A pharmacovigilance study of sodium-glucose co-transporter 2 inhibitors: adverse events in type 2 diabetic patients having heart failure with reduced ejection fraction

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Elmelegy, Zainab Fahmy, Ahmed Taha This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8939785/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 Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to reduce the risk of heart failure, provide cardiovascular benefit and preserve kidney function in type 2 diabetes mellitus (T2DM) patients. Pharmacovigilance for SGLT2 inhibitors involves monitoring, assessing, and understanding the safety profiles of these agents. Aim of the study To identify adverse drug reactions (ADR) (Type, Severity, and Causality) related to SGLT2 inhibitor use and to compare the identifiable ADRs between type 2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction Patients and methods This study included 65 T2DM patients with prior echocardiographic evidence of left-ventricular systolic dysfunction (LVSD) in addition to 65 control diabetic patients with normal left ventricular function were included. After obtaining full personal ,medical, past and drug history of included patients, a causality assessment using WHO-UMC system was applied as part of pharmacovigilance study to assess SGLT2 inhibitor ADRs in two different visits. Results Laboratory investigations in included patients revealed significantly higher serum potassium in cases group compared to control group. Comparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in both groups. Assessment of causality of recorded ADE in both groups revealed statistical significance as the majority of ADE were possible in both groups. Conclusion The study concludes that dapagliflozin and empagliflozin benefit diabetic patients with or without heart failure by improving mortality, ejection fraction, and kidney function, while slowing disease progression, underscoring their dual cardiovascular and renal protective role as effective therapies. Figures Figure 1 Figure 2 Introduction Diabetes mellitus (DM) is a group of metabolic diseases marked by persistent hyperglycemia due to defects in insulin secretion, insulin action, or both. The two major forms are type 1 diabetes, caused by autoimmune destruction of pancreatic β-cells, and type 2 diabetes, which results from insulin resistance combined with progressive β-cell dysfunction [ 1 ]. Chronic hyperglycemia leads to long-term damage of organs such as the heart, kidneys, eyes, and nerves. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes, making integrated management essential [ 2 ]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of oral antidiabetic drugs. They act by blocking glucose reabsorption in the proximal renal tubules, thereby promoting urinary glucose excretion and lowering blood glucose levels independently of insulin [ 3 ]. Beyond glycemic control, SGLT2 inhibitors have demonstrated significant benefits in reducing body weight, blood pressure, and progression of diabetic kidney disease. Their mechanism also improves cardiac hemodynamics by reducing preload and afterload, which contributes to cardiovascular protection [ 4 , 5 ]. Large-scale clinical trials have shown that SGLT2 inhibitors reduce the risk of major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular mortality in patients with type 2 diabetes [ 6 ]. These benefits extend even to non-diabetic patients with heart failure, highlighting their role as a cardio-renal-metabolic therapy. The drugs’ ability to lower intraglomerular pressure, reduce arterial stiffness, and improve myocardial energy efficiency explains their broad cardiovascular impact [ 7 ]. Pharmacovigilance—the science of monitoring, assessing, and preventing adverse drug reactions (ADRs) is crucial in the widespread use of SGLT2 inhibitors. While these agents are generally well tolerated, they are associated with specific risks such as genital mycotic infections, diabetic ketoacidosis (particularly euglycemic DKA), and rare cases of Fournier’s gangrene. Continuous pharmacovigilance ensures early detection of such ADRs, informs regulatory decisions, and guides clinicians in balancing benefits against risks [ 8 ]. The current study aimed to identify ADR (Type, Severity, and Causality) related to SGLT2 inhibitor use and to compare the identifiable ADRs between type2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction. Patients and Methods Study setting: This comparative cross-sectional study was based on a patient-reported side effect questionnaire to identify ADRs according to the preferred terms of the Medical Dictionary for Regulatory Activities (MedDRA). The study was conducted at Helwan University Hospitals and Ain Shams University hospitals Ethical approval : Ethical approval was obtained from ethical committee in Faculty of Medicine Helwan University and revised by ethical committee in Faculty of Medicine Ain Shams. REC-FMHU Serial number (107-2022) Inclusion Criteria: The study included adult diabetic patients (T2DM) aged 18 years and older. Diagnosis of diabetes was according to the guidelines of American Diabetes Association. Patients must have been previously diagnosed with echocardiographic evidence of Left ventricular systolic dysfunction (LVSD) [9] and were on SGLT2 inhibitor daily treatment. A control group enlisting patients fulfilling all the previous criteria except being diagnosed with heart failure (i.e., with Left Ventricle ejection fraction ≥ 