Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics.

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The American Diabetes Association recommends metformin, a biguanide medication, as the first option for oral control of type 2 diabetes because it has demonstrated promise in this regard. Aim of the study To evaluate and compare the effects of metformin and SGLT-2 inhibitors on general urine parameters in T2DM patients from Iraq. Method a prospective cohort study where 101 adult patients of both sexes aged under 70 years and newly diagnosed with T2DM, patients were divided into two groups, Metformin group (n=52), where metformin was prescribed as monotherapy by the clinician and SGLT-2 inhibitors group (n=49) where either dapagliflozin or empagliflozin were prescribed by the clinician, general urine examination was done for each patient in the first contact and after 12 weeks of treatment. Results The mean age was 57±9 years for the metformin group and 54±9 years for the SGLT-2 inhibitors group. There was no significant difference in leukocytes, erythrocytes, or epithelial cell counts between the metformin group and the SGLT2 inhibitor group before and after 12 weeks of treatment. There was a significant difference (p-value =0.043) in leukocytes and a non-significant difference in erythrocytes and epithelial cell counts before and after treatment in the SGLT-2 inhibitors group. Conclusions Diabetic patients on SGLT-2 inhibitors treatment demonstrated higher leukocyte count than metformin group patients, an indicator and predictor for higher susceptibility to urinary tract infections. 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F1000Research 2024, 13 :1397 ( https://doi.org/10.12688/f1000research.158805.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] Diana Noori Hussien https://orcid.org/0009-0003-7970-9038 1 , Samara Mowafaq Ali https://orcid.org/0000-0001-7105-6966 1 Diana Noori Hussien https://orcid.org/0009-0003-7970-9038 1 , Samara Mowafaq Ali https://orcid.org/0000-0001-7105-6966 1 PUBLISHED 21 Nov 2024 Author details Author details 1 Department of Pharmacology and Toxicology, College of Medicine, University of Baghdad, Baghdad, Baghdad Governorate, 10045, Iraq Diana Noori Hussien Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation Samara Mowafaq Ali Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Many antidiabetic medications with distinct modes of action are available, The sodium glucose cotransporter-2 (SGLT-2) inhibitors are among the most recent oral antihyperglycemic medications. The American Diabetes Association recommends metformin, a biguanide medication, as the first option for oral control of type 2 diabetes because it has demonstrated promise in this regard. Aim of the study To evaluate and compare the effects of metformin and SGLT-2 inhibitors on general urine parameters in T2DM patients from Iraq. Method a prospective cohort study where 101 adult patients of both sexes aged under 70 years and newly diagnosed with T2DM, patients were divided into two groups, Metformin group (n=52), where metformin was prescribed as monotherapy by the clinician and SGLT-2 inhibitors group (n=49) where either dapagliflozin or empagliflozin were prescribed by the clinician, general urine examination was done for each patient in the first contact and after 12 weeks of treatment. Results The mean age was 57±9 years for the metformin group and 54±9 years for the SGLT-2 inhibitors group. There was no significant difference in leukocytes, erythrocytes, or epithelial cell counts between the metformin group and the SGLT2 inhibitor group before and after 12 weeks of treatment. There was a significant difference (p-value =0.043) in leukocytes and a non-significant difference in erythrocytes and epithelial cell counts before and after treatment in the SGLT-2 inhibitors group. Conclusions Diabetic patients on SGLT-2 inhibitors treatment demonstrated higher leukocyte count than metformin group patients, an indicator and predictor for higher susceptibility to urinary tract infections. READ ALL READ LESS Keywords Urinary Tract Infection, Metformin, SGLT-2 inhibitors, diabetes mellitus. Corresponding Author(s) Diana Noori Hussien ( [email protected] ) Close Corresponding author: Diana Noori Hussien Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Hussien DN and Ali SM. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Hussien DN and Ali SM. Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :1397 ( https://doi.org/10.12688/f1000research.158805.1 ) First published: 21 Nov 2024, 13 :1397 ( https://doi.org/10.12688/f1000research.158805.1 ) Latest published: 21 Nov 2024, 13 :1397 ( https://doi.org/10.12688/f1000research.158805.1 ) Introduction Diabetes mellitus type 2 (T2DM) is linked to a high rate of death and morbidity, and it may harm the patient’s cardiovascular, renal, and neurological systems. 1 One of the main risk factors for type 2 diabetes is a family history of the disease. It is characterized by gradual dysfunction of β-cells; numerous studies have employed C peptide levels as a biomarker of β-cell function. 2 Patients with coronary artery disease have more health issues as a result of insulin resistance, which is the primary cause of type 2 diabetes. 