Increased risk of hypereosinophilia following initiation of glucagon-like peptide 1 receptor agonist: A symmetry analysis using the Danish health registries

IF 9 2区 医学 Q1 MEDICINE, GENERAL & INTERNAL Journal of Internal Medicine Pub Date : 2024-10-23 DOI:10.1111/joim.20025
Martin Torp Rahbek, Søren Andreas Just, Kasper Bruun Kristensen, Hussam Mahmoud Sheta, Jesper Hallas, Anton Pottegård, Lars Christian Lund
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Because these events are too rare to be detected in randomized controlled trials, we aimed to quantify the association between GLP1-RA initiation and incident hypereosinophilia (HE) using real-world data.</p><p>Leveraging nationwide Danish prescription [<span>3</span>] and laboratory data [<span>4</span>], we conducted a sequence symmetry analysis (SSA) investigating the occurrence of HE following initiation of GLP1-RA and for comparison sodium–glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) [<span>5</span>].</p><p>The SSA compares the occurrence of HE during a symmetric time window before and after initiation of the drug of interest. If there is no association between drug initiation and HE, we would expect HE to occur equally often during both windows. However, if GLP1-RA use increases eosinophil counts, we would expect HE to occur more frequently after initiation. The sequence ratio (SR) is calculated as the number of HE events after drug initiation divided by the number of HE events before drug initiation and corresponds to the incidence rate ratio obtained in the corresponding cohort study [<span>6</span>]. If the rate of HE is increased after initiation of GLP1-RA compared to the period before initiation, we would expect an SR above 1.</p><p>We identified all individuals who initiated a GLP1-RA, SGLT2i or DPP4i (Appendix) between 1 June 2015 and 31 May 2024 and obtained eosinophil counts of 1.5 × 10<sup>9</sup>/L or greater within the last 180 days before the drug initiation, or within the first 180 days after. Observed SRs were adjusted for temporal trends in HE [<span>5</span>]. In subgroup analyses, we evaluated semaglutide and other GLP1-RAs separately, as well as Ozempic and Wegovy. For sensitivity analyses, we calculated SRs for observation windows of 90 and 365 days and with mild (≥0.5–1.5 × 10<sup>9</sup>/L) and massive eosinophilia (≥5 × 10<sup>9</sup>/L) as outcomes. Finally, we used a thrombocyte count below 50 × 10<sup>9</sup>/L as a negative control outcome.</p><p>The study was approved by the institutional data protection board at the University of Southern Denmark and the Danish Health Data Authority (Project number FSEID-00006047). Ethical approval is not needed in Denmark for studies based purely on registry data.</p><p>We identified 213,521 individuals who initiated a GLP1-RA among whom 245 had HE within 1 year of drug initiation. The median age was 54 years (interquartile range [IQR] 42–63), 49% were female and median year of initiation of GLP1-RA was 2022 (IQR 2021–2023<i>)</i>. Of these, 193 individuals had HE after drug initiation, and 52 individuals had HE before drug initiation, yielding an SR of 3.83 (95% confidence interval [CI] 2.84–5.24). Among initiators of SGLT2i and DPP4i, we found SRs of 0.76 (<i>N</i> = 108/146, CI 0.59–0.97) and 0.89 (<i>N</i> = 68/76, CI 0.64–1.23).</p><p>In subgroup analyses, SRs for semaglutide, other GLP1-RAs, Wegovy and Ozempic were similar to results for all GLP1-RAs combined (Fig. 1). The outcome mild eosinophilia yielded an SR of 1.08 for GLP1-RA initiators (<i>N</i> = 1207/1136, CI 1.0–1.18). For massive eosinophilia, we observed 13 events after GLP1-RA initiation and less than 5 events before initiation. Analyses with shorter and longer observation windows yielded elevated SRs (SR 3.87, CI 2.62–5.85 and 2.50 [1.97–3.18]). For the negative-control outcomes, we found for GLP1-RA, SGLT2i and DPP4i, respectively, SRs of 1.64 (<i>N</i> = 44/27, CI 1.02–2.66), SR of 1.28 (<i>N</i> = 118/93, CI 0.98–1.68) and SR of 0.84 (<i>N</i> = 75/89, CI 0.62–1.15) after initiation. <b>Fig</b>. <b>S1</b> shows a steep increase in HE during the first 3 months after GLP1-RA initiation, which was not observed for SGLT2i or DPP4i initiators.</p><p>In this nationwide study, we found that HE is three times more likely to occur after initiation of GLP1-RAs compared to the period prior to initiation. This finding was specific to GLP1-RAs and not observed for other antidiabetic drugs. Albeit the negative control outcome generated a result that was non-null for GLP1-RAs, results for the negative control outcome were much closer to 1.0 compared to the main analysis and were compatible with the results for SGLT2i. Thus, our study provides evidence of a temporal association between the initiation of GLP1-RAs and HE. The main limitation of our study is that the outcome was biochemically defined HE and not end-organ damage due to HE. Another important limitation is that the study population only included individuals who initiated GLP1-RA and had an eosinophil count measured. Larger studies are needed to quantify the potential association between GLP1-RAs and clinically manifest HES.</p><p>The data underlying this article cannot be shared publicly due to Danish privacy regulations. Danish data are available to authorized researchers after application to the Danish Health Data Authority (https://sundhedsdatastyrelsen.dk).</p><p>The analytical source code can be obtained from https://gitlab.sdu.dk/lclund/glp1-hes/. A protocol was registered prior to data analysis and is available at https://osf.io/sabzk.</p><p>Martin Torp Rahbek and Lars Christian Lund had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. 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引用次数: 0

