Effects and safety of dulaglutide treatment on glucocorticoid-induced hyperglycemia in patients treated with CHOP therapy

Effects and safety of dulaglutide treatment on glucocorticoid-induced hyperglycemia in patients treated with CHOP therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects and safety of dulaglutide treatment on glucocorticoid-induced hyperglycemia in patients treated with CHOP therapy Takuya Suyama, Misayo Shimizu, Matsui Kumiko, Atsushi Shinagawa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4216351/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Glucocorticoid-induced hyperglycemia is a serious adverse event of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy and requires chemotherapy dose reduction and drug interruption for remediation. Previous reports have showed that the glucagon-like peptide 1 receptor agonist dulaglutide significantly improves glycemic control in glucocorticoid-induced hyperglycemia. Thus, we aimed to investigate the efficacy and safety of dulaglutide for glucocorticoid-induced hyperglycemia in patients with non-Hodgkin lymphoma treated with CHOP therapy. Methods: Ten newly diagnosed patients with non-Hodgkin lymphoma exhibiting glucocorticoid-induced hyperglycemia during initial cycle CHOP ± rituximab therapy were enrolled. Dulaglutide administration began during the second cycle. Glycemic control parameters (HbA1C, glycoalbumin, and fasting blood glucose) and adverse events were monitored alongside chemotherapy sessions. Results: Of the 10 patients, one patient discontinued CHOP treatment due to progression, one patient due to chemotherapy intolerance, and eight patients were finally evaluated. HbA1c and glycoalbumin reduced significantly post-dulaglutide initiation, thereby suggesting improved glycemic control without adverse events, such as hypoglycemia or pancreatitis. Challenges in glycemic assessment due to simultaneous declines in hemoglobin levels alongside HbA1C were noted. Conclusion: Dulaglutide exhibited promise in effectively managing glucocorticoid-induced hyperglycemia during CHOP therapy without serious adverse events. malignant lymphoma glucocorticoid-induced hyperglycemia dulaglutide CHOP therapy Figures Figure 1 Figure 2 Introduction The combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with or without rituximab is the most commonly used first-line chemotherapy for treatment of non-Hodgkin lymphoma (NHL). This involves the administration of prednisolone, a glucocorticoid, at a dosage of 100 mg/day for 5 d in each cycle [1, 2]. One of the significant adverse events associated with high-dose prednisolone is hyperglycemia, which increases the risk of febrile neutropenia (FN) development, thereby necessitating treatment modifications [3, 4]. Numerous reports indicate that hyperglycemia induced by rituximab (R)-CHOP can shorten survival, thus emphasizing the need for safe and effective glycemic control during prednisolone administration [5-8]. The most reliable method for glycemic control to address glucocorticoid-induced hyperglycemia is insulin administration. However, most patients are insulin-naive, and temporary multiple injections and measurements impose significant burdens, with potential risks of hypoglycemia during prednisolone tapering or discontinuation [9]. Poor glycemic control due to glucocorticoid-induced hyperglycemia has been linked to decreased effectiveness of incretins [10]. Studies have reported that exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, elevates GLP-1 levels in plasma of patients with glucocorticoid-induced hyperglycemia, thereby lowering the glucose curve without inducing hypoglycemia [11]. However, the effectiveness and safety of GLP-1 receptor agonists, specifically for short-term high-dose glucocorticoids during chemotherapy, remain undocumented. This study aimed to assess the effectiveness and safety of dulaglutide, a long-acting GLP-1 receptor agonist, in managing glucocorticoid-induced hyperglycemia in patients with NHL undergoing CHOP therapy. The objective was to reduce FN risk by achieving optimal glycemic control, thereby allowing uninterrupted chemotherapy treatment without modifications. Patients and methods This study was a prospective, single-center, open-label trial designed to assess the efficacy and safety of dulaglutide in managing glucocorticoid-induced hyperglycemia during CHOP ± R treatment. Patients were recruited between March 2020 and June 2023. Eligible participants included newly diagnosed patients with NHL aged over 18 years with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2, scheduled for six courses of CHOP ± R, and who exhibited glucocorticoid-induced hyperglycemia during the initial course. Glucocorticoid-induced hyperglycemia was defined as an elevation of blood glucose (fasting glucose level of ≥ 126 mg/dL or post-prandial glucose level of ≥ 200 mg/dL) during prednisolone administration within the CHOP regimen. Exclusion criteria included a history of type 1 diabetes mellitus (DM), hyperglycemic coma, diabetic ketoacidosis, or current treatment with a GLP-1 receptor agonist. All additional medications during CHOP treatment were at the physician's discretion, except for dipeptidyl peptidase-4 (DPP-4) inhibitors, which ceased at the initiation of dulaglutide treatment. The protocol received approval from the Ethics Committees at Hitachi General Hospital and was registered with the Japan Registry of Clinical Trials (JRCT 1031200022, Registration date: 27-April-2020). All patients provided written informed consent. Patients received CHOP therapy consisting of cyclophosphamide (750 mg/m 2 /d, 1 d), doxorubicin (50 mg/m 2 /d, 1 d), vincristine (1.4 mg/m 2 /d [max 2.0 mg], 1 d), and prednisolone (100 mg/body, 5 d), ± rituximab (R; 375 mg/m 2 /d, 1 d), every three weeks for six cycles. For patients who developed glucocorticoid-induced hyperglycemia during the first cycle of CHOP ± R therapy, dulaglutide (0.75 mg) was