Safety and efficacy of dapagliflozin in recurrent ascites: a pilot study

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Dapagliflozin, a sodium glucose linked transporter-2 inhibitor, induces natriuresis in patients with heart failure. A similar natriuretic effect may improve ascites in patients with cirrhosis. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in patients with cirrhosis with recurrent ascites. Methods Forty patients with recurrent ascites and cirrhosis were randomized to 1:1 in a double blinded fashion to receive either dapagliflozin (10 mg/day) with standard medical therapy (Group A) or placebo with standard medical therapy (Group B). The primary outcome was control of ascites at 6-months. Secondary outcomes were urine output, 24-hour urinary sodium, Child Turcotte Pugh (CTP), model for end stage liver disease (MELD) scores, survival at 6-months, incidence of acute kidney injury (AKI) and infections. Results The 2 groups were comparable at baseline. Control of ascites at 6-months was significantly better in group A than that in Group B (p = 0.04). Change in urinary sodium was significantly higher in Group A (p < 0.001]. However, there was no difference in change in urine output, CTP or MELD scores and survival (65% vs 72.2%, p = 0.75) between the groups at 6-months. Incidence of AKI (50% vs 15%, p = 0.04) and infections (55% vs 20%, p = 0.04) were significantly higher in Group A. Conclusions Significantly better control of ascites and higher natriuresis are observed with dapagliflozin. However, it does not improve disease severity scores or survival, and is associated with increased AKI and infections (NCT05014594). Trial Registration Number- clinical trials.gov (NCT05014594) SGLT-2 inhibitor Gliflozin cirrhosis decompensated cirrhosis natriuresis Figures Figure 1 Figure 2 Introduction The development of ascites is a landmark event in the natural history of cirrhosis and signifies a grim prognosis. Portal hypertension and splanchnic arterial vasodilatation are the major contributors in the development of ascites. Vasodilatation with the consequential decrease in effective circulating volume leads to the activation of sympathetic nervous system and renin angiotensin aldosterone system (RAAS), leading to antinatriuretic effects and retention of sodium and water thereby causing ascites ( 1 , 2 ). Management of ascites primarily consists of salt restriction, diuretics, large volume paracentesis (LVP) or transjugular intrahepatic portosystemic shunt (TIPS) with liver transplant being the ultimate panacea ( 3 , 4 , 5 , 6 ). Dapagliflozin, a Sodium glucose linked transporter-2(SGLT-2) inhibitor, is a part of the routine armamentarium for treatment of patients with Type 2 Diabetes Mellitus. Its safety is well established in non-diabetic patients too where it has been shown to improve cardiovascular outcomes. The risk of hypoglycemia is negligible as its action is independent of insulin ( 7 ). By virtue of its natriuretic effect, it has been shown to reduce hospitalizations in patients with heart failure irrespective of the presence of diabetes ( 8 ). We hypothesized that a similar natriuretic effect may help in suppressing the renin-angiotensin axis with improved mobilization of ascites in patients with cirrhosis. Pharmacokinetic data on the use of Dapagliflozin suggest that there is no need for dose modification in cirrhosis. The AUC and C max for Dapagliflozin in Child Pugh C cirrhosis is 67% and 40%, respectively ( 9 ). SGLT-2 inhibitors including dapagliflozin have been shown to improve fluid retention and serum sodium in patients with cirrhosis in case reports and small case series ( 10 , 11 , 12 , 13 ). However, SGLT-2 inhibitors have not been evaluated in randomized controlled trials. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in cirrhotic patients with recurrent ascites. Materials and methods This pilot, double-blind, randomized, placebo-controlled trial was conducted at a tertiary center from September 2021 till February 2023. Institutional Ethical approval was obtained, and the trial was registered at clinicaltrials.gov (NCT05014594). The study was compliant with the Declaration of Helsinki and has been reported according to CONSORT guidelines. Written informed consent was obtained from all patients. The consort diagram of the study is shown in Fig. 1 . Inclusion and exclusion criteria Adult patients < 70 years of age with recurrent ascites (defined as tense ascites recurring at least thrice within the last 1-year despite optimal standard medical treatment including LVP and diuretics) and cirrhosis (determined by clinical findings, hemogram, liver