Abstract

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are increasingly used in the treatment of Type 2 diabetes and as antiobesity drugs. Cases of hypereosinophilic syndrome (HES) following initiation of GLP1-RA have been reported [1]. HES is defined by eosinophil counts of 1.5 × 109/L or greater and related end-organ damage [2]. Because these events are too rare to be detected in randomized controlled trials, we aimed to quantify the association between GLP1-RA initiation and incident hypereosinophilia (HE) using real-world data.

Leveraging nationwide Danish prescription [3] and laboratory data [4], we conducted a sequence symmetry analysis (SSA) investigating the occurrence of HE following initiation of GLP1-RA and for comparison sodium–glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) [5].

The SSA compares the occurrence of HE during a symmetric time window before and after initiation of the drug of interest. If there is no association between drug initiation and HE, we would expect HE to occur equally often during both windows. However, if GLP1-RA use increases eosinophil counts, we would expect HE to occur more frequently after initiation. The sequence ratio (SR) is calculated as the number of HE events after drug initiation divided by the number of HE events before drug initiation and corresponds to the incidence rate ratio obtained in the corresponding cohort study [6]. If the rate of HE is increased after initiation of GLP1-RA compared to the period before initiation, we would expect an SR above 1.

We identified all individuals who initiated a GLP1-RA, SGLT2i or DPP4i (Appendix) between 1 June 2015 and 31 May 2024 and obtained eosinophil counts of 1.5 × 109/L or greater within the last 180 days before the drug initiation, or within the first 180 days after. Observed SRs were adjusted for temporal trends in HE [5]. In subgroup analyses, we evaluated semaglutide and other GLP1-RAs separately, as well as Ozempic and Wegovy. For sensitivity analyses, we calculated SRs for observation windows of 90 and 365 days and with mild (≥0.5–1.5 × 109/L) and massive eosinophilia (≥5 × 109/L) as outcomes. Finally, we used a thrombocyte count below 50 × 109/L as a negative control outcome.

The study was approved by the institutional data protection board at the University of Southern Denmark and the Danish Health Data Authority (Project number FSEID-00006047). Ethical approval is not needed in Denmark for studies based purely on registry data.

We identified 213,521 individuals who initiated a GLP1-RA among whom 245 had HE within 1 year of drug initiation. The median age was 54 years (interquartile range [IQR] 42–63), 49% were female and median year of initiation of GLP1-RA was 2022 (IQR 2021–2023). Of these, 193 individuals had HE after drug initiation, and 52 individuals had HE before drug initiation, yielding an SR of 3.83 (95% confidence interval [CI] 2.84–5.24). Among initiators of SGLT2i and DPP4i, we found SRs of 0.76 (N = 108/146, CI 0.59–0.97) and 0.89 (N = 68/76, CI 0.64–1.23).