administered once weekly starting from the second cycle. Assessment and Data Collection Glycemic control assessment involved measuring fasting blood glucose, HbA1C, and glycoalbumin every 3 weeks before each chemotherapy session. Concurrent measurements included body weight, hemoglobin (Hb), and albumin levels. Patients reported adverse events, including gastrointestinal symptoms and hypoglycemia occurrences, following each chemotherapy session using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. International Prognostic Index, Ann arbor stage, chemotherapy regimen, ECOG-PS, history of diabetes mellitus (DM), and medications were obtained from medical records. History of DM was defined as patient or medical record diagnosis or treatment for DM prior to starting chemotherapy. Statistical analysis The primary outcome assessed glycemic control using the HbA1C levels after the initiation of dulaglutide. Assessments were performed six times at intervals of three weeks: cycles 2, 3, 4, 5, and 6 before the commencement of chemotherapy courses and then three weeks after the completion of chemotherapy. The secondary outcome assessed glycemic control using the glycoalbumin and fasting blood glucose after the initiation of dulaglutide. Assessments were carried out concurrently with the HbA1C. Additionally, the occurrence of hypoglycemic episodes was evaluated. Hypoglycemic episodes were identified by blood glucose levels below 70 mg/dL or the manifestation of symptoms, such as cold sweats, dizziness, or altered consciousness. Changes in HbA1C, fasting blood glucose, and glycoalbumin were analyzed using repeated measures analysis of variance. Statistical analyses were conducted using EZR [12]. A two-sided p-value < 0.05 was deemed significant. Results Ten patients with NHL were enrolled; out of these, two patients discontinued chemotherapy and dulaglutide: one due to disease progression after three cycles and another due to chemotherapy intolerance after three cycles. Data collection was limited to the assessment of eight patients as data could not be obtained from the two patients who completed only three cycles. The eight patients had a median baseline age of 73 years and an equal male–female ratio of 1:1. Six patients had a history of DM. Patient characteristics were summarized in Table 1. The cohort comprised six patients with diffuse large B-cell lymphoma, one with follicular lymphoma, and one with peripheral T-cell lymphoma. Among these, seven received the R-CHOP regimen while one received the CHOP regimen. Six patients were on oral hypoglycemic agents prior to treatment, with frequent administration of DPP-4 inhibitor. The prednisone dose for all study participants was 500 mg per cycle. Seven patients achieved a complete response, while one patient achieved a partial response to chemotherapy. Primary outcome Fig. 1a illustrates the changes in HbA1C between the chemotherapy cycles 2, 3, 4, 5, and 6, and three weeks after treatment completion. The median baseline HbA1C was 6.7% (5.8–7.9). It increased to 7.4% (6.5–8.3) by the second chemotherapy cycle but significantly decreased after dulaglutide initiation (p=2.202e-6). Three weeks post-chemotherapy completion, the HbA1C median was 5.9% (5.7–7.5). However, there was a significant decline in Hb post-chemotherapy initiation (p = 0.0027) (Fig. 1b). Secondary outcome Fig. 2a illustrates the changes in glycoalbumin between the chemotherapy cycles 2, 3, 4, 5, and 6, and three weeks after treatment completion. The baseline glycoalbumin was 16.5% (14.2–21.1), increasing to 20.5% (12.4–23) by the second chemotherapy cycle but significantly decreasing after dulaglutide initiation (p = 2.282e-6). Three weeks post-chemotherapy completion, the median glycoalbumin was 15.9% (10.9–18.4). Albumin did not exhibit a significant decline post-chemotherapy initiation (p = 0.28) (Fig. 2b). There was a significant decrease in body weight post-chemotherapy initiation (p = 0.0006365) (Fig. 2c), but no significant change was observed in fasting blood glucose (p = 0.7069) (Fig. 2d). Regarding adverse events, no reports of hypoglycemia or pancreatic inflammation were observed. Non-hematologic toxicities graded by CTCAE ver4.0 included grade 1 fatigue in three cases (37.5%), grade 2 fatigue in one case (12.5%), grade 1 peripheral neuropathy in three cases (37.5%), grade 1 anorexia in two cases (25%), grade 2 anorexia in two cases (25%), and grade 1 constipation in two cases (25%). Discussion The study demonstrated the potential of dulaglutide in reducing glycoalbumin levels without adverse events, such as hypoglycemia or pancreatitis, thereby indicating its efficacy in managing glucocorticoid-induced hyperglycemia during CHOP therapy. However, challenges in assessing glycemic control due to simultaneous decreases in Hb levels alongside HbA1C were noted. Glucocorticoid-induced hyperglycemia during CHOP ± R therapy is a significant adverse event in lymphoma treatment, with an incidence rate of about 30% [3, 13, 14]. Glucocorticoid-induced hyperglycemia in patients with existing DM increases the risk of febrile neutropenia (FN), insulin use, and cardiovascular disease [13, 14]. Even in patients without DM, blood glucose levels exceeding 200 mg/dL during CHOP ± R therapy have been reported to extend FN hospitalization durations [4]. Moreover, glucocorticoid-induced hyperglycemia correlates significantly with chemotherapy modifications, thereby shortening the prognosis in non-diabetic individuals and patients with type 2 diabetes treated with CHOP ± R for NHL [5-8]. Approximately 65% of glucocorticoid-induced hyperglycemia occurs during the first treatment cycle. Reports suggest that CHOP therapy does not increase the risk of DM after 5 years; hence, short-term glycemic control during CHOP therapy is crucial [13, 14]. While insulin administration is the most reliable treatment for glucocorticoid-induced hyperglycemia, it poses challenges for insulin-naive individuals