50%) was also included. Exclusion Criteria: Patients diagnosed with T1DM or with HbA1C < 6.0% or severe hepatic disease were excluded. Pregnant or lactating female patients were also excluded. Sample Size calculation: Using PASS 11 Power Analysis and Sample Size Software (2011) software, a minimal sample of 65 participants in each group - totaling 130 participants- achieved a power of 80% to detect an effect size of 0.5 comparing proportions using a two-sided z test with a level of significance of 0.05. Data collection tool: The data was collected in the form of a questionnaire through two visits. It began with obtaining informed consent and verifying inclusion or exclusion criteria, followed by collecting demographic details, medical history, and family history. Clinical data were documented, including diagnoses, treating physician, healthcare facility, and all prescribed medications, with particular focus on the SGLT2 inhibitor used. Specific drug-related information was recorded such as start date, dosage, compliance, frequency, and end date if therapy was discontinued. Adverse events were systematically assessed according to the MedDRA System Organ Class, with severity graded using a standardized scale ranging from very mild (requiring treatment but not drug cessation) to lethal outcomes. Intermediate categories included mild reactions necessitating drug cessation, moderate events requiring hospital visits or prolonged stays, severe cases needing intensive medical care, and very severe events resulting in permanent disability. Finally, causality assessment using WHO-UMC system was applied as part of pharmacovigilance study to determine the relationship between the administered drug and the reported adverse events, ensuring a structured evaluation of safety outcomes [10]. Data analysis: The collected data was revised, coded, tabulated and introduced to a PC using Statistical package for Social Science (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Results The current study included 65 T2DM patients with prior echocardiographic evidence of LVSD in addition to 65 control diabetic patients with normal left ventricular function. No significant difference was detected between the two groups regarding age or gender, however, cardiovascular risk factors as hypertension, smoking and dyslipidemia were significantly presented in cases group compared to control group (Table 1). In addition, there was no significant difference between the two groups as regards SGLT2 type, treatment duration, treatment dosage, other drugs used (Figure 1) or other comorbid diseases (Figure 2). Laboratory investigations in included patients revealed significantly higher first serum potassium sample in cases group compared to control group. No significant difference was detected between cases group and control group regarding other laboratory investigations. Comparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in patients in both cases and control groups in the second sample compared to first sample (Table 2). Assessment of treatment outcome in included patients revealed non-significant difference between cases group and control group regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages (Table 3). Comparison of ejection fraction and laboratory investigations in cases group as regards type of SGLT2 used revealed no statistical significance. In addition, comparison of laboratory investigations between first and second samples showed significant increase in hematocrit value in the second sample compared to first sample (Table 4). Assessment of treatment outcome in cases group revealed no significant difference regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages. On the other hand, assessment of treatment outcome in control group revealed significant differences regarding eGFR 1 and 2 stages. Control group on Empagliflozin had better eGFR stages compared to those on Dapagliflozin (Table 5). Adverse drug events comparison between the cases and controls revealed no statistically significant difference. Most common ADE in cases group were polyuria, dry mouth, dysuria followed by constipation and dizziness. In control groups, the most common ADE were polyuria, dry mouth followed by constipation and dizziness. Assessment of causality of recorded ADEs in both groups revealed statistical significance as the majority of ADE are possible in both groups. In cases group, the most common ADE were polyuria, dry mouth, dysuria and dizziness (Table 6). Distribution of ADE in regards visit 1 or 2 in both groups revealed no statistically significant difference. In cases group, the most common ADE were polyuria, dry mouth, dysuria and dizziness. Similarly, distribution of ADE in regards resolved or not resolved in both groups revealed no statistically significant difference. In cases group, the most common ADE that weren’t resolved were polyuria, dry mouth and dysuria. Discussion The current study aimed to identify ADR related to SGLT2 inhibitor use and to compare the identifiable ADRs between type 2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction. Laboratory investigations revealed significantly higher serum potassium in cases group compared to control group in the first visit. Heart failure often leads to reduced kidney function, which impairs the kidneys' ability to excrete potassium and thus elevated serum levels [11]. In addition, drugs commonly used in heart failure management, such as ACE inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists, and potassium-sparing