function tests, endoscopic findings and imaging) were included in the trial. Patients with chronic kidney disease (eGFR 3 months, portal vein thrombosis, hepatocellular carcinoma(HCC), gastrointestinal bleed in the preceding 2-weeks, overt hepatic encephalopathy in the preceding 1-month, documented hypoglycemia in the preceding 1-month, serum sodium < 125 mEq/L, history of skeletal fracture in the preceding year or any past history of fragility fracture, history of peripheral vascular disease, acute kidney injury as defined by the International Club of Ascites criteria, infections within past 1-month, anatomic urologic defects that predispose to urinary tract infection, acute-on-chronic liver failure as per the APASL or CANONIC criteria, treatment with drug with known effects on systemic and renal hemodynamics within 7-days of assesment (excepting non-selective β-blockers) were excluded from the trial. Groups and randomization Recruited patients were randomized into two groups in a 1:1 allocation ratio using computer-generated random number table provided by an independent statistician. Allocation concealment was done by serially numbered opaque sealed envelopes. Patients and clinicians responsible for treatment were blinded to the group allocated. Only an independent research scholar who was not involved in patient care was aware about patient allocation and was involved in drug dispensation. The specified intervention was started within 1-week of randomization. Group A patients (n = 20) received Dapagliflozin (10 mg/day) along with standard medical therapy (SMT) while Group B patients (n = 20) received placebo of Dapagliflozin along with SMT. SMT included dietary sodium restriction, treatment with diuretics and LVP as needed. A combination of a loop-acting diuretic (furosemide 40–160 mg/day) and a distal-acting diuretic (spironolactone 100–400 mg/day) was given with dose escalation by one step at a time to target a reduction in body weight of < 1kg/day in patients with pedal edema and 4.5 kg from immediately previous nadir weight despite maximal diuretic therapy or inability to use an effective dose of diuretics due to diuretic-related side effects. Patients on non-selective beta blockers (NSBB) were allowed to continue to do so with dose modifications/withdrawal as per Baveno guidelines. Adequate etiology specific intervention like alcohol abstinence in alcoholic liver disease and initiation of antivirals in chronic viral hepatitis were ensured in all patients prior to enrolment. Patients were counseled to stay adequately hydrated and avoid alcohol intake at baseline and at every follow-up visit. All patients with chronic viral hepatitis had received antivirals and had undetectable viral load at baseline. Patients requiring fasting for > 6 hours (in order to perform endoscopy or other procedures), Dapaglifozin or placebo was discontinued 1-day prior to the procedure and was reinstituted once normal diet was resumed. Dapagliflozin or placebo was also temporarily discontinued in patients who developed AKI, infections, dyselectrolytemia, shock or hepatic encephalopathy and was resumed after control of the same. Investigations and monitoring All patients were followed up every 1–2 weeks in the 1st month and monthly thereafter (or more frequently if clinically indicated) for 6-months. At every follow-up visit, specific enquiry was made about urine output and lower urinary tract symptoms, and the body weight and abdominal girth was measured. Complete hemogram, serum bilirubin, AST, ALT, total proteins, albumin, prothrombin time and International normalized ratio were performed at baseline and monthly (or more frequently if indicated). Serum urea, creatinine, sodium and potassium was measured at baseline and every week in the 1st month, once every 2 weeks in the second month and monthly thereafter. Glycaemic control and lipid profile, 24-hour urine sodium, alpha fetoprotein and ultrasound abdomen were performed at baseline, 3-months and 6-months. Outcomes The primary outcome of the study was control of ascites at 6-months (complete response: total absence of ascites; partial response: presence of ascites not requiring paracentesis; non response: persistence of grade 3 ascites requiring paracentesis). Secondary outcomes included change in (Δ) urine output, 24-hour urinary sodium, HbA1c, mean arterial pressure, Child Turcotte Pugh (CTP) and Model for end stage liver disease- sodium (MELD-Na) scores, the incidence of AKI, infections, overt hepatic encephalopathy, hyponatremia (serum sodium < 130 mEq/l), hypokalemia (serum potassium 6 mEq/l), HCC, ketoacidosis (including euglycemic