3 Diabetes mellitus type 2 frequently results in diabetic nephropathy. Urine and plasma contain neutrophil gelatinase-associated lipocalin (NGAL), which is detectable beginning two to four hours following a kidney injury. When GFR decreased, serum NGAL rose noticeably. Regarding type 2 diabetes mellitus, serum NGAL may be a prognostic sign for the early identification of diabetic nephropathy. 4 In the general population, diabetes mellitus type II (DM) is one of the main causes of osteoporosis. 5 Longer diabetes duration was associated with a higher risk of UTI rather than glycemic control (HbA1C). Women receiving pharmaceutical treatment for diabetes were primarily at higher risk, indicating a correlation between the severity of diabetes and UTI risk. The most frequently isolated organism in all women, including young women, was E. coli. 6 Among female diabetics with problems of neuropathy, nephropathy, and retinopathy, the prevalence of asymptomatic pyuria has increased. As diabetic microangiopathy worsens, the prevalence of asymptomatic pyuria rises with the increasing period of having diabetes. 7 Medication and lifestyle modifications are two methods for treating type 2 diabetes. The American Diabetes Association 8 recommends that the biguanide medication metformin be used as the primary option for oral therapy of type 2 diabetes because it has demonstrated promise. Weight loss, vascular protection, and glucose metabolism are all positively impacted by metformin. 9 Patients with type 2 diabetes (T2DM) may have considerable differences in their glycemic control and adiposity indicators due to a variety of factors, including metformin dosages and treatment adherence. Elevating the metformin dose did not correlate with body fat percentage or insulin resistance. 10 Dapagliflozin is a popular oral antidiabetic medication that selectively and reversibly inhibits the sodium-glucose co-transporter-2 (SGLT-2). It increases urine glucose excretion, which can dramatically reduce hyperglycemia without affecting the function of the pancreatic β cell. Compared to the control group, dapagliflozin improves hemoglobin concentration and corrects anemia in patients with heart failure and CKD. 11 SGLT-2 inhibitors provide bacteria with a substrate to feed on since they increase the amount of glucose in the urinary system. As a result, they have already been connected to genitourinary tract infections. 12 The current study aims to evaluate and compare the effects of metformin and SGLT-2 inhibitors on general urine parameters in T2DM patients from Iraq. Methods Study design In a prospective study where 101 adult patients of both sexes aged under 70 years and newly diagnosed with T2DM based on the International Expert Committee criteria, 13 patients were recruited and called weekly from a single private clinician record who gave informed consent to access the weekly patient archives for 2 months. The recruited patients were then divided into two groups: the Metformin group (n=52), where metformin was prescribed as monotherapy by the clinician, and the SGLT-2 inhibitors group (n=49) where either dapagliflozin or empagliflozin were prescribed by the clinician, Each patient was invited to a private laboratory where sociodemographic data (age, education level, social status, and smoking status) and clinical data were collected during the face-to-face interviews with the patients. A microscopic general urine examination was then done for each patient on their first contact and after 12 weeks of treatment. Study settings The study was conducted in cooperation with a single private internist clinic and a single private laboratory in Baghdad, Iraq. The patients were recruited and did their first general urine examination in the period between the 1 st of January 2023 and the 1 st of March 2023, All patients underwent their second test before the 1 st of May 2023, and all patients and other private parties provided their written and informed consent to participate in the study. Participants Inclusion criteria Adult Patients of both sexes aged under 70 years old, newly diagnosed with T2DM, 13 taking either metformin monotherapy or SGLT-2 inhibitors (Dapagliflozin or Empagliflozin). Exclusion criteria Patients who refused to participate in the study, patients with ongoing acute or chronic kidney diseases, and patients with ongoing urinary tract infections. Analytic procedures Each patient was provided 15-30 ml of clean-catch midstream urine, the urine specimen was then prepared and examined under the High Power Field of the light microscope (Olympus BX51 Microscope, Olympus Corporation ® , Japan) to count the cells and provide the result of cellular microscopic examination. Outcome measures Each patient underwent two microscopic general urine examinations separated by 12 weeks of continuous diabetes treatment, data on the Erythrocyte count, Leukocyte count, and epithelial cell count was then obtained in the Cell/HPF unit to evaluate and compare the effect of both metformin and SGLT-2 inhibitors on these urinary parameters. Sample size estimation Each eligible patient completed the research tool in writing and completed the consent form. The following formula was utilized to determine the sample size 14 : n = Z 1 − α 2 2 σ 2 d 2 In this case, d indicates the precision of the quantitative variable estimate, n is the sample size, α is the first type, Z is the table-based normal distribution index that is taken into account at 5% type-one error (P<0.05), and σ stands for the small variable variance. 