Type 2 diabetes patients requiring empagliflozin in Southeast of Iran: Frequency and guideline adherence (2022–2023) / Pacientes con diabetes tipo 2 que requieren empagliflozina en el sureste de Irán: frecuencia y cumplimiento de las directrices (2022-2023)

Introduction: Empagliflozin plays a beneficial role in individuals with type 2 diabetes at high risk of cardiovascular complications. This study aimed to assess the prevalence of individuals with type 2 diabetes who required empagliflozin based on clinical guidelines between the years 2022 and 2023. Material and methods: This study was a descriptive-analytical cross-sectional study conducted on a target population of patients with type 2 diabetes. Patient data, including demographic characteristics, smoking status, hypertension, hyperlipidemia, renal insufficiency, retinopathy, and proteinuria, were collected. The indication for prescribing empagliflozin was determined based on the risk of cardiovascular complications. Results: A total of 398 individuals with type 2 diabetes with a mean age of 58.4 years were examined. Overall, 87.4% of the patients had an indication for empagliflozin prescription. The indication for empagliflozin prescription was significantly higher in men, individuals with hyperlipidemia, those over 55 years of age, obese individuals, and smokers. The mean age, body mass index, and triglyceride levels were higher in candidates for empagliflozin prescription. Male candidates for empagliflozin had significantly higher rates of smoking and systolic blood pressure compared to females. Conclusions: The findings of this study demonstrated that a significant percentage of individuals with type 2 diabetes had an indication for empagliflozin prescription based on clinical and laboratory criteria. (AU)

Introducción: La empagliflozina tiene un papel beneficioso en las personas con diabetes tipo 2 con alto riesgo de complicaciones cardiovasculares. Este estudio tuvo como objetivo evaluar la prevalencia de pacientes con este padecimiento que requerían empagliflozina según las guías clínicas entre los años 2022 y 2023. Material y métodos: Se trata de un estudio transversal descriptivo-analítico realizado en una población objetivo de personas con diabetes tipo 2. Se recogieron los datos de los pacientes, incluyendo las características demográficas, el hábito tabáquico, la hipertensión, la hiperlipidemia, la insuficiencia renal, la retinopatía y la proteinuria. La indicación para prescribir empagliflozina se determinó en función del riesgo de complicaciones cardiovasculares. Resultados: Se examinaron un total de 398 individuos con diabetes tipo 2 con una edad media de 58,4 años. En general, 87,4% de estos tenía una indicación para la prescripción de empagliflozina, la cual fue significativamente mayor en los hombres, aquellos con hiperlipidemia, obesidad, los mayores de 55 años y los fumadores. La edad media, el índice de masa corporal y los niveles de triglicéridos fueron mayores en los candidatos a la prescripción de este medicamento. Los candidatos masculinos a este fármaco tenían tasas significativamente más altas de tabaquismo y presión arterial sistólica, en comparación con las mujeres. Conclusiones: Los resultados de este estudio demostraron que un porcentaje significativo de personas con diabetes tipo 2 tenía una indicación para la prescripción de empagliflozina según los criterios clínicos y de laboratorio. (AU)

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia.

Background: A phenomenon known as legacy effect was observed that poor glycemic control at early stage of patients with newly-diagnosed type 2 diabetes (T2D) increases the risk of subsequent cardiovascular diseases (CVD). Early use of some novel anti-hyperglycemic agents, such as sodium-glucose transport protein 2 inhibitors (SGLT-2i), may attenuate this effect, but the evidence is limited. Methods: Two retrospective cohorts of newly diagnosed T2D patients from 2010-2023 were assembled using the Yinzhou Regional Health Care Database (YRHCD) with different definitions of the early exposure period - the 1-year exposure cohort and 2-year exposure cohort, which were comprised of subjects who had HbA1c measurement data within 1 year and 2 years after their T2D diagnosis, respectively. Using Cox proportional hazards models, we examined the association between high HbA1c level (HbA1c>7%) during the early exposure period and the risk of subsequent CVD. This analysis was performed in the overall cohort and three subpopulations with different treatments during the early exposure period, including patients initiating SGLT-2i or glucagon-like peptide-1 receptor agonists (GLP-1RA), patients using dipeptidyl peptidase-4 inhibitors (DPP-4i), and patients without using SGLT-2i, GLP-1RA, and DPP-4i. Besides, subgroup analyses were performed by stratifying patients into age <55 and ≥55 years. Results: A total of 21,477 and 22,493 patients with newly diagnosed T2D were included in the two final cohorts. Compared with patients with mean HbA1c ≤ 7% during the early exposure period, those with HbA1c>7% had higher risks of incident CVD, with a HR of 1.165 (95%CI, 1.056-1.285) and 1.143 (95%CI, 1.044-1.252) in 1-year and 2-year exposure period cohort. Compared to non-users, in patients initiating SGLT-2i/GLP-1RA within 1 or 2 years after T2D diagnosis, higher HbA1c level at baseline was not associated with CVD in both two cohorts. In subgroup analyses, results were generally consistent with the main analysis. Conclusions: Poor glycemic control in the early stage of T2D increased later CVD risk in Chinese adults with newly diagnosed T2D. Compared to non-users, this association was smaller and non-significant in patients receiving SGLT-2i/GLP-1RA during the early stage of T2D, indicating early use of these drugs may have the potential to mitigate legacy effects of hyperglycemia.