due to the burden of injections and self-glucose monitoring. Moreover, the use of insulin during short-term steroid treatment might induce hypoglycemia upon steroid reduction or cessation [9]. Therefore, insulin administration may not be the optimal option for glucocorticoid-induced hyperglycemia with lymphoma in insulin-naive patients. Studies suggest that the worsening effect of glucocorticoids on glycemic control is attributed to reduced incretin effectiveness, thereby indicating the potential benefit of incretin-based treatments [10]. Reports exist on DPP-4 inhibitors such as alogliptin showing improved glycemic control in glucocorticoid-induced hyperglycemia in chronic kidney disease [15]. Sitagliptin has also been reported to significantly lower HbA1C in 15 patients with diabetes receiving steroid therapy [16]. However, a double-blind placebo-controlled trial in 14 non-diabetic individuals with metabolic syndrome revealed that the co-administration of prednisolone (PSL) 30 mg and sitagliptin did not prevent postprandial glucose elevation [17]. Two studies reported the effectiveness of GLP-1 receptor agonists, which act more directly on incretins than DPP-4 inhibitors, in the context of glucocorticoid-induced hyperglycemia. In a randomized double-blind placebo-controlled study involving healthy individuals, exenatide, a GLP-1 receptor agonist, was administered simultaneously with PSL 80 mg or placebo with PSL 80 mg for 2 d. The exenatide-treated group exhibited a decrease in the glucose curve 4 h after a meal, an improvement in insulin sensitivity, and a reduction in postprandial glucagon levels compared to those in the non-exenatide group [11]. Additionally, a retrospective study of patients receiving dulaglutide for steroid-induced hyperglycemia reported a reduction in insulin dosage and frequency without causing gastrointestinal disorders or hypoglycemia [18]. This study lacked glucagon level measurements but observed improvements in HbA1C and glycoalbumin. As hemoglobin concurrently decreased, HbA1C may have been an inappropriate indicator for DM control in this study. However, the significant reduction in glycoalbumin with no effect on albumin levels suggested good glycemic control. While fasting blood glucose did not decrease, studies on incretin-based treatments have reported significant reductions in HbA1C without corresponding decreases in fasting blood glucose, thereby aligning with the results observed in this case [15]. The weight loss observed may be attributed to both chemotherapy and dulaglutide. No adverse events, such as hypoglycemia or pancreatitis, were noted, although appetite loss and nausea were observed. Dulaglutide has been reported in Phase 3 trials among Japanese patients to cause gastrointestinal adverse events, such as nausea, constipation, and diarrhea compared to insulin glargine. This makes it difficult to distinguish between the adverse events of chemotherapy and dulaglutide [19]. However, our study also has some limitations. First, the monitoring of blood sugar in this study was insufficient. Generally, with high-dose glucocorticoid administration in the morning, glucose elevation is primarily detected in post-lunch and post-dinner glucose levels [9,18]. Therefore, continuous glucose monitoring is necessary for the comprehensive assessment of blood sugar levels in glucocorticoid-induced hyperglycemia. Additionally, as fasting blood glucose did not show significant reductions with incretin-based treatment, it was considered inadequate as a blood sugar monitoring parameter [20]. Second, our study had a small sample size and lacked a comparative arm. Third, the study did not assess long-term efficacy and safety. However, short-term evaluation of DM control during chemotherapy was deemed sufficient in this study as the exacerbation of DM due to glucocorticoid occurs only in the initial year, and long-term reports suggest no change in the incidence rate of DM [13]. Conclusion This study suggests that dulaglutide may offer effective glycemic control for glucocorticoid-induced hyperglycemia during CHOP therapy. It appeared relatively safe during chemotherapy, with no significant adverse events, such as hypoglycemia or pancreatitis, and the appetite loss observed was indistinguishable from chemotherapy-related adverse effects. Continuous and large-scale studies incorporating sustained glucose monitoring are necessary to further assess the utility of dulaglutide in patients treated with CHOP therapy. Declarations Acknowledgements We would like to thank Editage (www.editage.jp) for English language editing. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Takuya Suyama, Misayo Shimizu and Shinagawa Atsushi. The first draft of the manuscript was written by Takuya Suyama, Matsui Kumiko, and Masatoshi Tsuru and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Compliance with Ethical Standards Conflict of interest The authors declare that they have no competing interests. Ethics approval Approval was obtained from the Ethics Committee of Hitachi General Hospital. The procedures used in this study adhere to the tenets of Declaration of Helsinki. Consent to participate Informed consent to participate was obtained from all participants prior to intervention commencement. Consent for publication Informed consent to publish data was obtained from all participants. Data availability The data can be made available from the corresponding author upon reasonable request. References Sehn LH, Donaldso J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, MacPherson N, O'Reilly S, Spinelli JJ, Sutherland J, Wilson KS, Gascoyne RD, Connors JM. (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. 