15 A first type error in this study has values of 0.05, 96.3, 7.38, and 0.99, correspondingly for z, σ, and d. XXX were taken into consideration as the sample size and were included in the data analysis after accounting for the 10% non-response. 16 For every region in the nation, a sample size of XXX was determined with a design effect of 2, 80% statistical power with a two-sided test, and α = 0.05 to detect a 10% decrease. It was assumed that 30% of people had an irregular legal status at time 1 (the current study) and 20% at time 2 (the subsequent study round). 17 Ethical considerations The study was approved by the Institutional Review Board (IRB) in the College of Medicine/University of Baghdad (Approval no. 03-11 on 31 st of December 2023), the ethical approval for the current study was uploaded to the Zenodo: Ethical approval and reporting guidelines. https://doi.org/10.5281/zenodo.14037291 . 18 This project contains the following file: (Ethical approval.jpg). Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Statistical analysis The obtained data were entered, coded, displayed, and examined using a computer utilizing the IBM SPSS-29 statistical package (IBM Statistical Packages for Social Sciences, version 29, Chicago, IL, USA) that was made accessible as a database software program. Simple metrics of frequency, percentage, mean, standard deviation, and range (minimum-maximum values) were used to present the data. 19 The Students-t test was used to determine the significance of the difference between two independent means (quantitative data). When evaluating the significance of differences in percentages (qualitative data), the Pearson Chi-square test (χ 2 -test) was employed, along with Yate’s adjustment or the Fisher Exact test if necessary. The P value was considered statistically significant if it was equal to or less than 0.05. 20 Results Sociodemographic and clinical characteristics of the participants The study included 101 patients with type 2 diabetes mellitus; 52 were receiving metformin, and 49 were receiving either dapagliflozin or empagliflozin. The mean age of the patients was 57±9 for metformin and 54±9 for SGLT2 inhibitors; 63.5% were illiterate, 94.2% of the metformin group and 93.9% of SGLT2 inhibitor group were married, 78.8% of the metformin group and 81.6% of SGLT2 inhibitor group were non-smokers, and 53.8% of metformin group and 57.1% of SGLT2 inhibitor group were hypertensive ( Table 1 ). Table 1. Sociodemographic and clinical characteristics of the participants. Metformin SGLT-2 inhibitors P value No % No % Age (years) <40 years 2 3.8 5 10.2 0.397 40---49 8 15.4 11 22.4 50---59 23 44.2 22 44.9 60---69 14 26.9 9 18.4 ≥70years 5 9.6 2 4.1 Mean±SD (Range) 57±9 (39-76) 54±9 (30-75) 0.097 Gender Male 15 28.8 16 32.7 0.678 Female 37 71.2 33 67.3 Marital status Married 49 94.2 46 93.9 0.940 Single 3 5.8 3 6.1 Education Primary & Secondary 36 69.2 33 67.3 0.839 Illiterate 16 30.8 16 32.7 Smoking Smoker 11 21.2 9 18.4 0.725 Not smoker 41 78.8 40 81.6 Hypertension Hypertensive 28 53.8 28 57.1 0.739 Not 24 46.2 21 42.9 * Significant difference between percentages using Pearson Chi-square test (χ 2 -test) at 0.05 level. # Significant difference between two independent means using Students-t-test at 0.05 level. There was no significant difference (p-value > 0.05) in leukocytes, erythrocytes, or epithelial cell counts before and after treatment between the metformin group and the SGLT2 inhibitor group, as shown in Table 2 . Table 2. General urine exam results before and after three months of treatment for both groups. Metformin SGLT-2 Inhibitors P value MetxSGL2 first visit P value MetxSGL2 After 12 w First visit After 12 w First visit After 12 w No % No % No % No % Test Positive 2 3.8 1 1.9 3 6.1 5 10.2 0.598 0.078 Negative 50 96.2 51 98.1 46 93.9 44 89.8 P value 0.558 0.461 Leukocytes (HPF) 1---2 12 23.1 9 17.3 3 6.1 9 18.4 0.196 0.252 3---4 21 40.4 35 67.3 26 53.1 28 57.1 5---6 9 17.3 4 7.7 9 18.4 4 8.2 7---8 8 15.4 3 5.8 8 16.3 3 6.1 9---10 2 3.8 1 1.9 3 6.1 5 10.2 P value 0.076 0.026 * Erythrocytes (HPF) Absent 3 5.8 3 5.8 1 2.0 3 6.1 0.663 0.630 1---2 45 86.5 43 82.7 41 83.7 41 83.7 3---4 3 5.8 5 9.6 4 8.2 2 4.1 5---6 - - 1 1.9 1 2.0 2 4.1 7---8 - - - - 1 2.0 - - 9---10 1 1.9 - - 1 2.0 1 2.0 P value 0.637 0.700 Epithelial cells (HPF) Absent 2 3.8 1 1.9 2 4.1 1 2.0 0.875 0.583 Few 29 55.8 41 78.8 28 57.1 34 69.4 [+] 17 32.7 8 15.4 14 28.6 8 16.3 [++] 4 7.7 2 3.8 4 8.2 5 10.2 [+++] - - - - 1 2.0 1 2.0 P value 0.098 0.616 * Significant difference between percentages using Pearson Chi-square test (χ 2 -test) at 0.05 level. There was no significant difference (p-value>0.05) in leukocytes, erythrocytes, or epithelial cell counts before and after treatment in the metformin group, as shown in Table 3 . Table 3. General urine exam results before and after three months of treatment for the metformin group. Metformin First visit After 12 weeks P value No % No % Test Positive 2 3.8 1 1.9 0.558 Negative 50 96.2 51 98.1 Leukocytes (HPF) 1---2 12 23.1 9 17.3 0.076 3---4 21 40.4 35 67.3 5---6 9 17.3 4 7.7 7---8 8 15.4 3 5.8 9---10 2 3.8 1 1.9 Erythrocytes (HPF) Absent 3 5.8 3 5.8 0.637 1---2 45 86.5 43 82.7 3---4 3 5.8 5 9.6 5---6 - - 1 1.9 7---8 - - - - 9---10 1 1.9 - - Epithelial cells (HPF) Absent 2 3.8 1 1.9 0.098 Few 29 55.8 41 78.8 [+] 17 32.7 8 15.4 [++] 4 7.7 2 3.8 [+++] - - - - * Significant difference between percentages using Pearson Chi-square test (χ 2 -test) at 0.05 