Effects of dapagliflozin against streptozotocin and isoproterenol-induced heart failure via investigating NLRP3 and PPAR-γ signaling.

Heart failure is a condition in which the heart's one or both ventricles are unable to either receive an adequate amount of blood or eject an adequate amount of blood. Diabetes is considered one of the major risk factors for cardiovascular diseases. The current research is designed to evaluate the cardioprotective effects of dapagliflozin in streptozotocin and isoproterenol-induced comorbid rats. The COX-2, TNF-α, NF-КB, NLRP3, PPAR-γ, CKMB, TROP-I, AR, GP and SGLT were docked against dapagliflozin, propranolol and metformin. Dapagliflozin restored adequate blood flow and halted myofibril damage. Moreover, it's evident from this study that dapagliflozin significantly decreased serum concentration of various blood markers, decreased relative growth rate and QT interval prolongation, as compared to the negative control group. However, it improved the ventricular ejection fraction in rats of the treatment group. The GST, GSH and CAT levels were increased, as compared to normal. On the contrary, a decrease in LPO concentrations was observed. Evaluation of the coronal section of heart tissues showed the anti-inflammatory expressions evaluated through H & E staining and immunohistochemical techniques and with ELISA and PCR. In a nutshell, dapagliflozin reverses myocardial necrosis and apoptosis.

Evaluating the efficacy and safety of empagliflozin addition to insulin and oral antidiabetic medication (OAD) regimen in poorly controlled type 2 diabetes and obese patients.

Insulin resistance complicates diabetes care. Its effectiveness and tolerability as an addition to metformin, DPP4 inhibitor and insulin treatment in type 2 diabetic patients will be examined in this research. Participants with type 2 diabetes from poor socio-economic backgrounds had HbA1c values ≥8.5% when using Insulin+Metformin+DPP-4 inhibitors. They received 10mg Empagliflozin daily for 12 weeks (n=143). The main outcome was change in HbA1c at 12th week from baseline. Secondary outcomes were baseline weight and week 12 FPG. Adjusted mean (SE) HbA1c increases at week 12 were: Mean ± SD 10.38 (6.8-17.0) vs. Mean±SD 9.05±1.77 (5.60-16.0) with empagliflozin 10mg. When added to the regimen, empagliflozin significantly reduced FPG, systolic and diastolic blood pressure. The mean (SE) BMI increases from baseline were 31.28±5.89 (16.0-66.0) and 29.73±5.47 (3.0-46.0) with 10mg empagliflozin. Two individuals experienced urinary tract infections as AEs, but no genital infections. Adding empagliflozin 10mg daily to metformin+DPP4 inhibitor+insulin improved glycemic control, body weight and blood pressure for 12 weeks. The intervention was well-tolerated, highlighting empagliflozin's therapeutic potential.

Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes.

BACKGROUND: Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence. OBJECTIVES: This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure. MAIN RESULTS: Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain. AUTHORS' CONCLUSIONS: SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.

[New perspectives in the diagnosis and treatment of heart failure with preserved ejection fraction (HFpEF)]. / Avancées dans le diagnostic et traitement de l'insuffisance cardiaque à fraction d'éjection préservée.

Heart failure with preserved ejection fraction (HFpEF), defined as ≥50 %, affects 1 to 3 % of the population and represents a diagnostic challenge. Clinical scores have been developed to facilitate the diagnosis of affected patients, who can now benefit from new treatments. Recent studies have shown a reduction in cardiovascular morbidity and mortality with sodium-glucose cotransporter-2 (SGLT-2) inhibitors in this population. Other promising drugs, currently in the study phase, could potentially change the management approach in the near future. Finally, controlling symptoms, signs of congestion and the frequently encountered comorbidities in this population remain crucial.

L'insuffisance cardiaque à fraction d'éjection préservée (HFpEF), soit ≥ 50 %, touche 1 à 3 % de la population et représente un défi diagnostique. Des scores cliniques ont été développés pour faciliter l'identification des patients concernés qui peuvent désormais bénéficier de nouveaux traitements. Des études récentes ont en effet montré une diminution de la morbimortalité cardiovasculaire grâce aux inhibiteurs du cotransporteur sodium-glucose de type 2 (iSGLT2) dans cette population. D'autres médicaments prometteurs actuellement en phase d'étude pourraient aussi changer la prise en charge dans un futur proche. Enfin, le contrôle des symptômes et signes de congestion ainsi que le traitement des comorbidités fréquemment rencontrées dans cette population restent essentiels.