ketoacidosis), hyperosmolar nonketotic coma, skeletal fractures and survival at 6-months. Sample size and statistical analysis As this was a pilot study with no substantial prior data available on the use of Dapagliflozin in ascites, no formal sample size and power calculations were performed a-priori. A convenient sample size of twenty patients in each arm was taken. Data recorded in a clinical record form was entered into Microsoft Excel and was analysed on an intention-to-treat basis using MedCalc® Statistical Software version 22.014 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org ; 2023). Quantitative data were expressed as means ± SD or median (interquartile range), and was compared using student t-test for normally distributed data, Mann–Whitney U test for unpaired skewed data, and Wilcoxon signed rank tests for paired skewed data. For categoric data, the Fisher exact test was used for comparisons involving single degree of freedom while chi-square test was used for comparisons with higher degrees of freedom. Missing data due to death or loss to follow-up was imputed by carrying forward the last recorded value. Survival analysis was performed by the Kaplan–Meier method and compared using the log-rank test. Patients who were lost to follow-up evaluation or withdrawn from the study were censored. All statistical analyses were performed 2-sided with P < 0.05 being considered statistically significant. Results Baseline characteristics of the two groups are shown in Table 1 . Both groups were comparable at baseline. Alcoholic liver disease was the commonest etiology in both groups. All patients had grade 3 ascites at baseline. There was no difference in the number of LVPs in the preceding 6-months between the two groups [4 ( 3 – 5 ) vs 4 ( 3 – 4 ), p = 0.63]. Table 1 Baseline characteristics of study population Characteristics Group A (n = 20) Group B (n = 20) p value Age (years) 52.1 (8.6) 49.7 (8.9) 0.43 Gender (Males: Females) 18:2 17:3 > 0.99 Etiology of cirrhosis [n (%)] -Hepatitis B -Hepatitis C -MASLD -ALD -ALD + Hepatitis C 1 (5%) 3 (15%) 5 (25%) 10 (50%) 1 (5%) 2 (10%) 5 (25%) 3 (15%) 9 (45%) 1 (5%) 0.84 Hemoglobin (g/dL) 9.24 ± 1.72 8.85 ± 1.31 0.33 Platelets (X10 9 /L) 87 (60–110) 80 (70–134) 0.29 Total Bilirubin (mg/dL) 2.6 (2.1–3.2) 2.8 (2.1–3.6) 0.57 INR 1.7 ± 0.4 1.8 ± 0.3 0.23 Serum albumin (g/dL) 3 ± 0.4 2.9 ± 0.35 0.81 Serum Creatinine (mg/dL) 1.2 (0.8–1.4) 1.1 (0.7–1.4) 0.57 HbA1c 5.1 ± 0.4 5.2 ± 0.7 0.13 Type 2 Diabetes mellitus 1 (5%) 2 (10%) > 0.99 CTP score 10 ( 8 – 11 ) 11 ( 8 – 12 ) 0.32 MELD Na score 22 ± 4.8 22 ± 6.1 0.21 24-hour urine volume (mL) 800 (600–1080) 850 (630–1050) 0.18 24-hour urinary sodium (mEq) 46.5 ± 12.7 48.4 ± 9.7 0.23 Mean Arterial Pressure (mm of Hg) 74.2 ± 7.5 75.6 ± 8.3 0.65 Receiving non-selective β blockers 7 (35%) 8 (40%) > 0.99 CTP- Child-Turcotte-Pugh, MELD- Model for end-stage liver disease, MASLD: Metabolic-dysfunction associated steatotic liver disease; ALD: alcohol associated liver disease Primary outcome At 6-months, complete and partial control of ascites was seen in 3 (15%) and 11 (55%) patients, respectively, in Group A. This was significantly better than that in Group B where none of the patients had complete response while 7 (35%) patients had partial response (p = 0.04). Secondary outcomes There was significant improvement in natriuresis in Group A with the median change in 24-hour urinary sodium at 6-months from baseline (Δ 24-hours urinary sodium) being significantly higher than that in Group B [13.3 (-10.9 to 30.1) mEq vs -4.4 (-16.4 to 5.6) mEq, p < 0.001]. However, there was no difference in change in urine output, HbA1c, MAP, CTP or MELD-Na scores between the groups at 6-months (Table 2 ). Table 2 Comparison of outcomes between the two groups at 6-months Characteristics Group A (n = 20) Group B (n = 20) p value Control of ascites -Complete response -Partial response - No response 3 (15%) 11 (55%) 6 (30%) 0 7 (35%) 13 (65%) 0.04 Δ 24-hour urinary sodium (mEq) 13.3 (-10.9 to 30.1) -4.4 (-16.4 to 5.6) < 0.001 Δ 24-hour urinary volume (mL) 110 (-20 to 150) 10 (-90 to 50) 0.09 ∆ CTP Score -1 (-2 to + 2) 1 (-1 to 2) 0.57 ∆ MELD-Na Score 1 (-3 to 8) 1 (-4 to 6) 0.76 ∆ MAP (mm of Hg) 0 (-6 to 8) -2 (-8 to 6) 0.23 Acute kidney injury 10 (50%) 3 (15%) 0.04 Infections - urinary tract infection - pneumonia - spontaneous bacterial peritonitis - blood stream infection 11 (55%) 2 (10%) 1 (5%) 4 (20%) 4 (20%) 4 (20%)* 0 1 (5%) 2 (10%)* 2 (10%)* 0.048 0.24 > 0.99 0.66 0.66 Hepatic encephalopathy 2 (10%) 1 (5%) 0.61 Hyponatremia 5 (25%) 3 (15%) 0.69 Hypokalemia 1 (5%) 3 (15%) 0.6 Hyperkalemia 1 (5%) 1 (5%) > 0.99 Hepatocellular carcinoma 