Author's reply to the “Comment on ‘Concomitant use of metformin and proton pump inhibitors increases vitamin B12 deficiency risk in type 2 diabetes’”

IF 3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Choungwon Jung, Soyoung Park, Hyunah Kim
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引用次数: 0

Abstract

Dear editor,

We appreciate the thoughtful comments from Liao et al.1 regarding our study2 and are pleased to address the points they raised and to provide clarification on our methodology and interpretation.

First, Liao et al. pointed out the physiological plausibility of the ≥2 weeks use of concurrent metformin and proton pump inhibitor (PPI) use on vitamin B12 deficiency. We would like to clarify that the 2-week threshold was only used to define overlapping PPI use based on previous literature, in order to capture a broad range of concurrent exposure durations3. In fact, in our as-treated analysis, where PPI discontinuation was included as a censoring event, the total person-years for the metformin + PPI group (n = 5,600) was 1589, corresponding to an average follow-up duration of approximately 3.4 months (around 13.6 weeks) per person. This shows that the actual duration of concurrent drug exposure was longer than 2 weeks in most of the patients in our cohort.

Second, although the absolute risk increase observed in our study appears modest as Liao et al. mentioned, the potential public health implications are more substantial when viewed at the population level. In our cohort, 11,761 of 117,727 (approximately 10%) of patients with type 2 diabetes mellitus (T2DM) were exposed to concurrent metformin and PPI (metformin + PPI). Extrapolating this proportion to the total T2DM population in Korea suggests that nearly 530,000 patients may have received metformin + PPI, which would result in an estimated 584 additional cases of vitamin B12 deficiency per year. This projection is not merely speculative, as our findings are based on the National Health Insurance Service—National Sample Cohort (NHIS-NSC), a stratified 2% sample of the entire Korean population.

Third, while the subgroup analyses demonstrated trends consistent with the overall pooled results across age- and sex-based strata, these subgroup analyses were exploratory in nature and not powered to detect statistical interactions. We acknowledge the absence of formal interaction testing as a limitation; however, further analyses were not feasible due to data access restrictions following the approved analysis period.

Lastly, we agree that vitamin B12 screening should be tailored based on individual patient risk factors. Our findings support the interpretation of concomitant metformin and PPI use as one such risk factor to consider, but not as justification for universal testing. Given the known association between vitamin B12 deficiency and the risk of diabetic neuropathy, the American Diabetes Association (ADA) recommends regular vitamin B12 monitoring in patients presenting with symptoms such as anemia or neuropathy, or in those with additional risk factors, including >4 years of metformin use, malabsorption syndromes, or low dietary intake4.

The authors declare no conflict of interest.

Approval of the research protocol: The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Sookmyung Women's University (SMWU) (IRB number: SMWU-2204-HR-016). The requirement for informed.

Informed Consent: N/A.

Approval date of Registry and the Registration No. of the study/trial: N/A.

This study utilized secondary data sources, specifically the National Health Insurance Service—National Sample Cohort (NHIS-NSC). As the research involved analysis of publicly available data and did not include direct interaction with human subjects, ethical approval was not required. Consequently, there is no applicable approval date or registration number for this study.

Animal Studies: N/A.

Abstract Image

作者对“合用二甲双胍和质子泵抑制剂增加2型糖尿病患者维生素B12缺乏风险的评论”的回复。
尊敬的编辑:我们感谢Liao等人对我们研究的周到评论,我们很高兴回答他们提出的问题,并澄清我们的方法和解释。首先,Liao等人指出了在维生素B12缺乏症中同时使用二甲双胍和质子泵抑制剂(PPI)≥2周的生理合理性。我们想澄清的是,2周阈值仅用于定义基于先前文献的重叠PPI使用,以便捕获大范围的并发暴露持续时间3。事实上,在我们的治疗分析中,将PPI停药纳入审查事件,二甲双胍+ PPI组(n = 5600)的总人年为1589人,对应于每人平均随访时间约3.4个月(约13.6周)。这表明,在我们的队列中,大多数患者同时药物暴露的实际持续时间超过2周。其次,尽管在我们的研究中观察到的绝对风险增加似乎不大,但从人口水平来看,潜在的公共卫生影响更大。在我们的队列中,117,727例(约10%)2型糖尿病(T2DM)患者中有11,761例同时暴露于二甲双胍和PPI(二甲双胍+ PPI)。将这一比例外推到韩国的T2DM总人群中,表明近53万患者可能接受了二甲双胍+ PPI治疗,这将导致每年约584例维生素B12缺乏症。这一预测不仅仅是推测性的,因为我们的研究结果是基于国民健康保险服务-国民样本队列(NHIS-NSC),即整个韩国人口的2%分层样本。第三,虽然亚组分析显示的趋势与基于年龄和性别的阶层的总体汇总结果一致,但这些亚组分析本质上是探索性的,无法检测到统计上的相互作用。我们承认缺乏正式的交互测试是一个限制;但是,由于在核准的分析期之后数据访问受到限制,进一步的分析是不可行的。最后,我们同意维生素B12筛查应该根据个体患者的风险因素进行调整。我们的研究结果支持将二甲双胍和PPI合用作为一种需要考虑的风险因素的解释,但不能作为普遍检测的理由。鉴于维生素B12缺乏与糖尿病性神经病变风险之间的已知关联,美国糖尿病协会(ADA)建议对出现贫血或神经病变等症状的患者,或有其他风险因素的患者,包括使用二甲双胍4年、吸收不良综合征或饮食摄入量低的患者,定期监测维生素B12。作者声明无利益冲突。研究方案的批准:研究方案由淑明女子大学(SMWU)的机构审查委员会(IRB)审查和批准(IRB编号:SMWU-2204- hr -016)。对知情的要求。知情同意:无。注册局批准日期及注册编号研究/试验:无。本研究使用二手数据来源,特别是国家健康保险服务-国家样本队列(NHIS-NSC)。由于该研究涉及对公开数据的分析,不包括与人类受试者的直接互动,因此不需要伦理批准。因此,本研究没有适用的批准日期或注册号。动物研究:无。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Diabetes Investigation
Journal of Diabetes Investigation ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
9.40%
发文量
218
审稿时长
6-12 weeks
期刊介绍: Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).
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