diuretics, can increase serum potassium levels [12]. Comparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in both groups. In addition, comparison of laboratory investigations between first and second samples showed significant increase in hematocrit value in the second sample compared to first sample. Similarly, previous reports of hemoconcentration were mentioned by Raschi et al., (2017) especially with patients on Dapagliflozin or Empagliflozin therapy [13]. This effect is thought to be due to their diuretic properties, which reduces plasma volume, and their ability to stimulate erythropoiesis by increasing erythropoietin levels [14, 15]. Comparison of ejection fraction and laboratory investigations in cases group as regards type of SGLT2 used revealed no statistical significance. Both Dapagliflozin and Empagliflozin had shown positive effects on ejection fraction. In DAPA-HF Trial, Dapagliflozin significantly reduced the risk of cardiovascular death and worsening heart failure in patients with HFrEF [16]. It improved symptoms, physical function, and quality of life. Moreover, in DELIVER Trial, Dapagliflozin also benefits patients with HFpEF, reducing the risk of heart failure hospitalization and cardiovascular death [17]. Concerning Empagliflozin, the EMPEROR-Reduced trial revealed that Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization in patients with HFrEF. The benefits were consistent across different levels of ejection fraction [18]. While in EMPEROR-Preserved trial, Empagliflozin was effective in reducing heart failure hospitalizations in patients with HFpEF [19]. In the present study, assessment of treatment outcome in cases group revealed no significant difference regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages. Concerning the control group, assessment of treatment outcome in control group revealed significant difference regarding eGFR 1 and 2 stages. Control group on Empagliflozin had better eGFR stages compared to those on Dapagliflozin. While both medications are effective in improving eGFR and slowing the progression of kidney disease, some studies suggest that Empagliflozin may have a slightly better effect on eGFR compared to Dapagliflozin which is similar to our results [20, 21]. The EMPA-REG OUTCOME trial demonstrated that Empagliflozin significantly slowed the decline in eGFR and reduced the risk of kidney disease progression in patients with type 2 diabetes and established cardiovascular disease [20]. The EMPA-KIDNEY trial further supported these findings, showing that Empagliflozin improved eGFR and reduced the risk of serious renal events in patients with chronic kidney disease, including those with type 2 diabetes [22]. Adverse drug events comparison between the cases and controls revealed no statistically significant difference. Most common ADE in cases group were polyuria, dry mouth, dysuria followed by constipation and dizziness. In control group, most common ADE were polyuria, dry mouth followed by constipation and dizziness. In the same context, Zhou et al., (2021) reported that SGLT2i-related AEs were presented in 30.03% of patients treated with Empagliflozin and reported in 22.67% of patients treated with Dapagliflozin [23]. SGLT2 inhibitors, such as Dapagliflozin and Empagliflozin, are generally well-tolerated, and common ADEs reported were in agreement with our results. Patients often experience a higher frequency of urination, which can be bothersome. Also, increased frequency of urination can lead to a higher risk of UTIs [24]. Dry mouth is a less common side effect of SGLT2 inhibitors. It can occur due to the diuretic effect of these medications, which increases urination and can lead to dehydration [25]. Constipation is also a reported side effect of SGLT2 inhibitors. This can be related to changes in fluid balance and dehydration caused by increased urination [26]. Dizziness is a common side effect and is often related to the diuretic effect of SGLT2 inhibitors, which can lead to a drop in blood pressure and dehydration [24]. Conclusion The current study concludes that both dapagliflozin and empagliflozin provide substantial benefits for patients with diabetes, regardless of the presence of heart failure. These agents demonstrated positive effects on mortality, ejection fraction, and eGFR, while also contributing to the slowing of kidney disease progression. Collectively, the findings highlight their dual role in improving cardiovascular outcomes and preserving renal function, reinforcing their value as effective therapeutic options in the management of diabetic patients. Limitations While this study provides a robust comparative analysis of SGLT2 inhibitor safety profiles in a specific clinical population, certain considerations regarding its scope should be noted. First, the sample size of 130 participants was statistically powered to detect a significant effect size for the primary safety and efficacy outcomes. However, as with many clinical studies of this scale, the detection of extremely rare adverse drug reactions (ADRs) may require larger multi-center pharmacovigilance cohorts. Second, the comparative cross-sectional design offers a valuable snapshot of real-world safety signals during two distinct visits, though long-term longitudinal monitoring would be required to assess temporal trends over several years. Third, the reliance on patient-reported side effect questionnaires ensured a patient-centered approach to safety monitoring, though these subjective reports may occasionally differ from clinician-graded assessments. Abbreviations CVD: Cardiovascular disease SGLT2: Sodium-glucose cotransporter-2 ADRs: Adverse drug reactions T2DM: Type 2 diabetes mellitus LVSD: Left ventricular systolic dysfunction WHO: World Health Organization UMC: Uppsala Monitoring Centre ARBs: Angiotensin receptor blockers HFrEF: Heart Failure with Reduced Ejection Fraction eGFR: Estimated Glomerular Filtration Rate UTIs: Urinary Tract Infections Declarations Ethics approval and consent to participate: Ethical approval was obtained from ethical committee in Faculty of Medicine Helwan University and revised by ethical committee in Faculty of Medicine Ain Shams. REC-FMHU Serial number (107-2022) Consent for publication: All participants provided consent for publication of relevant data. Availability of data and materials: The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Authors' contributions: RSS (Rimonda Samuel Salama): Conceptualized the study, developed the methodology, performed data collection, conducted the formal analysis, and wrote the original manuscript draft. AASE (Ahmed Abdel Salam M. Elmelegy): Contributed to conceptualization, methodology, and provided clinical supervision and critical review of the manuscript. ZAF (Zainab Abdel Salam Fahmy): Contributed to conceptualization, provided cardiology-specific clinical oversight, and reviewed the final manuscript. 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Curr Drug Saf. 2018;13(2):84–91. 10.2174/1574886313666180226103408 . Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8939785","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":622827957,"identity":"b07a7ede-357e-4d06-96d2-3e52b47b5b06","order_by":0,"name":"Rimonda Salama","email":"data:image/png;base64,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","orcid":"","institution":"Helwan University","correspondingAuthor":true,"prefix":"","firstName":"Rimonda","middleName":"","lastName":"Salama","suffix":""},{"id":622827959,"identity":"aaada69c-e8c4-4725-be20-4e603fe25d9f","order_by":1,"name":"Ahmed M. Elmelegy","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"M.","lastName":"Elmelegy","suffix":""},{"id":622827969,"identity":"bdc59949-7114-4d3e-b0fb-fb36cda82897","order_by":2,"name":"Zainab Fahmy","email":"","orcid":"","institution":"Ain Shams University","correspondingAuthor":false,"prefix":"","firstName":"Zainab","middleName":"","lastName":"Fahmy","suffix":""},{"id":622827970,"identity":"d5c17ec7-069e-4db0-ab6c-c79683ec9a0a","order_by":3,"name":"Ahmed Taha","email":"","orcid":"","institution":"Helwan University","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Taha","suffix":""}],"badges":[],"createdAt":"2026-02-22 14:38:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8939785/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8939785/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107254273,"identity":"0de0dcce-2f9e-4793-b723-3bf458bfaedc","added_by":"auto","created_at":"2026-04-19 12:00:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21237,"visible":true,"origin":"","legend":"\u003cp\u003eOther drugs used in both groups\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8939785/v1/0d3f7c88635af2b9f7dce1dd.png"},{"id":107254275,"identity":"03d1f08b-cc4d-410e-9c44-a74cd769c931","added_by":"auto","created_at":"2026-04-19 12:00:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35251,"visible":true,"origin":"","legend":"\u003cp\u003eOther diseases in both groups\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8939785/v1/b4481d4f6260868a40a76ca6.png"},{"id":109205215,"identity":"ddf22bc7-404b-4eb2-9559-c31f82521287","added_by":"auto","created_at":"2026-05-13 15:03:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":188363,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8939785/v1/df672311-48e7-437e-8143-20d624cd8f6c.pdf"},{"id":107484534,"identity":"df303afd-d3a5-49fc-88bc-f67c6482779d","added_by":"auto","created_at":"2026-04-22 02:32:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29391,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8939785/v1/8dc13c13b94b7e17962d6201.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A pharmacovigilance study of sodium-glucose co-transporter 2 inhibitors: adverse events in type 2 diabetic patients having heart failure with reduced ejection fraction","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetes mellitus (DM) is a group of metabolic diseases marked by persistent hyperglycemia due to defects in insulin secretion, insulin action, or both. The two major forms are type 1 diabetes, caused by autoimmune destruction of pancreatic β-cells, and type 2 diabetes, which results from insulin resistance combined with progressive β-cell dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Chronic hyperglycemia leads to long-term damage of organs such as the heart, kidneys, eyes, and nerves. