矿物质缺乏, 尤其是钙、镁离子及维生素的缺乏, 会引发继发性甲状旁腺功能亢进, 促进骨溶解和骨基质蛋白合成, 降低骨密度^[41], 雷贝拉唑可使钙代谢紊乱和增强破骨细胞活性导致雌性小鼠的骨质减少, 且奥美拉唑和雷贝拉唑会使甲状旁腺激素升高促使骨钙释放, 长期会导致骨丢失^[56]。

有研究对长期应用PPI的患者和健康人群及髋骨/股骨骨折患者和无骨折患者进行对比分析, 发现长期使用PPI会导致成骨活动降低, 破骨活动增加, 使患者骨密度丢失, 提高髋关节及腰椎骨质疏松的发病率。所以尤其在老年患者用药时, 要注意用药剂量及用药时长, 且服药期间需密切观察患者的多种表征, 做好用药安全性的评估及不良反应的及时处理^{[8, 49, 51]}。

2.5.3　心血管疾病风险

PPI对心血管代谢的影响涉及多重机制。首先是对于内皮功能的损伤, PPI能抑制二甲基精氨酸二甲氨基水解酶(dimethylarginine dimethylaminohydrolase, DDAH), 升高血浆中的不对称二甲基精氨酸(asymmetrical dimethylarginine, ADMA), 从而抑制一氧化氮合成, 导致血管收缩进而促进动脉粥样硬化和血栓的形成^{[57, 58]}。其次是药物代谢方面, PPI与抗血小板药物氯吡格雷长期使用通过抑制CYP2C19酶的活性, 减少抗血小板药物的代谢活性产物, 增加血栓形成的风险, 尤其在携带CYP2C19功能丧失等位基因的患者中, 心肌梗死和血栓风险显著增加^{[57, 59]}。此外, 长期使用PPI导致的电解质紊乱和营养失衡会协同加剧血管损伤^[58]。比如PPI引发的低钙血症, 会加剧血管的平滑肌收缩; 引发的低镁血症, 可能会诱发心律失常; PPI降低维生素B₁₂和维生素C的吸收, 维生素B₁₂缺乏影响同型半胱氨酸的代谢, 增加动脉粥样硬化的风险; 维生素C作为抗氧化剂, 其吸收减少可加重体内氧化应激反应, 缺乏时进一步加剧内皮血管的损伤^[46]。

研究显示, 对于年龄较大的绝经后妇女, 长时间使用PPI会增加其患有原发性心血管疾病的风险; 一项瑞典的全国队列研究发现, 经皮冠状动脉干预后的PPI和氯吡格雷使用, 会增加发生重大心血管事件的风险; 系统评价和荟萃分析进一步证实, PPI的使用与心肌梗死及总体心血管疾病发生率增加相关。综上, 对高龄且存在心血管基础疾病的患者, PPI使用需严格评估获益风险比, 必要时应选用替代治疗方案^{[60, 61]}。

2.5.4　非代谢性疾病风险

长期使用PPI除了代谢性相关的不良反应外, 首先可使维生素B₁₂缺乏导致同型半胱氨酸水平升高, 还会改变肠道菌群组成, 通过“肠-脑轴”诱发神经炎症, 干扰β-淀粉样蛋白清除, 促进认知功能下降, 从而增加阿尔茨海默病的发病率; 其次可导致胃酸缺乏, 削弱胃内抗菌屏障, 反馈性刺激胃泌素分泌, 持续高胃泌素血症可促进胃黏膜细胞增殖, 继而引发腺体萎缩、肠上皮化生和增加幽门螺旋杆菌的感染风险; 动物研究表明, 孕期暴露于泮托拉唑可能通过干扰胎儿脂肪细胞分化, 增加成年后肥胖易感性, 此外PPI还可能影响甲状腺激素代谢, 长期使用与亚临床甲状腺功能减退风险轻度升高相关, 还引发过敏反应及皮肤病变等不良反应^{[50, 62]}。

3　总结与展望

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PPI作为抑制胃酸分泌的药物, 在代谢性疾病防治中的治疗潜力和风险并存。PPI能通过抑制食欲相关激素水平减少能量的摄入、改善脂肪细胞的分化和胰岛素敏感性、升高胃泌素介导β细胞修复或新生以增强胰岛素分泌, 还能通过抗炎、抗氧化机制减少肝脏的脂肪堆积和肝脏纤维化进程, PPI可与GLP-1受体激动剂、二甲双胍等联用产生协同增效作用。另一方面, 其在治疗时带来的潜在风险也不容忽视, 长期使用可引起钙、镁等离子的电解质紊乱及维生素B₁₂的吸收障碍、肠道菌群失调、骨代谢异常所导致骨质疏松和骨折风险升高, 甚至能通过影响药物代谢酶而增加心血管疾病的风险。表1是对PPI在代谢性疾病中的应用进行总结。

目前对于PPI的研究多停留在临床用药效果上, 对其治疗代谢性疾病的作用机制研究不充分, 未来研究应聚焦其在代谢调控中的多向作用, 通过机制解析、联合干预及新药开发, 实现从“经验性使用”到“靶向性代谢调节”的转型, 为肥胖、糖尿病、脂肪肝等高发代谢性疾病提供更安全有效的治疗选择。

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2026年第61卷第2期

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doi: 10.16438/j.0513-4870.2025-0549

接收时间：2025-04-22
首发时间：2026-09-21
出版时间：2026-02-12

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收稿日期：2025-04-22
修回日期：2025-07-30

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¹内蒙古医科大学药学院, 内蒙古呼和浩特 010110

²中国医学科学院北京协和医学院, 药物研究所, 北京 100050

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王国成, E-mail: 8662384@qq.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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