BackgroundClopidogrel is a cornerstone antiplatelet drug used in cardiovascular, cerebrovascular, and peripheral artery diseases. The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. Discontinuing clopidogrel and substituting it with ticagrelor has been revealed as an effective treatment in previous studies. Since hypoglycemia serves as a risk factor for cardiovascular and cerebrovascular events, we aimed to determine the association between hypoglycemia/IAS and clopidogrel and to investigate whether clopidogrel is a modifiable and causal risk factor of hypoglycemia/IAS.MethodsMEDLINE, Embase, Cochrane databases, and clinical trial registries were searched for randomized controlled trials (RCTs) of clopidogrel from inception to 28 February 2022. RCTs comparing clopidogrel with placebo or other antiplatelet drugs were eligible if meeting the inclusion criteria: 1) clopidogrel was administrated 75 mg qd orally as a long-term antiplatelet prescription at least for months, and 2) hypoglycemia-inducible drugs were not used in the control arm. One investigator abstracted articles and performed a quality assessment. Uncertainties were resolved by discussions with two investigators independently. Odds ratio (OR) and risk difference (RD) were calculated and performed with subgroup analyses. The pre-specified protocol was registered in PROSPERO (CRD42022299622).ResultsSix trials with 61,399 participants in total fulfilled the criteria and were included in the meta-analysis. Clopidogrel might not be associated with higher hypoglycemia odds (OR 0.95, 95% CI 0.65 to 1.40). However, Asian participants (p = 0.0437) seemed more likely to develop clopidogrel-associated hypoglycemia. Clopidogrel-associated hypoglycemia occurred at the highest rate of 0.03% (RD −0.00023, 95% CI −0.00077 to 0.00031), and this increased to 0.91% (RD 0.00210, 95% CI −0.00494 to 0.00914) in an aging population and to 0.18% (RD 0.00040, 95% CI −0.00096 to 0.00177) when Asian ratio of the population was elevated.ConclusionsWe raise the concern that clopidogrel might be a modifiable and causal risk factor of hypoglycemia. The Asian population might be more vulnerable and need additional care.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42022299622.

中文翻译：

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低血糖作为服用氯吡格雷患者的潜在风险：一项系统评价和荟萃分析

背景氯吡格雷是用于心血管、脑血管和外周动脉疾病的基石抗血小板药物。氯吡格雷代谢物的巯基可诱发以低血糖为主要症状的胰岛素自身免疫综合征（IAS）。之前的研究表明，停用氯吡格雷并用替卡格雷代替它是一种有效的治疗方法。由于低血糖是心血管和脑血管事件的危险因素，我们的目的是确定低血糖/IAS 和氯吡格雷之间的关联，并研究氯吡格雷是否是低血糖/IAS 的可改变和因果危险因素。MethodsMEDLINE、Embase、Cochrane 数据库和在临床试验注册库中搜索了从开始到 2022 年 2 月 28 日期间氯吡格雷的随机对照试验 (RCT)。比较氯吡格雷与安慰剂或其他抗血小板药物的随机对照试验符合纳入标准：1) 氯吡格雷作为长期抗血小板处方口服给药 75 mg qd 至少数月，以及 2) 在研究中未使用低血糖诱导药物控制臂。一名研究人员提取了文章并进行了质量评估。不确定性通过与两名研究者独立讨论来解决。优势比 (OR) 和风险差 (RD) 被计算并通过亚组分析进行。预先指定的方案已在 PROSPERO (CRD42022299622) 中注册。结果共有 61,399 名参与者的六项试验符合标准，并被纳入荟萃分析。氯吡格雷可能与较高的低血糖几率无关（OR 0.95，95% CI 0.65 至 1.40）。然而，亚洲参与者 (p = 0.0437) 似乎更有可能发生氯吡格雷相关的低血糖症。氯吡格雷相关的低血糖发生率最高，为 0.03%（RD −0.00023，95% CI −0.00077 至 0.00031），并且在老龄化人群中增加至 0.91%（RD 0.00210，95% CI −0.00494 至 0.00914），并且0.18%（RD 0.00040，95% CI -0.00096 至 0.00177）当亚洲人口比例升高时。结论我们担心氯吡格雷可能是低血糖的一个可改变的因果危险因素。亚洲人口可能更脆弱，需要额外的照顾。系统审查注册 95% CI −0.00494 至 0.00914）在人口老龄化中和 0.18%（RD 0.00040，95% CI −0.00096 至 0.00177）当亚洲人口比例升高时。结论我们担心氯吡格雷可能是一种可改变的因果风险低血糖的因素。亚洲人口可能更脆弱，需要额外的照顾。系统审查注册 95% CI −0.00494 至 0.00914）在人口老龄化中和 0.18%（RD 0.00040，95% CI −0.00096 至 0.00177）当亚洲人口比例升高时。结论我们担心氯吡格雷可能是一种可改变的因果风险低血糖的因素。亚洲人口可能更脆弱，需要额外的照顾。系统审查注册https://www.crd.york.ac.uk/prospero, 标识符 CRD42022299622。