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes, making integrated management essential [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of oral antidiabetic drugs. They act by blocking glucose reabsorption in the proximal renal tubules, thereby promoting urinary glucose excretion and lowering blood glucose levels independently of insulin [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Beyond glycemic control, SGLT2 inhibitors have demonstrated significant benefits in reducing body weight, blood pressure, and progression of diabetic kidney disease. Their mechanism also improves cardiac hemodynamics by reducing preload and afterload, which contributes to cardiovascular protection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLarge-scale clinical trials have shown that SGLT2 inhibitors reduce the risk of major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular mortality in patients with type 2 diabetes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These benefits extend even to non-diabetic patients with heart failure, highlighting their role as a cardio-renal-metabolic therapy. The drugs\u0026rsquo; ability to lower intraglomerular pressure, reduce arterial stiffness, and improve myocardial energy efficiency explains their broad cardiovascular impact [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePharmacovigilance\u0026mdash;the science of monitoring, assessing, and preventing adverse drug reactions (ADRs) is crucial in the widespread use of SGLT2 inhibitors. While these agents are generally well tolerated, they are associated with specific risks such as genital mycotic infections, diabetic ketoacidosis (particularly euglycemic DKA), and rare cases of Fournier\u0026rsquo;s gangrene. Continuous pharmacovigilance ensures early detection of such ADRs, informs regulatory decisions, and guides clinicians in balancing benefits against risks [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe current study aimed to identify ADR (Type, Severity, and Causality) related to SGLT2 inhibitor use and to compare the identifiable ADRs between type2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy setting:\u0026nbsp;\u003c/strong\u003eThis comparative cross-sectional study was based on a patient-reported side effect questionnaire to identify ADRs according to the preferred terms of the Medical Dictionary for Regulatory Activities (MedDRA).\u0026nbsp;The study was conducted at Helwan University Hospitals and Ain Shams University hospitals\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e: Ethical approval was obtained from ethical committee in Faculty of Medicine Helwan University and revised by ethical committee in Faculty of Medicine Ain Shams. REC-FMHU Serial number (107-2022)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion Criteria:\u0026nbsp;\u003c/strong\u003eThe study included adult diabetic patients (T2DM) aged 18 years and older. Diagnosis of diabetes was according to the guidelines of American Diabetes Association. Patients must have been previously diagnosed with echocardiographic evidence of Left ventricular systolic dysfunction (LVSD) [9] and were on SGLT2 inhibitor daily treatment. \u0026nbsp;A control group enlisting patients fulfilling all the previous criteria except being diagnosed with heart failure (i.e., with Left Ventricle ejection fraction \u0026ge; 50%) was also included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria:\u0026nbsp;\u003c/strong\u003ePatients diagnosed with T1DM or with HbA1C \u0026lt; 6.0% or severe hepatic disease were excluded. Pregnant or lactating female patients were also excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size calculation:\u0026nbsp;\u003c/strong\u003eUsing\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePASS 11 Power Analysis and Sample Size Software (2011) software, a minimal sample of 65 participants in each group - totaling 130 participants- achieved a power of 80% to detect an effect size of 0.5 comparing proportions using a two-sided z test with a level of significance of 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection tool:\u003c/strong\u003e The data was collected in the form of a questionnaire through two visits. It began with obtaining informed consent and verifying inclusion or exclusion criteria, followed by collecting demographic details, medical history, and family history. Clinical data were documented, including diagnoses, treating physician, healthcare facility, and all prescribed medications, with particular focus on the SGLT2 inhibitor used. Specific drug-related information was recorded such as start date, dosage, compliance, frequency, and end date if therapy was discontinued.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdverse events were systematically assessed according to the MedDRA System Organ Class, with severity graded using a standardized scale ranging from \u003cstrong\u003every mild\u003c/strong\u003e (requiring treatment but not drug cessation) to lethal outcomes. Intermediate categories included \u003cstrong\u003emild reactions\u003c/strong\u003e necessitating drug cessation, \u003cstrong\u003emoderate events\u003c/strong\u003e requiring hospital visits or prolonged stays, \u003cstrong\u003esevere cases\u003c/strong\u003e needing intensive medical care, and \u003cstrong\u003every severe events\u003c/strong\u003e resulting in permanent disability.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, causality assessment using WHO-UMC system was applied as part of pharmacovigilance study to determine the relationship between the administered drug and the reported adverse events, ensuring a structured evaluation of safety outcomes [10].\u003c/p\u003e\n\u003cp\u003eData analysis: The collected data was revised, coded, tabulated and introduced to a PC using Statistical package for Social Science \u003cstrong\u003e(IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).