level. There was a significant difference (p-value = 0.026) in leukocytes and a non-significant difference in erythrocytes and epithelial cell counts before and after treatment in the SGLT2 inhibitor group ( Table 4 ). Table 4. General urine exam results before and after three months of treatment for the SGLT2 inhibitor group. SGLT-2 Inhibitors First visit After 12 weeks P value No % No % Test Positive 3 6.1 5 10.2 0.461 Negative 46 93.9 44 89.8 Leukocytes (HPF) 1---2 3 6.1 9 18.4 0.026 * 3---4 26 53.1 28 57.1 5---6 9 18.4 4 8.2 7---8 8 16.3 3 6.1 9---10 3 6.1 5 10.2 Erythrocytes (HPF) Absent 1 2.0 3 6.1 0.700 1---2 41 83.7 41 83.7 3---4 4 8.2 2 4.1 5---6 1 2.0 2 4.1 7---8 1 2.0 - - 9---10 1 2.0 1 2.0 Epithelial cells (HPF) Absent 2 4.1 1 2.0 0.616 Few 28 57.1 34 69.4 [+] 14 28.6 8 16.3 [++] 4 8.2 5 10.2 [+++] 1 2.0 1 2.0 * Significant difference between percentages using Pearson Chi-square test (c2-test) at 0.05 level. There was a significant difference (p-value = 0.043) in leukocytes and a non-significant difference in erythrocytes and epithelial cell counts before and after treatment in the dapagliflozin group, as shown in Table 5 . Table 5. general urine exam results before and after three months of treatment for the dapagliflozin group. Oral hypoglycemic drug: Dapagliflozin SGLT-2 INHIBITORS First Visit After 12 weeks P value No % No % Test Positive 1 4.0 3 12.0 0.297 Negative 24 96.0 22 88.0 Leukocytes (HPF) 1---2 1 4.0 5 20.0 0.043 * 3---4 13 52.0 14 56.0 5---6 4 16.0 3 12.0 7---8 6 24.0 - - 9---10 1 4.0 3 12.0 Erythrocytes (HPF) Absent 1 4.0 - - 0.798 1---2 19 76.0 20 80.0 3---4 2 8.0 2 8.0 5---6 1 4.0 2 8.0 7---8 1 4.0 - - 9---10 1 4.0 1 4.0 Epithelial cells (HPF) Absent 1 4.0 - - 0.138 Few 11 44.0 18 72.0 [+] 11 44.0 4 16.0 [++] 2 8.0 2 8.0 [+++] - - 1 4.0 * Significant difference between percentages using Pearson Chi-square test (χ 2 -test) at 0.05 level. There was no significant difference (p-value> 0.05) in leukocytes, erythrocytes, or epithelial cell counts before and after treatment in the empagliflozin group, as shown in Table 6 . Table 6. general urine exam results before and after three months of treatment for the empagliflozin group. Oral hypoglycemic drug: Empagliflozin SGLT-2 INHIBITORS First Visit After 12 weeks P value No % No % Test Positive 2 8.3 2 8.3 - Negative 22 91.7 22 91.7 Leukocytes (HPF) 1---2 2 8.3 8 33.3 0.144 3---4 13 54.2 10 41.7 5---6 5 20.8 1 4.2 7---8 2 8.3 3 12.5 9---10 2 8.3 2 8.3 Erythrocytes (HPF) Absent - - 3 12.5 0.081 1---2 22 91.7 21 87.5 3---4 2 8.3 - - 5---6 - - - - 7---8 - - - - 9---10 - - - - Epithelial cells (HPF) Absent 1 4.2 1 4.2 0.849 Few 17 70.8 16 66.7 [+] 3 12.5 4 16.7 [++] 2 8.3 3 12.5 [+++] 1 4.2 - - * Significant difference between percentages using Pearson Chi-square test (χ 2 -test) at 0.05 level. Discussion Our study’s findings show that the metformin group and the SGLT2 inhibitor group did not significantly differ in their counts of leukocytes, erythrocytes, or epithelial cells before or after treatment, as shown in Table 2 . In comparison to other antidiabetic medications, the use of SGLT2 inhibitors is not linked to an increased incidence of UTIs, according to the findings of a study conducted by Wajd Alkabbani in 2022 to evaluate the risk of UTIs related to SGLT2 inhibitors in type 2 diabetes. 21 Additionally, Table 3 shows no statistically significant difference in the metformin group’s counts of leukocytes, erythrocytes, or epithelial cells before and after treatment. In a study published in 2022, Fu-Shun Yen compared the morbidity and mortality linked to sepsis and UTI in patients with diabetes between metformin users and nonusers. The findings indicated that among patients with type 2 diabetes, metformin use was not significantly associated with a lower risk of sepsis, recurrent UTI, or UTI. Compared to metformin nonuse, it was linked to a decreased risk of death from a UTI or sepsis. 22 In contrast, the SGLT2 inhibitor group’s data revealed a non-significant change in the numbers of erythrocytes and epithelial cells before and after treatment but a significant difference in leukocytes ( Tables 4 , 5 ). According to research by Zhigui Zheng, they were published in 2023, dapagliflozin 10 mg/day for a treatment period longer than 24 weeks was associated with a significantly higher risk of urinary tract infection (UTI) than placebo or other active treatments. As a result, patients with type 2 diabetes mellitus should carefully consider the risk of UTI before beginning high-dose, long-term dapagliflozin therapy or adding it on top of existing treatment. 23 However, when one of the four SGLT2 inhibitors—dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin is used in a meta-analysis study to estimate the association between the use of these drugs and the risk of UTI, the results indicate that dapagliflozin appears to independently increase the risk of UTI, though the mechanism underlying this intra-class variation in risk is unclear. 24 Another study conducted in 2013 by Kristina M. Johnsson revealed a small increase in the incidence of urinary tract infection when type 2 diabetes is treated with once-daily dapagliflozin 5 or 10 mg. Most infections were mild to severe and controlled clinically. 