In subgroup analyses, SRs for semaglutide, other GLP1-RAs, Wegovy and Ozempic were similar to results for all GLP1-RAs combined (Fig. 1). The outcome mild eosinophilia yielded an SR of 1.08 for GLP1-RA initiators (N = 1207/1136, CI 1.0–1.18). For massive eosinophilia, we observed 13 events after GLP1-RA initiation and less than 5 events before initiation. Analyses with shorter and longer observation windows yielded elevated SRs (SR 3.87, CI 2.62–5.85 and 2.50 [1.97–3.18]). For the negative-control outcomes, we found for GLP1-RA, SGLT2i and DPP4i, respectively, SRs of 1.64 (N = 44/27, CI 1.02–2.66), SR of 1.28 (N = 118/93, CI 0.98–1.68) and SR of 0.84 (N = 75/89, CI 0.62–1.15) after initiation. Fig. S1 shows a steep increase in HE during the first 3 months after GLP1-RA initiation, which was not observed for SGLT2i or DPP4i initiators.

In this nationwide study, we found that HE is three times more likely to occur after initiation of GLP1-RAs compared to the period prior to initiation. This finding was specific to GLP1-RAs and not observed for other antidiabetic drugs. Albeit the negative control outcome generated a result that was non-null for GLP1-RAs, results for the negative control outcome were much closer to 1.0 compared to the main analysis and were compatible with the results for SGLT2i. Thus, our study provides evidence of a temporal association between the initiation of GLP1-RAs and HE. The main limitation of our study is that the outcome was biochemically defined HE and not end-organ damage due to HE. Another important limitation is that the study population only included individuals who initiated GLP1-RA and had an eosinophil count measured. Larger studies are needed to quantify the potential association between GLP1-RAs and clinically manifest HES.

The data underlying this article cannot be shared publicly due to Danish privacy regulations. Danish data are available to authorized researchers after application to the Danish Health Data Authority (https://sundhedsdatastyrelsen.dk).

The analytical source code can be obtained from https://gitlab.sdu.dk/lclund/glp1-hes/. A protocol was registered prior to data analysis and is available at https://osf.io/sabzk.

Martin Torp Rahbek and Lars Christian Lund had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Lars Christian Lund, Martin Torp Rahbek, Anton Pottegård, Jesper Hallas and Kasper Bruun Kristensen conceptualized the study. Søren Andreas Just and Hussam Mahmoud Sheta provided important input to the methodology and interpretation. Lars Christian Lund performed the data analysis. Martin Torp Rahbek drafted the original manuscript, and all authors critically revised the manuscript and approved the final version for publication. Martin Torp Rahbek attests that Anton Pottegård, Jesper Hallas, Lars Christian Lund, Søren Andreas Just, Kasper Bruun Kristensen and Hussam Mahmoud Sheta meet authorship criteria and that no others meeting the criteria have been omitted.

LCL reports participation in research projects funded by Menarini Pharmaceuticals and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the current work. JH reports participation in post-authorization safety studies funded by Novo Nordisk with money paid to his employer and with no personal fees involved. AP reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Novo Nordisk, Servier and LEO Pharma, all regulator-mandated phase IV-studies, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this article. HMS is currently employed by Novo Nordisk but did not have any affiliation with Novo Nordisk at the time of data analysis and manuscript draft writing. MTR, KBK and SAJ report no conflicts of interest.

None.