\u003c/strong\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe current study included 65 T2DM patients with prior echocardiographic evidence of LVSD in addition to 65 control diabetic patients with normal left ventricular function. No significant difference was detected between the two groups regarding age or gender, however, cardiovascular risk factors as hypertension, smoking and dyslipidemia were significantly presented in cases group compared to control group (Table 1). In addition, there was no significant difference between the two groups as regards SGLT2 type, treatment duration, treatment dosage, other drugs used (Figure 1) or other comorbid diseases (Figure 2).\u003c/p\u003e\n\u003cp\u003eLaboratory investigations in included patients revealed significantly higher first serum potassium sample in cases group compared to control group. No significant difference was detected between cases group and control group regarding other laboratory investigations. Comparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in patients in both cases and control groups in the second sample compared to first sample (Table 2).\u003c/p\u003e\n\u003cp\u003eAssessment of treatment outcome in included patients revealed non-significant difference between cases group and control group regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages (Table 3). Comparison of ejection fraction and laboratory investigations in cases group as regards type of SGLT2 used revealed no statistical significance. In addition, comparison of laboratory investigations between first and second samples showed significant increase in hematocrit value in the second sample compared to first sample (Table 4).\u003c/p\u003e\n\u003cp\u003eAssessment of treatment outcome in cases group revealed no significant difference regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages. On the other hand, assessment of treatment outcome in control group revealed significant differences regarding eGFR 1 and 2 stages. Control group on Empagliflozin had better eGFR stages compared to those on Dapagliflozin (Table 5).\u003c/p\u003e\n\u003cp\u003eAdverse drug events comparison between the cases and controls revealed no statistically significant difference. Most common ADE in cases group were polyuria, dry mouth, dysuria followed by constipation and dizziness. In control groups, the most common ADE were polyuria, dry mouth followed by constipation and dizziness. Assessment of causality of recorded ADEs in both groups revealed statistical significance as the majority of ADE are possible in both groups. In cases group, the most common ADE were polyuria, dry mouth, dysuria and dizziness (Table 6).\u003c/p\u003e\n\u003cp\u003eDistribution of ADE in regards visit 1 or 2 in both groups revealed no statistically significant difference. In cases group, the most common ADE were polyuria, dry mouth, dysuria and dizziness. Similarly, distribution of ADE in regards resolved or not resolved in both groups revealed no statistically significant difference. In cases group, the most common ADE that weren\u0026rsquo;t resolved were polyuria, dry mouth and dysuria.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study aimed to identify ADR related to SGLT2 inhibitor use and to compare the identifiable ADRs between type 2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction. Laboratory investigations revealed significantly higher serum potassium in cases group compared to control group in the first visit. Heart failure often leads to reduced kidney function, which impairs the kidneys\u0026apos; ability to excrete potassium and thus elevated serum levels [11]. In addition, drugs commonly used in heart failure management, such as ACE inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists, and potassium-sparing diuretics, can increase serum potassium levels [12].\u003c/p\u003e\n\u003cp\u003eComparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in both groups. In addition, comparison of laboratory investigations between first and second samples showed significant increase in hematocrit value in the second sample compared to first sample. Similarly, previous reports of hemoconcentration were mentioned by \u003cstrong\u003eRaschi et al., (2017)\u003c/strong\u003e especially with patients on Dapagliflozin or Empagliflozin therapy [13]. This effect is thought to be due to their diuretic properties, which reduces plasma volume, and their ability to stimulate erythropoiesis by increasing erythropoietin levels [14, 15].\u003c/p\u003e\n\u003cp\u003eComparison of ejection fraction and laboratory investigations in cases group as regards type of SGLT2 used revealed no statistical significance. Both Dapagliflozin and Empagliflozin had shown positive effects on ejection fraction. In DAPA-HF Trial, Dapagliflozin significantly reduced the risk of cardiovascular death and worsening heart failure in patients with HFrEF [16]. It improved symptoms, physical function, and quality of life. Moreover,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ein DELIVER Trial, Dapagliflozin also benefits patients with HFpEF, reducing the risk of heart failure hospitalization and cardiovascular death [17].\u003c/p\u003e\n\u003cp\u003eConcerning Empagliflozin, the EMPEROR-Reduced trial revealed that Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization in patients with HFrEF. The benefits were consistent across different levels of ejection fraction [18]. While in EMPEROR-Preserved trial, Empagliflozin was effective in reducing heart failure hospitalizations in patients with HFpEF [19].\u003c/p\u003e\n\u003cp\u003eIn the present study, assessment of treatment outcome in cases group revealed no significant difference regarding mortality, treatment cessation and its cause, eGFR 1 and 2 results and stages. Concerning the control group, assessment of treatment outcome in control group revealed significant difference regarding eGFR 1 and 2 stages. Control group on Empagliflozin had better eGFR stages compared to those on Dapagliflozin.