Genito-urinary infectious adverse events related to sodium glucose cotransporter-2 inhibitors: a network meta-analysis and meta-regression.

INTRODUCTION: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are an emerging class of drugs with wide indications. Controversial evidence exists regarding the risk of urinary tract infection (UTI) and genital infections (GI) with SGLT2is paving way for undertaking this network meta-analysis and meta-regression study. METHODS: Data from randomized trials evaluating SGLT2is reporting the number of patients with UTI and GI were included. Odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. Meta-regression analysis identified risk factors. Number needed to harm (NNH) was estimated. RESULTS: Two hundred and sixty-four articles were included [UTI (213 studies; 150,140 participants) and GI (188 studies; 121,275 participants)]. An increased risk of UTI (OR: 1.11; 95% CI: 1.06, 1.16) and GI (OR: 3.5, 95% CI: 3.1, 3.9) was observed. Men showed a lower risk of UTI (OR: 0.2; 95% CI: 0.2, 0.3) and GI (OR: 0.4; 95% CI: 0.4, 0.5). Meta-regression analyses revealed BMI ≥ 30 kg/m2 and duration of SGLT2i treatment for ≥6 months as risk factors. NNH was 16 for UTI and 25 for GI. CONCLUSION: SGLT2is increase the risk of UTI and GI that needs to be incorporated in the treatment guidelines with precautions in high-risk patients. PROSPECTIVE PROTOCOL REGISTRATION: https://osf.io/5fwyk.

[Heart failure with preserved left ventricular ejection fraction (HFpEF)].

INTRODUCTION: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a common and very important disease entity because of its association with frequent repeat hospitalization and high mortality. Hallmarks of the underlying pathophysiology include a small left ventricular cavity due to concentric remodeling, impaired left ventricular compliance and left atrial dysfunction. This leads to an increase in left atrial and pulmonary pressure on exertion and in advanced stages of the disease already at rest with consecutive exertional dyspnea and exercise intolerance. Additional cardiovascular mechanisms including atrial fibrillation, chronotropic incompetence and coronary artery disease as well as non-cardiac co-morbidities contribute to a variable extent to the clinical picture. The diagnostic work-up is demanding and complex but the concepts have significantly improved during the last years. The study results of the Sodium Glucose cotransporter-2 inhibitors (SGLT-2-inhibitors) have revolutionized the treatment of HFpEF. In the present article, we provide an overview about the current understanding of the pathophysiology of HFpEF, the principles of the diagnostic pathways and a summary of the intervention studies in the field, and we propose an approach for the treatment in clinical practice.

A hierarchical kidney outcome using win statistics in patients with heart failure from the DAPA-HF and DELIVER trials.

Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06-1.15) in the combined dataset, 1.08 (95% CI = 1.01-1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05-1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.

Early initiation of Dapagliflozin and its effect on health related quality of life in acute heart failure: a randomised controlled trial.

OBJECTIVE: To determine the role of dapagliflozin in improving functional status and health-related quality of life in acute heart failure cases. METHODS: The prospective, randomised controlled study was conducted from July 2022 to January 2023 at the Pharmacology Department of Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, in collaboration with the Armed Forces Institute of Cardiology, Rawalpindi, and comprised hospitalised adult patients of either gender with acute heart failure. They were randomised into two equal groups, with intervention group A receiving oral dapagliflozin 10mg daily in addition to conventional therapy, and with control group B receiving conventional therapy alone. Health-related quality of life was assessed using Kansas City Cardiomyopathy Questionnaire. Improvement in functional status was assessed by New York Heart Association functional classification. Data was obtained at baseline and after 12-week follow-up. Data was compared using SPSS 26. RESULTS: Of the 150 patients, 75(50%) were group A; 62(82.66%) males and 13(17.3%) females with mean age 63.76±10.05 years. There were 75(50%) patients in group B; 60(80%) males and 15(20%) females with mean age 66.13±11.73 years (p>0.05). The study was completed by 73(97.3%) in group A and 69(92%) in group B. The Kansas City Cardiomyopathy Questionnaire scores improved post-intervention compared to baseline values (p<0.001) in both groups. Group A showed comparatively greater improvement in health status compared to group B (p<0.05). CONCLUSIONS: Early initiation of dapagliflozin in patients admitted with acute heart failure was found to be associated with rapid and significant improvement in health and functional status. Clinical Trial Link: https://www.irct.ir. RCT No. (IRCT20220529055013N).