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Endocr Pract 15(5):469-474. https://doi.org/10.4158/EP08331.RAR Table Table 1: Baseline characteristics of study participants: Median age (years) 73 (67–86) International Prognostic Index low 1 (12.5%) Male 4 (50%) low-intermediate 1 (12.5%) high-intermediate 4 (50%) ECOG performance high 2 (25%) 0 5 (62.5%) 1 3 (37.5%) History of diabetes 6 (75%) Disease type Treatment Diffuse large B-cell lymphoma 6 (75%) CHOP 1 (12.5%) Follicular lymphoma 1 (12.5%) R-CHOP 7 (87.5%) Peripheral T-cell lymphoma 1 (12.5%) Median HbA1C (%) 6.7 (5.8–7.9) Ann Arbor stage Median glycoalbumin (%) 16.5 (14.2–21.1) 1 2 (25%) 2 1 (12.5%) Medication of diabetes 3 1 (12.5%) DPP-4 inhibitor 6 (75%) 4 4 (50%) SGLT2 inhibitor 4 (50%) metformin 1 (12.5%) sulfonylurea 1 (12.5%) pioglitazone 1 (12.5%) ECOG, Eastern Cooperative Oncology Group; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; HbA1C, Hemoglobin A1C; DPP-4, Dipeptidyl peptidase-4; SGLT2, Sodium-glucose cotransporter2 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4216351","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":289151598,"identity":"da6310c7-353c-42f2-abf6-fe5521452dc8","order_by":0,"name":"Takuya Suyama","email":"data:image/png;base64,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","orcid":"","institution":"NHO Kanmon Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Suyama","suffix":""},{"id":289151602,"identity":"82f7f3f8-b009-4a54-a35e-9aeb3882bc67","order_by":1,"name":"Misayo Shimizu","email":"","orcid":"","institution":"Hitachi General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Misayo","middleName":"","lastName":"Shimizu","suffix":""},{"id":289151606,"identity":"aa9b22b6-2e28-421c-9aff-e3a190282121","order_by":2,"name":"Matsui Kumiko","email":"","orcid":"","institution":"NHO Kanmon Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Matsui","middleName":"","lastName":"Kumiko","suffix":""},{"id":289151611,"identity":"6104d4a5-dacd-43c0-aff8-c8d44f3fbbe3","order_by":3,"name":"Atsushi Shinagawa","email":"","orcid":"","institution":"Hitachi General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Shinagawa","suffix":""},{"id":289151616,"identity":"e4b30e5c-a4fe-4579-9321-ce80afba1357","order_by":4,"name":"Masatoshi Tsuru","email":"","orcid":"","institution":"NHO Kanmon Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Masatoshi","middleName":"","lastName":"Tsuru","suffix":""}],"badges":[],"createdAt":"2024-04-04 07:53:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4216351/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4216351/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54597081,"identity":"9f54f7b0-7c96-4ff4-9705-9160d31e6bba","added_by":"auto","created_at":"2024-04-12 19:12:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52957,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in HbA1C and Hb at each cycle and at the completion of CHOP therapy\u003c/p\u003e\n\u003cp\u003e(a) HbA1C exhibited a significant decrease with each successive cycle starting from cycle 2 (p=2.202e-6). (b) Hb showed a significant decline from Cycle 1, but exhibited a mild recovery at the final assessment (p=0.0006365).\u003c/p\u003e\n\u003cp\u003eHb, hemoglobin; HbA1C, Hemoglobin A1C\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4216351/v1/637dff95c11111104e9189eb.png"},{"id":54596518,"identity":"27a7a30e-1389-4685-92ca-9ae491721db4","added_by":"auto","created_at":"2024-04-12 19:04:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44168,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in the changes of glycoalbumin, albumin, body weight, and fasting blood glucose at each cycle and at the completion of CHOP therapy\u003c/p\u003e\n\u003cp\u003e(a) Glycoalbumin exhibited a decrease from cycle 2 through cycle 3 and 4, followed by a plateau (p=2.282e-6). (b) Albumin did not show a significant decrease throughout the course of treatment (p=0.28). (c) Body weight demonstrated a gradual decline with each successive cycle starting from Cycle 1 (p=0.0006365) (d) Fasting blood glucose did not exhibit a significant decrease (p=0.7069).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4216351/v1/eaa9668b205b3253e0284bfa.png"},{"id":60113813,"identity":"4add05dc-7afc-487a-9d48-d591483b53fe","added_by":"auto","created_at":"2024-07-12 02:48:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":411300,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4216351/v1/ebcbd9fb-51f1-4b31-bbd7-5f3f1ffad2a8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects and safety of dulaglutide treatment on glucocorticoid-induced hyperglycemia in patients treated with CHOP therapy","fulltext":[{"header":" Introduction","content":"\u003cp\u003eThe combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with or without rituximab is the most commonly used first-line chemotherapy for treatment of non-Hodgkin lymphoma (NHL). This involves the administration of prednisolone, a glucocorticoid, at a dosage of 100 mg/day for 5 d in each cycle [1, 2]. One of the significant adverse events associated with high-dose prednisolone is hyperglycemia, which increases the risk of febrile neutropenia (FN) development, thereby necessitating treatment modifications [3, 4]. Numerous reports indicate that hyperglycemia induced by rituximab (R)-CHOP can shorten survival, thus emphasizing the need for safe and effective glycemic control during prednisolone administration [5-8].\u003c/p\u003e\n\u003cp\u003eThe most reliable method for glycemic control to address glucocorticoid-induced hyperglycemia is insulin administration. However, most patients are insulin-naive, and temporary multiple injections and measurements impose significant burdens, with potential risks of hypoglycemia during prednisolone tapering or discontinuation [9]. Poor glycemic control due to glucocorticoid-induced hyperglycemia has been linked to decreased effectiveness of incretins [10]. Studies have reported that exenatide, a\u0026nbsp;glucagon-like peptide 1 (GLP-1) receptor agonist, elevates GLP-1 levels in plasma of patients with glucocorticoid-induced hyperglycemia, thereby lowering the glucose curve without inducing hypoglycemia [11]. However, the effectiveness and safety of GLP-1 receptor agonists, specifically for short-term high-dose glucocorticoids during chemotherapy, remain undocumented.