0 0 - Ketoacidosis 0 0 - Hyperosmolar non-ketotic coma 0 0 - Skeletal fractures 0 0 - * One patient in Group B had concomitant spontaneous bacterial peritonitis and blood stream infection which was counted as a single episode of infection Infections were significantly more common in Group A (55%) compared to Group B (20%, p = 0.04) with a relative risk of 2.7 (1.1–7.3). However, there was no difference in the specific sites of sepsis including urinary tract infection (UTI) between the two groups (Table 2 ). There was a significantly higher incidence of AKI in Group A [10 (50%) vs 3 (15%), p = 0.04) with a relative risk of 3.3 (1.3–10.2). AKI was precipitated by sepsis in 12 of these patients and one episode was precipitated by variceal bleed. The trial intervention (Dapagliflozin or placebo) was temporarily halted in all these patients. All episodes were volume unresponsive and were diagnosed as HRS-AKI in all except one instance. Complete resolution of AKI with albumin and terlipressin was documented in 5 patients (4 patients in Group A and 1 patient in Group B) in whom the allocated trial intervention was re-initiated. Among the remaining 8 patients, 6 patients (5 patients in Group A and 1 patient in Group B) died. Two patients (1 patient in each Group) had incomplete response of AKI and were permanently discontinued from subsequent trial interventions. There was no difference in the incidence of hepatic encephalopathy [2 (10%) vs 1 (5%), p = 0.61] between the two groups. None of the patients developed hepatocellular carcinoma, skeletal fracture, ketoacidosis or hyperosmolar coma. At trial completion, 7 patients died while the trial intervention had been prematurely withdrawn due to non-resolution of AKI in 1 patient in Group A. In Group B, 5 patients died, 2 patients were lost to follow-up and 1 patient was prematurely withdrawn from trial intervention. Among the 12 deaths observed in the trial, 11 were attributed to acute-on-chronic liver failure while intracranial bleed accounted for the demise of 1 patient in Group B. None of the patients underwent liver transplantation or TIPS. Survival at 6-months was similar between the two groups [65% vs 72.2%; Hazard ratio: 0.83 (0.26–2.63), p = 0.75] (Fig. 2 ). Discussion Therapeutic options for ascites in cirrhosis short of liver transplantation, are limited to diuretics, neurohormonal modulators, vasoconstrictors, LVP and TIPS ( 3 , 4 , 5 ). Among the non-invasive pharmacologic modalities, the largest body of evidence is with the use of mineralocorticoid antagonists like aldosterone which inhibit the RAAS pathway, prevents distal absorption of sodium in the renal tubule and leads to net natriuresis. However, spironolactone with or without loop diuretics may lead to various adverse effects including dyselectrolytemia, renal dysfunction, volume depletion, hypotension and hepatic encephalopathy. The hemodynamic perturbations associated with other neurohormonal modulators of RAAS like ACE inhibitors and angiotensin receptor blockers are likely to be more severe than that with mineralocorticoid antagonists and they are not used for managing ascites in cirrhosis. Tolvaptan, a vasopressin (V2) receptor antagonist, promotes free water excretion, and is commonly used for management of ascites in some countries like Japan ( 14 ). However, this is not widely practiced elsewhere due to concerns of dehydration, hypernatremia, renal dysfunction and rebound hyponatremia on withdrawal ( 3 ). Since vasodilation lies at the root of ascites pathogenesis in cirrhosis, vasoconstrictors like midodrine have also been used in the management of recurrent and refractory ascites and may be particularly useful in those with low MAP ( 3 , 4 , 15 ). As such, the development of alternate pharmacologic therapies for ascites in cirrhosis remains an unmet need. The effectiveness of SGLT-2 inhibitors for safely controlling ascites have been recently described in small case series and case reports ( 10 ). In this pilot double-blind, randomized controlled trial, we showed that Dapagliflozin led to significantly better control of ascites and higher natriuresis. The mechanism of action involves the blockage of glucose and sodium reabsorption in the proximal tubule leading to osmotic diuresis and increased urinary sodium excretion. A second plausible mechanism involves neurohormonal modulation with inhibition of renin secretion and RAAS suppression via tubuloglomerular feedback due to increased sodium delivery to the macula densa ( 16 ). We could not look at the plasma renin activity due to logistical difficulties during the COVID-19 pandemic. The main concern with the use of