\u003c/p\u003e\n\u003cp\u003eWhile both medications are effective in improving eGFR and slowing the progression of kidney disease, some studies suggest that Empagliflozin may have a slightly better effect on eGFR compared to Dapagliflozin which is similar to our results [20, 21]. The EMPA-REG OUTCOME trial demonstrated that Empagliflozin significantly slowed the decline in eGFR and reduced the risk of kidney disease progression in patients with type 2 diabetes and established cardiovascular disease [20]. The EMPA-KIDNEY trial further supported these findings, showing that Empagliflozin improved eGFR and reduced the risk of serious renal events in patients with chronic kidney disease, including those with type 2 diabetes [22].\u003c/p\u003e\n\u003cp\u003eAdverse drug events comparison between the cases and controls revealed no statistically significant difference. Most common ADE in cases group were polyuria, dry mouth, dysuria followed by constipation and dizziness. In control group, most common ADE were polyuria, dry mouth followed by constipation and dizziness.\u003c/p\u003e\n\u003cp\u003eIn the same context, \u003cstrong\u003eZhou et al., (2021)\u003c/strong\u003e reported that SGLT2i-related AEs were presented in 30.03% of patients treated with Empagliflozin and reported in 22.67% of patients treated with Dapagliflozin [23]. SGLT2 inhibitors, such as Dapagliflozin and Empagliflozin, are generally well-tolerated, and common ADEs reported were in agreement with our results. Patients often experience a higher frequency of urination, which can be bothersome. Also, increased frequency of urination can lead to a higher risk of UTIs [24]. Dry mouth is a less common side effect of SGLT2 inhibitors. It can occur due to the diuretic effect of these medications, which increases urination and can lead to dehydration [25]. Constipation is also a reported side effect of SGLT2 inhibitors. This can be related to changes in fluid balance and dehydration caused by increased urination [26]. Dizziness is a common side effect and is often related to the diuretic effect of SGLT2 inhibitors, which can lead to a drop in blood pressure and dehydration [24].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current study concludes that both dapagliflozin and empagliflozin provide substantial benefits for patients with diabetes, regardless of the presence of heart failure. These agents demonstrated positive effects on mortality, ejection fraction, and eGFR, while also contributing to the slowing of kidney disease progression. Collectively, the findings highlight their dual role in improving cardiovascular outcomes and preserving renal function, reinforcing their value as effective therapeutic options in the management of diabetic patients.\u003c/p\u003e\n"},{"header":"Limitations","content":"\u003cp\u003eWhile this study provides a robust comparative analysis of SGLT2 inhibitor safety profiles in a specific clinical population, certain considerations regarding its scope should be noted. First, the sample size of 130 participants was statistically powered to detect a significant effect size for the primary safety and efficacy outcomes. However, as with many clinical studies of this scale, the detection of extremely rare adverse drug reactions (ADRs) may require larger multi-center pharmacovigilance cohorts. Second, the comparative cross-sectional design offers a valuable snapshot of real-world safety signals during two distinct visits, though long-term longitudinal monitoring would be required to assess temporal trends over several years. Third, the reliance on patient-reported side effect questionnaires ensured a patient-centered approach to safety monitoring, though these subjective reports may occasionally differ from clinician-graded assessments.\u0026nbsp;\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003eCVD: Cardiovascular disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGLT2: Sodium-glucose cotransporter-2 \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eADRs: Adverse drug reactions\u003c/p\u003e\n\u003cp\u003eT2DM: Type 2 diabetes mellitus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLVSD: Left ventricular systolic dysfunction\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e\n\u003cp\u003eUMC: Uppsala Monitoring Centre\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eARBs: Angiotensin receptor blockers\u003c/p\u003e\n\u003cp\u003eHFrEF: Heart Failure with Reduced Ejection Fraction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eeGFR: Estimated Glomerular Filtration Rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUTIs: Urinary Tract Infections\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from ethical committee in \u0026nbsp;Faculty of Medicine Helwan University and revised by ethical committee in \u0026nbsp;Faculty of \u0026nbsp;Medicine Ain Shams. REC-FMHU Serial number (107-2022)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All participants provided consent for publication of relevant data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eRSS (Rimonda Samuel Salama): Conceptualized the study, developed the methodology, performed data collection, conducted the formal analysis, and wrote the original manuscript draft.