\u003c/p\u003e\n\u003cp\u003eThis study aimed to assess the effectiveness and safety of dulaglutide, a long-acting GLP-1 receptor agonist, in managing glucocorticoid-induced hyperglycemia in patients with NHL undergoing CHOP therapy. The objective was to reduce FN risk by achieving optimal glycemic control, thereby allowing uninterrupted chemotherapy treatment without modifications.\u0026nbsp;\u003c/p\u003e"},{"header":"Patients and methods ","content":"\u003cp\u003eThis study was a prospective, single-center, open-label trial designed to assess the efficacy and safety of dulaglutide in managing glucocorticoid-induced hyperglycemia during CHOP ± R treatment. Patients were recruited between March 2020 and June 2023. Eligible participants included newly diagnosed patients with NHL aged over 18 years with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2, scheduled for six courses of CHOP ± R, and who exhibited glucocorticoid-induced hyperglycemia during the initial course. Glucocorticoid-induced hyperglycemia was defined as an elevation of blood glucose (fasting glucose level of ≥ 126 mg/dL or post-prandial glucose level of ≥ 200 mg/dL) during prednisolone administration within the CHOP regimen.\u003c/p\u003e\n\u003cp\u003eExclusion criteria included a history of type 1 diabetes mellitus (DM), hyperglycemic coma, diabetic ketoacidosis, or current treatment with a GLP-1 receptor agonist. All additional medications during CHOP treatment were at the physician's discretion, except for dipeptidyl peptidase-4 (DPP-4) inhibitors, which ceased at the initiation of dulaglutide treatment.\u003c/p\u003e\n\u003cp\u003eThe protocol received approval from the Ethics Committees at Hitachi General Hospital and was registered with the Japan Registry of Clinical Trials (JRCT 1031200022, Registration date: 27-April-2020). All patients provided written informed consent.\u003c/p\u003e\n\u003cp\u003ePatients received CHOP therapy consisting of cyclophosphamide (750 mg/m\u003csup\u003e2\u003c/sup\u003e/d, 1 d), doxorubicin (50 mg/m\u003csup\u003e2\u003c/sup\u003e/d, 1 d), vincristine (1.4 mg/m\u003csup\u003e2\u003c/sup\u003e/d [max 2.0 mg], 1 d), and prednisolone (100 mg/body, 5 d), ± rituximab (R; 375 mg/m\u003csup\u003e2\u003c/sup\u003e/d, 1 d), every three weeks for six cycles. For patients who developed glucocorticoid-induced hyperglycemia during the first cycle of CHOP ± R therapy, dulaglutide (0.75 mg) was administered once weekly starting from the second cycle.\u003c/p\u003e\n\u003cp\u003eAssessment and Data Collection\u003c/p\u003e\n\u003cp\u003eGlycemic control assessment involved measuring fasting blood glucose, HbA1C, and glycoalbumin every 3 weeks before each chemotherapy session. Concurrent measurements included body weight, hemoglobin (Hb), and albumin levels. Patients reported adverse events, including gastrointestinal symptoms and hypoglycemia occurrences, following each chemotherapy session using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInternational Prognostic Index, Ann arbor stage, chemotherapy regimen, ECOG-PS, history of diabetes mellitus (DM), and medications were obtained from medical records. History of DM was defined as patient or medical record diagnosis or treatment for DM prior to starting chemotherapy.\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eThe primary outcome assessed glycemic control using the HbA1C levels after the initiation of dulaglutide. Assessments were performed six times at intervals of three weeks: cycles 2, 3, 4, 5, and 6 before the commencement of chemotherapy courses and then three weeks after the completion of chemotherapy.\u003c/p\u003e\n\u003cp\u003eThe secondary outcome assessed glycemic control using the glycoalbumin and fasting blood glucose after the initiation of dulaglutide. Assessments were carried out concurrently with the HbA1C. Additionally, the occurrence of hypoglycemic episodes was evaluated. Hypoglycemic episodes were identified by blood glucose levels below 70 mg/dL or the manifestation of symptoms, such as cold sweats, dizziness, or altered consciousness. Changes in HbA1C, fasting blood glucose, and glycoalbumin were analyzed using repeated measures analysis of variance. Statistical analyses were conducted using EZR [12]. A two-sided p-value \u0026lt; 0.05 was deemed significant.\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003eTen patients with NHL were enrolled; out of these, two patients discontinued chemotherapy and dulaglutide: one due to disease progression after three cycles and another due to chemotherapy intolerance after three cycles. Data collection was limited to the assessment of eight patients as data could not be obtained from the two patients who completed only three cycles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe eight patients had a median baseline age of 73 years and an equal male\u0026ndash;female ratio of 1:1. Six patients had a history of DM. Patient characteristics were summarized in Table 1. The cohort comprised six patients with diffuse large B-cell lymphoma, one with follicular lymphoma, and one with peripheral T-cell lymphoma. Among these, seven received the R-CHOP regimen while one received the CHOP regimen. Six patients were on oral hypoglycemic agents prior to treatment, with frequent administration of DPP-4 inhibitor. The prednisone dose for all study participants was 500 mg per cycle. Seven patients achieved a complete response, while one patient achieved a partial response to chemotherapy.\u003c/p\u003e\n\u003cp\u003ePrimary outcome\u003c/p\u003e\n\u003cp\u003eFig. 1a illustrates the changes in HbA1C between the chemotherapy cycles 2, 3, 4, 5, and 6, and three weeks after treatment completion. The median baseline HbA1C was 6.7% (5.8\u0026ndash;7.9). It increased to 7.4% (6.5\u0026ndash;8.3) by the second chemotherapy cycle but significantly decreased after dulaglutide initiation (p=2.202e-6). Three weeks post-chemotherapy completion, the HbA1C median was 5.9% (5.7\u0026ndash;7.5). However, there was a significant decline in Hb post-chemotherapy initiation (p = 0.0027) (Fig. 1b).