25 Our findings about empagliflozin indicated that there was no discernible change in the counts of leukocytes, erythrocytes, or epithelial cells in the group receiving therapy before and after the medication (see Table 6 ). According to the results of a study conducted in 2024 by Cristina Rebordosa, patients with type 2 diabetes who started taking empagliflozin compared to those who started taking a dipeptidyl peptidase-4 (DPP-4) inhibitor had higher risks of DKA and GI and lower risks of ALI, AKI, CKD, and severe UTI complications when using empagliflozin. 26 However, results from a study conducted in 2021 by Arbinda Pokhare on type 2 diabetes patients using empagliflozin revealed that UTIs (17.8%), nasopharyngitis (11.9%), and hypoglycemia (10.71%) were the most often reported side effects of the medication. 27 According to Chunmei Xu’s study, SGLT2i was found to have comparable anti-hyperglycemic efficacy to metformin monotherapy, including reducing blood glucose and HbA1c without significantly raising the incidence of UTIs. It also significantly reduced cardiovascular risk factors. However, a study by Mustafa Tanriverdi 28 revealed that glucosuria and SGLT-2i use predicted UTI in T2D patients. It also suggested that urine culture is crucial when determining the kind and mode of administration of antibacterial treatment, particularly for patients on SGLT-2i treatment. 29 In contrast to individuals on non-SGLT2 inhibitors, patients taking dapagliflozin and empagliflozin had a higher incidence of UTIs, according to a study by Uitracul. Furthermore, when treated with SGLT2 inhibitors, patients who were older and female had a considerably higher incidence of UTI, but patients who had permanent jobs had a reduced risk. 30 Among 17 trials evaluating dapagliflozin, 499 events suggestive of UTIs were recorded in 7145 participants (raw event rate 7.0%). A meta-analysis of these trials revealed that, in comparison to the control, dapagliflozin was linked to an increased risk of events that could be indicative of UTIs. 31 Furthermore, SGLT2 inhibitor-induced glucosuria probably contributes to an increased risk of genital infections and urinary tract infections to a lesser degree. Treatment with SGLT2 inhibitors does not raise the risk of upper UTIs (pyelonephritis). Furthermore, SGLT2 inhibitors have been linked to an increase in benign urine symptoms brought on by osmotic diuresis, such as an increase in urine output. This might have also made it more likely that patients on SGLT2 inhibitors would have been diagnosed with infections. 32 Limitations of the study Superior evidence could be provided by studying more urinary parameters on a larger sample of T2DM Iraqi patients taking metformin and SGLT-2 Inhibitors and by extending the monitoring period to evaluate the risk and incidence of urinary tract infections among these patients in controlled trials. Conclusions Diabetic patients on SGLT-2 inhibitors treatment demonstrated higher leukocyte count than metformin group patients, an indicator and predictor for higher susceptibility to urinary tract infections. Ethical considerations The study was approved by the Institutional Review Board (IRB) in the College of Medicine/University of Baghdad (Approval no. 03-11 on 31 st of December 2023), the ethical approval for the current study was uploaded to the Zenodo: Ethical approval and reporting guidelines. https://doi.org/10.5281/zenodo.14037291 . 18 This project contains the following file: • (Ethical approval.jpg). Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Consent to participate All patients and other private parties provided written and informed consent to participate in the study. Authors’ contribution DNH contributed to conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, software, validation, visualization, and writing-original draft preparation. SMA contributed to conceptualization, data curation, investigation, methodology, project administration, resources, supervision, writing – review & editing. Data availability Underlying data Zenodo: “Impact of Metformin vs SGLT-2i on urinary parameters (Latest Version)”, https://doi.org/10.5281/zenodo.14055980 . 33 This project contains the following underlying data file: • ( Data: Latest version.xlsx ). Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Reporting guidelines STROBE criteria for cohort studies was used as reporting criteria for the current study. The complete filled-in reporting guideline document for the current study was uploaded to Zenodo: Ethical Approval and Reporting Guidelines. https://doi.org/10.5281/zenodo.14037291 . 18 This project contains the following file: • (Reporting guidelines.doc). Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0) ( https://creativecommons.org/licenses/by/4.0/ ). References 1. Health UDo, Services H: National Diabetes Information Clearinghouse (NDIC). National diabetes statistics.2011. 2. Abed B: The Relationship between Family History and C-peptide Level in Type2 Diabetic Patients. Journal of the Faculty of Medicine Baghdad. 2013; 55 : 258–264. Publisher Full Text 3. Arif M, Rasheed M, Ismaeel A: Study some biochemical parameters in patients with Coronary artery disease with and without Type 2 diabetesStudy of some Biochemical Parameters in Patients with Coronary Artery Disease with and without Type 2 Diabete. Journal of the Faculty of Medicine Baghdad. 2024; 66 : 51–57. Publisher Full Text 4. Allawi A, Kahdem A, Nada SZ, et al. : Neutrophil gelatinase associated lipocalin (NGAL) in early detection of nephropathy in type 2 diabetic Iraqi patients. 