\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAASE (Ahmed Abdel Salam M. Elmelegy): Contributed to conceptualization, methodology, and provided clinical supervision and critical review of the manuscript.\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eZAF (Zainab Abdel Salam Fahmy): Contributed to conceptualization, provided cardiology-specific clinical oversight, and reviewed the final manuscript.\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAMT (Ahmed Mohammed Taha): Contributed to the study methodology, assisted with data analysis software, and participated in the revision of the manuscript.\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eAll authors read and approved the final manuscript.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNot applicable\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIslam K, Islam R, Nguyen I, Malik H, Pirzadah H, Shrestha B, et al. 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JAMA Cardiol. 2022;7(12):1227\u0026ndash;34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamacardio.2022.3736\u003c/span\u003e\u003cspan address=\"10.1001/jamacardio.2022.3736\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler J, Packer M, Filippatos G, Ferreira JP, Zeller C, Schnee J, et al. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur Heart J. 2022;43(5):416\u0026ndash;26. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehab798\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehab798\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler J, Usman MS, Filippatos G, Ferreira JP, B\u0026ouml;hm M, Brueckmann M, et al. 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Eur Heart J Cardiovasc Pharmacother. 2024;10(5):432\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ehjcvp/pvae045\u003c/span\u003e\u003cspan address=\"10.1093/ehjcvp/pvae045\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShin H, Paik JM, Everett BM, Glynn R, Wexler DJ, Patorno E. 915-P: Head-to-Head Comparison of Dapagliflozin vs. Empagliflozin\u0026mdash;Cardiovascular and Safety Events. Diabetes. 2024;73(Supplement1):915\u0026ndash;P. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2337/db24-915-P\u003c/span\u003e\u003cspan address=\"10.2337/db24-915-P\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShao SC, Chang KC, Hung MJ, Yang NI, Chan YY, Chen HY, et al. 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Curr Drug Saf. 2018;13(2):84\u0026ndash;91. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/1574886313666180226103408\u003c/span\u003e\u003cspan address=\"10.2174/1574886313666180226103408\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e\n"}],"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":"","lastPublishedDoi":"10.21203/rs.3.rs-8939785/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8939785/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to reduce the risk of heart failure, provide cardiovascular benefit and preserve kidney function in type 2 diabetes mellitus (T2DM) patients. Pharmacovigilance for SGLT2 inhibitors involves monitoring, assessing, and understanding the safety profiles of these agents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim of the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo identify adverse drug reactions (ADR) (Type, Severity, and Causality) related to SGLT2 inhibitor use and to compare the identifiable ADRs between type 2 diabetic patients without heart failure and diabetic patients having heart failure with reduced ejection fraction\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 65 T2DM patients with prior echocardiographic evidence of left-ventricular systolic dysfunction (LVSD) in addition to 65 control diabetic patients with normal left ventricular function were included. After obtaining full personal ,medical, past and drug history of included patients, a causality assessment using WHO-UMC system was applied as part of pharmacovigilance study to assess SGLT2 inhibitor ADRs in two different visits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLaboratory investigations in included patients revealed significantly higher serum potassium in cases group compared to control group. Comparison of laboratory investigations between first and second samples in each group individually revealed significant increase in hematocrit value in both groups. Assessment of causality of recorded ADE in both groups revealed statistical significance as the majority of ADE were possible in both groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study concludes that dapagliflozin and empagliflozin benefit diabetic patients with or without heart failure by improving mortality, ejection fraction, and kidney function, while slowing disease progression, underscoring their dual cardiovascular and renal protective role as effective therapies.\u003c/p\u003e","manuscriptTitle":"A pharmacovigilance study of sodium-glucose co-transporter 2 inhibitors: adverse events in type 2 diabetic patients having heart failure with reduced ejection fraction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:00:53","doi":"10.21203/rs.3.rs-8939785/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":"27ba0008-e80a-4f0c-b69a-eed267e6d3a5","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-11T10:39:05+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T10:57:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:00:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8939785","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8939785","identity":"rs-8939785","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}