\u003c/p\u003e\n\u003cp\u003eSecondary outcome\u003c/p\u003e\n\u003cp\u003eFig. 2a illustrates the changes in glycoalbumin between the chemotherapy cycles 2, 3, 4, 5, and 6, and three weeks after treatment completion. The baseline glycoalbumin was 16.5% (14.2\u0026ndash;21.1), increasing to 20.5% (12.4\u0026ndash;23) by the second chemotherapy cycle but significantly decreasing after dulaglutide initiation (p = 2.282e-6). Three weeks post-chemotherapy completion, the median glycoalbumin was 15.9% (10.9\u0026ndash;18.4). Albumin did not exhibit a significant decline post-chemotherapy initiation (p = 0.28) (Fig. 2b). There was a significant decrease in body weight post-chemotherapy initiation (p = 0.0006365) (Fig. 2c), but no significant change was observed in fasting blood glucose (p = 0.7069) (Fig. 2d).\u003c/p\u003e\n\u003cp\u003eRegarding adverse events, no reports of hypoglycemia or pancreatic inflammation were observed. Non-hematologic toxicities graded by CTCAE ver4.0 included grade 1 fatigue in three cases (37.5%), grade 2 fatigue in one case (12.5%), grade 1 peripheral neuropathy in three cases (37.5%), grade 1 anorexia in two cases (25%), grade 2 anorexia in two cases (25%), and grade 1 constipation in two cases (25%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study demonstrated the potential of dulaglutide in reducing glycoalbumin levels without adverse events, such as hypoglycemia or pancreatitis, thereby indicating its efficacy in managing glucocorticoid-induced hyperglycemia during CHOP therapy. However, challenges in assessing glycemic control due to simultaneous decreases in Hb levels alongside HbA1C were noted.\u003c/p\u003e\n\u003cp\u003eGlucocorticoid-induced hyperglycemia during CHOP ± R therapy is a significant adverse event in lymphoma treatment, with an incidence rate of about 30% [3, 13, 14]. Glucocorticoid-induced hyperglycemia in patients with existing DM increases the risk of febrile neutropenia (FN), insulin use, and cardiovascular disease [13, 14]. Even in patients without DM, blood glucose levels exceeding 200 mg/dL during CHOP ± R therapy have been reported to extend FN hospitalization durations [4]. Moreover, glucocorticoid-induced hyperglycemia correlates significantly with chemotherapy modifications, thereby shortening the prognosis in non-diabetic individuals and patients with type 2 diabetes treated with CHOP ± R for NHL [5-8]. Approximately 65% of glucocorticoid-induced hyperglycemia occurs during the first treatment cycle. Reports suggest that CHOP therapy does not increase the risk of DM after 5 years; hence, short-term glycemic control during CHOP therapy is crucial [13, 14].\u003c/p\u003e\n\u003cp\u003eWhile insulin administration is the most reliable treatment for glucocorticoid-induced hyperglycemia, it poses challenges for insulin-naive individuals due to the burden of injections and self-glucose monitoring. Moreover, the use of insulin during short-term steroid treatment might induce hypoglycemia upon steroid reduction or cessation [9]. Therefore, insulin administration may not be the optimal option for glucocorticoid-induced hyperglycemia with lymphoma in insulin-naive patients. Studies suggest that the worsening effect of glucocorticoids on glycemic control is attributed to reduced incretin effectiveness, thereby indicating the potential benefit of incretin-based treatments [10]. Reports exist on DPP-4 inhibitors such as alogliptin showing improved glycemic control in glucocorticoid-induced hyperglycemia in chronic kidney disease [15]. Sitagliptin has also been reported to significantly lower HbA1C in 15 patients with diabetes receiving steroid therapy [16]. However, a double-blind placebo-controlled trial in 14 non-diabetic individuals with metabolic syndrome revealed that the co-administration of prednisolone (PSL) 30 mg and sitagliptin did not prevent postprandial glucose elevation [17]. Two studies reported the effectiveness of GLP-1 receptor agonists, which act more directly on incretins than DPP-4 inhibitors, in the context of glucocorticoid-induced hyperglycemia. In a randomized double-blind placebo-controlled study involving healthy individuals, exenatide, a GLP-1 receptor agonist, was administered simultaneously with PSL 80 mg or placebo with PSL 80 mg for 2 d. The exenatide-treated group exhibited a decrease in the glucose curve 4 h after a meal, an improvement in insulin sensitivity, and a reduction in postprandial glucagon levels compared to those in the non-exenatide group [11]. Additionally, a retrospective study of patients receiving dulaglutide for steroid-induced hyperglycemia reported a reduction in insulin dosage and frequency without causing gastrointestinal disorders or hypoglycemia [18].\u003c/p\u003e\n\u003cp\u003eThis study lacked glucagon level measurements but observed improvements in HbA1C and glycoalbumin. As hemoglobin concurrently decreased, HbA1C may have been an inappropriate indicator for DM control in this study. However, the significant reduction in glycoalbumin with no effect on albumin levels suggested good glycemic control. While fasting blood glucose did not decrease, studies on incretin-based treatments have reported significant reductions in HbA1C without corresponding decreases in fasting blood glucose, thereby aligning with the results observed in this case [15]. The weight loss observed may be attributed to both chemotherapy and dulaglutide. No adverse events, such as hypoglycemia or pancreatitis, were noted, although appetite loss and nausea were observed. Dulaglutide has been reported in Phase 3 trials among Japanese patients to cause gastrointestinal adverse events, such as nausea, constipation, and diarrhea compared to insulin glargine. This makes it difficult to distinguish between the adverse events of chemotherapy and dulaglutide [19].