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International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. 2009; 32 (7): 1327–1334. PubMed Abstract | Publisher Full Text | Free Full Text 14. Moore DS, McCabe GP: Introduction to the practice of statistics. WH Freeman/Times Books/Henry Holt & Co; 1989. 15. Dawson B, Trapp RG: Basic & clinical biostatistics. Basic & clinical biostatistics.2004; 438. 16. Javaheri Tehrani F, Nikpour S, Haji Kazemi EA, et al. : The effect of education based on health belief model on health beliefs of women with urinary tract infection. International Journal of Community-Based Nursing and Midwifery. 2014; 2 (1): 2–11. PubMed Abstract 17. Pham PN, Johnston LG, Keegan K, et al. : Innovative Strategies for Remotely Sampling Hard-to-Reach Populations: Assessing Phone Versus Internet Respondent-Driven Sampling Approaches Among Venezuelan Refugees and Migrants in Colombia. American Journal of Epidemiology. 2023; 192 (10): 1613–1623. 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Rebordosa C, Thomsen RW, Tave AK, et al. : Liver, renal, genitourinary and diabetic ketoacidosis risks among new users of empagliflozin versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: Post-authorization safety study based on multinational cohorts. Diabetes, Obesity and Metabolism. 2024; 26 (4): 1291–1304. PubMed Abstract | Publisher Full Text 27. Pokharel A, Kc S, Thapa P, et al. : The Effect of Empagliflozin on Liver Fat in Type 2 Diabetes Mellitus Patients With Non-Alcoholic Fatty Liver Disease. Cureus. 2021; 13 (7): e16687. PubMed Abstract | Publisher Full Text 28. Xu C, He L, Zhang J, et al. : The Cardiovascular Benefits and Infections Risk of SGLT2i versus Metformin in Type 2 Diabetes: A Systemic Review and Meta-Analysis. Metabolites. 2022; 12 (10). PubMed Abstract | Publisher Full Text | Free Full Text 29. Tanrıverdi M, Baştemir M, Demirbakan H, et al. : Association of SGLT-2 inhibitors with bacterial urinary tract infection in type 2 diabetes. BMC Endocrine Disorders. 2023; 23 (1): 211. PubMed Abstract | Publisher Full Text | Free Full Text 30. Uitrakul S, Aksonnam K, Srivichai P, et al. : The Incidence and Risk Factors of Urinary Tract Infection in Patients with Type 2 Diabetes Mellitus Using SGLT2 Inhibitors: A Real-World Observational Study. Medicines (Basel). 2022; 9 (12). Publisher Full Text 31. Liu J, Li L, Li S, et al. : Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Scientific Reports. 2017; 7 (1): 2824. PubMed Abstract | Publisher Full Text | Free Full Text 32. Geerlings S, Fonseca V, Castro-Diaz D, et al. : Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Research and Clinical Practice. 2014; 103 (3): 373–381. PubMed Abstract | Publisher Full Text 33. Hussien DN: Impact of Metformin vs SGLT-2i on urinary parameters (Latest Version). 1.0 ed.2024. Zenodo. Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 21 Nov 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Pharmacology and Toxicology, College of Medicine, University of Baghdad, Baghdad, Baghdad Governorate, 10045, Iraq Diana Noori Hussien Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Validation, Visualization, Writing – Original Draft Preparation Samara Mowafaq Ali Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 21 Nov 2024, 13:1397 https://doi.org/10.12688/f1000research.158805.1 Copyright © 2024 Hussien DN and Ali SM. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Hussien DN and Ali SM. Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :1397 ( https://doi.org/10.12688/f1000research.158805.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 21 Nov 2024 Views 0 Cite How to cite this report: Umapathysivam MM and Nguyen H. Reviewer Report For: Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :1397 ( https://doi.org/10.5256/f1000research.174446.r354138 ) The direct URL for this report is: https://f1000research.com/articles/13-1397/v1#referee-response-354138 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Jan 2025 Mahesh M. Umapathysivam , Royal Adelaide Hospital, The University of Adelaide, Adelaide, South Australia, Australia; Southern Adelaide Diabetes and Endocrine Service, Flinders Medical Centre, Bedford Park, Australia; The University of Adelaide Adelaide Medical School, Adelaide, South Australia, Australia Huyen Nguyen , Endocrine, Southern Adelaide Local Health Network, Bedford Park, South Australia, Australia Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.174446.r354138 Summary of Context: Multiple agents are available for the treatment of type 2 diabetes. Current American diabetes association guidelines suggest initial treatment with metformin and intensification with SGLT2i or GLP-1RA as preferred second line agents depending on ... Continue reading READ ALL Summary of Context: Multiple agents are available for the treatment of type 2 diabetes. Current American diabetes association guidelines suggest initial treatment with metformin and intensification with SGLT2i or GLP-1RA as preferred second line agents depending on patient characteristics. SGLT2i reduce glycaemia by increasing urinary glucose an effect that has been associated with candidiasis but whilst large cardiovascular outcome trials have not demonstrated increased rates of UTI (these should be referenced), this study design can miss safety signals. This study aimed to contribute to the literature in the field on this complication by prospectively following patients