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开始服用胰高血糖素样肽 1 受体激动剂后嗜酸性粒细胞增多症的风险增加:利用丹麦健康登记进行的对称性分析。
胰高血糖素样肽 1 受体激动剂(GLP1-RA)越来越多地用于治疗 2 型糖尿病和作为抗肥胖药物。有报道称,开始使用 GLP1-RA 后出现了嗜酸性粒细胞过多综合征(HES)病例 [1]。嗜酸性粒细胞过多综合征的定义是嗜酸性粒细胞计数达到或超过 1.5 × 109/L 以及相关的内脏器官损伤[2]。由于这些事件过于罕见,无法在随机对照试验中检测到,因此我们旨在利用真实世界的数据来量化 GLP1-RA 启动与嗜酸性粒细胞过多症(HE)事件之间的关联。利用丹麦全国范围内的处方[3]和实验室数据[4],我们进行了序列对称性分析(SSA),调查开始服用 GLP1-RA 以及钠-葡萄糖协同转运体 2 抑制剂(SGLT2i)和二肽基肽酶 4 抑制剂(DPP4i)[5]后嗜酸性粒细胞增多症的发生情况。如果开始用药与高血压之间没有关联,我们预计高血压在两个时间窗内发生的频率相同。但是,如果使用 GLP1-RA 会增加嗜酸性粒细胞的数量,我们就会认为在开始用药后嗜酸性粒细胞增多的发生率会更高。序列比(SR)的计算方法是用开始用药后的 HE 事件数除以开始用药前的 HE 事件数,并与相应队列研究中获得的发病率比值相对应[6]。我们确定了在 2015 年 6 月 1 日至 2024 年 5 月 31 日期间开始使用 GLP1-RA、SGLT2i 或 DPP4i(附录),且在开始用药前最后 180 天内或用药后最初 180 天内嗜酸性粒细胞计数达到或超过 1.5 × 109/L 的所有患者。观察到的 SR 根据 HE 的时间趋势进行了调整 [5]。在亚组分析中,我们分别评估了semaglutide和其他GLP1-RA,以及Ozempic和Wegovy。在敏感性分析中,我们计算了 90 天和 365 天观察窗的 SR,并将轻度(≥0.5-1.5 × 109/L)和大量嗜酸性粒细胞增多(≥5 × 109/L)作为结果。最后,我们将血小板计数低于 50 × 109/L 作为阴性对照结果。该研究获得了南丹麦大学机构数据保护委员会和丹麦健康数据管理局的批准(项目编号 FSEID-00006047)。在丹麦,纯粹基于登记数据的研究不需要伦理批准。我们确定了 213,521 名开始服用 GLP1-RA 的患者,其中 245 人在开始服药后 1 年内出现高血压。年龄中位数为 54 岁(四分位数间距 [IQR] 42-63),49% 为女性,开始服用 GLP1-RA 的年份中位数为 2022 年(IQR 2021-2023)。其中,193 人在开始用药后出现高血压,52 人在开始用药前出现高血压,SR 为 3.83(95% 置信区间 [CI] 2.84-5.24)。在亚组分析中,semaglutide、其他 GLP1-RA、Wegovy 和 Ozempic 的 SR 与所有 GLP1-RA 合并的结果相似(图 1)。轻度嗜酸性粒细胞增多结果显示,GLP1-RA 启动者的 SR 为 1.08(N = 1207/1136,CI 1.0-1.18)。对于大量嗜酸性粒细胞增多,我们观察到 GLP1-RA 启动后发生了 13 起事件,而启动前发生的事件不到 5 起。对较短和较长的观察窗口进行分析后,发现SRs升高(SR为3.87,CI为2.62-5.85和2.50 [1.97-3.18])。对于阴性对照结果,我们发现 GLP1-RA、SGLT2i 和 DPP4i 的 SR 分别为 1.64(N = 44/27,CI 1.02-2.66)、1.28(N = 118/93,CI 0.98-1.68)和 0.84(N = 75/89,CI 0.62-1.15)。图 S1 显示,在开始使用 GLP1-RA 后的前 3 个月,HE 的发病率急剧上升,而在开始使用 SGLT2i 或 DPP4i 的患者中未观察到这一现象。这一发现仅针对 GLP1-RAs,在其他抗糖尿病药物中并未观察到。尽管阴性对照结果对 GLP1-RAs 而言并非无效,但与主要分析结果相比,阴性对照结果更接近于 1.0,并且与 SGLT2i 的结果一致。因此,我们的研究为 GLP1-RAs 的启动与 HE 之间的时间关联提供了证据。我们研究的主要局限性在于,研究结果是生化定义的高血压,而不是高血压导致的内脏损害。另一个重要的局限性是,研究对象只包括开始服用 GLP1-RA 并测量了嗜酸性粒细胞计数的人。需要进行更大规模的研究,以量化GLP1-RA与临床表现的HES之间的潜在关联。
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 Internal Medicine
Journal of Internal Medicine 医学-医学:内科
CiteScore
22.00
自引率
0.90%
发文量
176
审稿时长
4-8 weeks
期刊介绍: JIM – The Journal of Internal Medicine, in continuous publication since 1863, is an international, peer-reviewed scientific journal. It publishes original work in clinical science, spanning from bench to bedside, encompassing a wide range of internal medicine and its subspecialties. JIM showcases original articles, reviews, brief reports, and research letters in the field of internal medicine.
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Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial. Different ways of diagnosing selective glomerular hypofiltration syndromes such as shrunken pore syndrome and the associated increase in mortality. Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease. Issue Information Association among major adverse cardiovascular events with immune checkpoint inhibitors: A systematic review and meta-analysis.
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