\u003c/p\u003e\n\u003cp\u003eHowever, our study also has some limitations. First, the monitoring of blood sugar in this study was insufficient. Generally, with high-dose glucocorticoid administration in the morning, glucose elevation is primarily detected in post-lunch and post-dinner glucose levels [9,18]. Therefore, continuous glucose monitoring is necessary for the comprehensive assessment of blood sugar levels in glucocorticoid-induced hyperglycemia. Additionally, as fasting blood glucose did not show significant reductions with incretin-based treatment, it was considered inadequate as a blood sugar monitoring parameter [20]. Second, our study had a small sample size and lacked a comparative arm. Third, the study did not assess long-term efficacy and safety. However, short-term evaluation of DM control during chemotherapy was deemed sufficient in this study as the exacerbation of DM due to glucocorticoid occurs only in the initial year, and long-term reports suggest no change in the incidence rate of DM [13].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study suggests that dulaglutide may offer effective glycemic control for glucocorticoid-induced hyperglycemia during CHOP therapy. It appeared relatively safe during chemotherapy, with no significant adverse events, such as hypoglycemia or pancreatitis, and the appetite loss observed was indistinguishable from chemotherapy-related adverse effects. Continuous and large-scale studies incorporating sustained glucose monitoring are necessary to further assess the utility of dulaglutide in patients treated with CHOP therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors\u0026nbsp;contributed to the study conception and design. Material preparation, data collection and analysis were performed by Takuya Suyama, Misayo Shimizu and Shinagawa Atsushi. The first draft of the manuscript was written by Takuya Suyama,\u0026nbsp;Matsui Kumiko, and Masatoshi Tsuru\u0026nbsp;and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval was obtained from the Ethics Committee of Hitachi General Hospital. The procedures used in this study adhere to the tenets of\u0026nbsp;Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent to participate was obtained from all participants prior to intervention commencement.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent to publish data was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data can be made available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSehn LH, Donaldso J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, MacPherson N, O\u0026apos;Reilly S, Spinelli JJ, Sutherland J, Wilson KS, Gascoyne RD, Connors JM. 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Metabolism 61:1003-9. https://doi.org/10.1016/j.metabol.2011.11.015\u003c/li\u003e\n \u003cli\u003eHan Z, Xu H, Zhao M, Jing F, Xue H, Xiao S (2022) Diabetes and the Prognosis in Patients With Non-Hodgkin Lymphoma: A Meta-analysis of Cohort Studies.\u003cspan lang=\"\"\u003eClin Lymphoma Myeloma Leuk 22:e77-e88.\u0026nbsp;\u003c/span\u003e\u003cspan lang=\"\"\u003ehttps://doi.org/10.1016/j.clml.2021.08.013\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003eWallace MD, Metzger NL (2018) Optimizing the Treatment of Steroid-Induced Hyperglycemia. Ann Pharmacother 52:86-90. https://doi.org/10.1177/1060028017728297\u003c/li\u003e\n \u003cli\u003eJensen DH, Aaboe K, Henriksen JE, V\u0026oslash;lund A, Holst JJ, Madsbad S, Krarup T (2012) Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes. Diabetologia 55:1406-https://doi.org/10.1007/s00125-012-2459-7\u003c/li\u003e\n \u003cli\u003evan Raalte DH, van Genugten RE, Linssen MM, Ouwens DM, Diamant M (2011) Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans. Diabetes Care 34:412-7. https://doi.org/10.2337/dc10-1677\u003c/li\u003e\n \u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transplant 48:452\u0026ndash;458. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n \u003cli\u003eBaech J, Severinsen MT, \u0026Oslash;vlisen AK, Frederiksen H, Vestergaard P, Torp-Pedersen C, J\u0026oslash;rgensen J, Clausen MR, Poulsen CB, Brown P, Gang AO, Pedersen RS, Ekstr\u0026ouml;m Smedby K, Eloranta S, Jakobsen LH, El-Galaly TC (2022) Risk of diabetes and the impact on preexisting diabetes in patients with lymphoma treated with steroid-containing immunochemotherapy. Blood Adv 6:4427-4435. https://doi.org/10.1182/bloodadvances.2021006859\u003c/li\u003e\n \u003cli\u003eLee SY, Kurita N, Yokoyama Y, Seki M, Hasegawa Y, Okoshi Y, Chiba S (2014) Glucocorticoid-induced diabetes mellitus in patients with lymphoma treated with CHOP chemotherapy. Support Care Cancer 22:1385-90. https://doi.org/10.1007/s00520-013-2097-8\u003c/li\u003e\n \u003cli\u003eOhashi N, Tsuji N, Naito Y, Iwakura T, Isobe S, Ono M, Fujikura T, Tsuji T, Sakao Y, Yasuda H, Kato A, Fujigaki Y (2014) Alogliptin improves steroid-induced hyperglycemia in treatment-na\u0026iuml;ve Japanese patients with chronic kidney disease by decrease of plasma glucagon levels. Med Sci Monit 20:587-93. 10.12659/MSM.889872\u003c/li\u003e\n \u003cli\u003eKatsuyama H, Sako A, Adachi H, Hamasaki H, Yanai H (2015) Effects of 6-month sitagliptin treatment on metabolic parameters in diabetic patients taking oral glucocorticoids: a retrospective cohort study. J Clin Med Res 7:479-84. 