with either metformin or SGLT2 monotherapy and then examining a surrogate for urinary tract infection - number of leucocytes per high power field on microscopy at base line and then at 12 weeks. Notably this end point may be limited due to increased urinary volume with SGLT2i treatment or increased leukocyte number in setting of non-bacterial infection e.g. candidiasis. The study reports the number of leucocytes in various categories and other cell populations before and after therapy with metformin and SGLT2i. There was no difference when groups were compared but there was an increase in urinary leucocytosis after 12 weeks of SGLT2i compared to baseline. In the text it does not explicitly state at any point state if this is increased or decreased or the magnitude of change. . The results report. I have not recommended for indexing in current state as there is inconsistency between results and conclusion and this need to be addressed prior to consideration of indexing. The following specific suggestions are offered to strengthen the article; Title: Use people first language i.e. “diabetic” is not appropriate it should be “person with diabetes” or similar. The title should reflect what was measured i.e. urinary tract infections were not measured urinary leucocytosis was measured. Abstract: This should follow STROBE format more closely. Remove “because it has demonstrated promise in this regard”. State T2DM in full then abbreviate. Be clearer in the language around the results and state direction of effect and magnitude. Conclusion is not consistent with results – The results state “There was no significant difference in leukocytes, erythrocytes, or epithelial cell counts between the metformin group and the SGLT2 inhibitor group before and after 12 weeks of treatment” whilst conclusion states “Diabetic patients on SGLT-2 inhibitors treatment demonstrated higher leukocyte count than metformin group patient”. Please check capitalisation throughout. Introduction: Remove content that does not relate to the proposed study – e.g. discussion of relation between diabetes and osteoporosis and discussion of NGAL. This section should focus on setting up the justification for the study. Reference 12 for association between SGLT2i and infection is incorrect. Please review. Samples size section is incomplete with multiple areas marked XXX. Methods: Ethics: Patients completed written informed consent but study states 63.5% were illiterate please clarify. It would be helpful to know renal function and Hba1c at baseline and at 12 weeks if possible. It would be helpful to know why individuals were treated with SGLT2i monotherapy rather than metformin. Are these populations very different? Ascertainment bias should also be included as a limitation. A definition of a “positive test” need to be provided. Results: More description of results is required. It would help the reader to know the direction of effect for significant results and the magnitude of the difference. Presentation of the average number of leukocytes with comparison of students T test would be useful I am unsure what “it was assumed that 30% of people had an irregular legal status at time 1 and 20% at time 2” means Conclusion: There is conflict throughout between the reporting of results and interpretation. To my reading there is no statistical difference between metformin group and SGLT2i group. There is an increase statistically significant increase in leukocytes after initiation of SLT2i compared to before. This should form the basis of discussion. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No References 1. Zinman B, Wanner C, Lachin JM, Fitchett D, et al.: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med . 2015; 373 (22): 2117-28 PubMed Abstract | Publisher Full Text 2. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, et al.: Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med . 2019; 380 (4): 347-357 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Type 2 Diabetes, Genetics, SGLT2i DKA, inpatient glucose management, incretin hormones We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Umapathysivam MM and Nguyen H. Reviewer Report For: Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :1397 ( https://doi.org/10.5256/f1000research.174446.r354138 ) The direct URL for this report is: https://f1000research.com/articles/13-1397/v1#referee-response-354138 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 21 Nov 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 1 21 Nov 24 read Mahesh M. Umapathysivam , The University of Adelaide, Adelaide, Australia; Southern Adelaide Diabetes and Endocrine Service, Flinders Medical Centre, Bedford Park, Australia; The University of Adelaide Adelaide Medical School, Adelaide, Australia Huyen Nguyen , Southern Adelaide Local Health Network, Bedford Park, Australia Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Umapathysivam M et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Jan 2025 | for Version 1 Mahesh M. Umapathysivam , Royal Adelaide Hospital, The University of Adelaide, Adelaide, South Australia, Australia; Southern Adelaide Diabetes and Endocrine Service, Flinders Medical Centre, Bedford Park, Australia; The University of Adelaide Adelaide Medical School, Adelaide, South Australia, Australia Huyen Nguyen , Endocrine, Southern Adelaide Local Health Network, Bedford Park, South Australia, Australia 0 Views copyright © 2025 Umapathysivam M et al. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Summary of Context: Multiple agents are available for the treatment of type 2 diabetes. Current American diabetes association guidelines suggest initial treatment with metformin and intensification with SGLT2i or GLP-1RA as preferred second line agents depending on patient characteristics. SGLT2i reduce glycaemia by increasing urinary glucose an effect that has been associated with candidiasis but whilst large cardiovascular outcome trials have not demonstrated increased rates of UTI (these should be referenced), this study design can miss safety signals. This study aimed to contribute to the literature in the field on this complication by prospectively following patients with either metformin or SGLT2 monotherapy and then examining a surrogate for urinary tract infection - number of leucocytes per high power field on microscopy at base line and then at 12 weeks. Notably this end point may be limited due to increased urinary volume with SGLT2i treatment or increased leukocyte number in setting of non-bacterial infection e.g. candidiasis. The study reports the number of leucocytes in various categories and other cell populations before and after therapy with metformin and SGLT2i. There was no difference when groups were compared but there was an increase in urinary leucocytosis after 12 weeks of SGLT2i compared to baseline. In the text it does not explicitly state at any point state if this is increased or decreased or the magnitude of change. . The results report. I have not recommended for indexing in current state as there is inconsistency between results and conclusion and this need to be addressed prior to consideration of indexing. The following specific suggestions are offered to strengthen the article; Title: Use people first language i.e. “diabetic” is not appropriate it should be “person with diabetes” or similar. The title should reflect what was measured i.e. urinary tract infections were not measured urinary leucocytosis was measured. Abstract: This should follow STROBE format more closely. Remove “because it has demonstrated promise in this regard”. State T2DM in full then abbreviate. Be clearer in the language around the results and state direction of effect and magnitude. Conclusion is not consistent with results – The results state “There was no significant difference in leukocytes, erythrocytes, or epithelial cell counts between the metformin group and the SGLT2 inhibitor group before and after 12 weeks of treatment” whilst conclusion states “Diabetic patients on SGLT-2 inhibitors treatment demonstrated higher leukocyte count than metformin group patient”. Please check capitalisation throughout. Introduction: Remove content that does not relate to the proposed study – e.g. discussion of relation between diabetes and osteoporosis and discussion of NGAL. This section should focus on setting up the justification for the study. Reference 12 for association between SGLT2i and infection is incorrect. Please review. Samples size section is incomplete with multiple areas marked XXX. Methods: Ethics: Patients completed written informed consent but study states 63.5% were illiterate please clarify. It would be helpful to know renal function and Hba1c at baseline and at 12 weeks if possible. It would be helpful to know why individuals were treated with SGLT2i monotherapy rather than metformin. Are these populations very different? Ascertainment bias should also be included as a limitation. A definition of a “positive test” need to be provided. Results: More description of results is required. It would help the reader to know the direction of effect for significant results and the magnitude of the difference. Presentation of the average number of leukocytes with comparison of students T test would be useful I am unsure what “it was assumed that 30% of people had an irregular legal status at time 1 and 20% at time 2” means Conclusion: There is conflict throughout between the reporting of results and interpretation. To my reading there is no statistical difference between metformin group and SGLT2i group. There is an increase statistically significant increase in leukocytes after initiation of SLT2i compared to before. This should form the basis of discussion. Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? No Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No References 1. Zinman B, Wanner C, Lachin JM, Fitchett D, et al.: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med . 2015; 373 (22): 2117-28 PubMed Abstract | Publisher Full Text 2. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, et al.: Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med . 2019; 380 (4): 347-357 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Type 2 Diabetes, Genetics, SGLT2i DKA, inpatient glucose management, incretin hormones We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Umapathysivam MM and Nguyen H. Peer Review Report For: Comparison of the severity of urinary tract infections between Metformin and SGL2 Inhibitors among Iraqi Type 2 Diabetics. [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :1397 ( https://doi.org/10.5256/f1000research.174446.r354138) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1397/v1#referee-response-354138 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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