10.14740/jocmr2153w\u003c/li\u003e\n \u003cli\u003evan Genugten RE, van Raalte DH, Muskiet MH, Heymans MW, Pouwels PJ, Ouwens DM, Mari A, Diamant M (2014) Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial. Eur J Endocrinol 170:429-39. https://doi.org/10.1530/EJE-13-0610\u003c/li\u003e\n \u003cli\u003eUchinuma H, Ichijo M, Harima N, Tsuchiya K (2020) Dulaglutide improves glucocorticoid-induced hyperglycemia in inpatient care and reduces dose and injection frequency of insulin. BMC Endocr Disord 20:58. https://doi.org/10.1186/s12902-020-0542-5\u003c/li\u003e\n \u003cli\u003eKaneko S, Oura T, Matsui A, Shingaki T, Takeuchi (2017) Efficacy and safety of subgroup analysis stratified by baseline HbA1c in a Japanese phase 3 study of dulaglutide 0.75 mg compared with insulin glargine in patients with type 2 diabetes. M.Endocr J 64:1165-1172. https://doi.org/10.1507/endocrj.EJ17-0189\u003c/li\u003e\n \u003cli\u003eClore JN, Thurby-Hay L (2009) Glucocorticoid-induced hyper-glycemia. Endocr Pract 15(5):469-474. https://doi.org/10.4158/EP08331.RAR\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1: Baseline characteristics of study participants:\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"656\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eMedian age (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e73 (67\u0026ndash;86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eInternational Prognostic Index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003elow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003elow-intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003ehigh-intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eECOG performance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003ehigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e5 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e3 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eHistory of diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eDisease type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eDiffuse large B-cell lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eCHOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eFollicular lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eR-CHOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e7 (87.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003ePeripheral T-cell lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eMedian HbA1C (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e6.7 (5.8\u0026ndash;7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003eAnn Arbor stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eMedian glycoalbumin (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e16.5 (14.2\u0026ndash;21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e2 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eMedication of diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eDPP-4 inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e6 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003eSGLT2 inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003emetformin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003esulfonylurea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.926829268292686%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.634146341463415%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.469512195121951%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"29.115853658536587%\"\u003e\n \u003cp\u003epioglitazone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.853658536585366%\"\u003e\n \u003cp\u003e1 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG, Eastern Cooperative Oncology Group; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; HbA1C, Hemoglobin A1C; DPP-4, Dipeptidyl peptidase-4; SGLT2, Sodium-glucose cotransporter2\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"malignant lymphoma, glucocorticoid-induced hyperglycemia, dulaglutide, CHOP therapy","lastPublishedDoi":"10.21203/rs.3.rs-4216351/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4216351/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eGlucocorticoid-induced hyperglycemia is a serious adverse event of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy and requires chemotherapy dose reduction and drug interruption for remediation. Previous reports have showed that the glucagon-like peptide 1 receptor agonist dulaglutide significantly improves glycemic control in glucocorticoid-induced hyperglycemia. Thus, we aimed to investigate the efficacy and safety of dulaglutide for glucocorticoid-induced hyperglycemia in patients with non-Hodgkin lymphoma treated with CHOP therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eTen newly diagnosed patients with non-Hodgkin lymphoma exhibiting glucocorticoid-induced hyperglycemia during initial cycle CHOP ± rituximab therapy were enrolled. Dulaglutide administration began during the second cycle. Glycemic control parameters (HbA1C, glycoalbumin, and fasting blood glucose) and adverse events were monitored alongside chemotherapy sessions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of the 10 patients, one patient discontinued CHOP treatment due to progression, one patient due to chemotherapy intolerance, and eight patients were finally evaluated. HbA1c and glycoalbumin reduced significantly post-dulaglutide initiation, thereby suggesting improved glycemic control without adverse events, such as hypoglycemia or pancreatitis. Challenges in glycemic assessment due to simultaneous declines in hemoglobin levels alongside HbA1C were noted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eDulaglutide exhibited promise in effectively managing glucocorticoid-induced hyperglycemia during CHOP therapy without serious adverse events.\u003c/p\u003e","manuscriptTitle":"Effects and safety of dulaglutide treatment on glucocorticoid-induced hyperglycemia in patients treated with CHOP therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-12 19:04:54","doi":"10.21203/rs.3.rs-4216351/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab8c7fd6-b519-41be-ac86-c6e8948f8c45","owner":[],"postedDate":"April 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-12T02:40:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-12 19:04:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4216351","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4216351","identity":"rs-4216351","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}