SGLT-2inhibitors is the risk of UTI ( 7 ). Although Dapagliflozin was associated with an increased risk of infections, there was no difference in the incidence of UTI or other specific sites of infection. These observations are difficult to explain. Indeed, there is evidence to suggest that Dapagliflozin may be protective against severe pneumonia and septic shock in diabetic patients ( 17 ). It should be noted that patients with decompensated cirrhosis are extremely prone to infections with 4–5 times higher risk than in non-cirrhotics patients ( 18 , 19 , 20 ). We admit that given the small sample size of our study and the extremely high risk of infections in patients with decompensated cirrhosis, our finding of increased incidence of infections in the Dapagliflozin arm may well have been a random “chance” observation. There was also a significantly higher risk of AKI among patients on Dapagliflozin. All episodes of AKI in our study were volume unresponsive and all except one patient had sepsis. The relative contribution of sepsis, Dapagliflozin and diuretics to the development of AKI in these patients is speculative. Insights from patients with diabetic kidney disease suggests that unlike loop diuretics or vaptans, Dapagliflozin decreases extracellular water only when the extracellular water to total body water ratio is high and thus, Dapagliflozin may have a lower propensity to cause dehydration ( 21 ). SGLT-2 inhibitors like Dapagliflozin may also have a differential effect on extracellular water with more of the water being lost from the interstitial space compared to the intravascular compartment ( 22 ). As such, in non-cirrhotic patients, Dapagliflozin has been described to have a renal protective effect ( 23 ) and it is possible that the finding of higher risk of AKI in our study may be attributable to sepsis and not to alteration of renal hemodynamics by Dapagliflozin per se. In conclusion, Dapagliflozin was shown to improve ascites control and increase natriuresis with no effect on disease severity scores or survival in this pilot, double-blind, randomized, placebo-controlled trial. However, there are substantial concerns over the risk of AKI and infections. It is difficult to attribute causality to these adverse events due to the small sample size of this pilot trial. Our findings need to be corroborated in further larger studies with due precautions regarding these concerns including pre-specified endpoints for trial termination based on the development of these adverse events. Abbreviations RAAS: renin angiotensin aldosterone system LVP:large volume paracentesis TIPS: transjugular intrahepatic portosystemic shunt SGLT-2:Sodium glucose linked transporter-2 HCC: hepatocellular carcinoma CTP: Child Turcotte Pugh MELD-Na: Model for end stage liver disease- sodium UTI: urinary tract infection Declarations Conflict of interest: We declare no competing interests Financial disclosures: None Funding: Partially funded by Society for the study of Liver Diseases. Acknowledgments: The paper was presented as an oral abstract at The Liver Meeting 2023, AASLD’s 74 th annual meeting. Author Contributions: VS: conceptualization and design of the study, patient recruitment, data interpretation and critical revision of manuscript, study coordinator; AD: study design, patient recruitment, data analysis and manuscript writing; RA: patient enrollment and revision of manuscript; AS: revision of manuscript: SC: drug dispensation and revision of manuscript; NB: patient enrollment and manuscript writing References Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8(5):1151-7. Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. Journal of hepatology. 2015;63(5):1272-84. Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, et al. 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Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab. 2017;313(5):E563-e76. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Oct, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 02 Sep, 2024 Reviews received at journal 17 Aug, 2024 Reviewers agreed at journal 31 Jul, 2024 Reviewers invited by journal 29 Jul, 2024 Editor assigned by journal 28 Jul, 2024 Submission checks completed at journal 18 Jul, 2024 First submitted to journal 14 Jul, 2024 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4739647","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":338587344,"identity":"24ac735a-4730-4d50-9b5c-8d5a7e095760","order_by":0,"name":"Virendra Singh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYDCCwyDCwCKBgb0ByOBhSIAIGxDUIpHAwHOAWC0HwCRQiwREcQJBd/Ed533AXFAgkSc/8+0x6QIZuzwG/sXHJBgK7uDUInmY3YB5hoFEscHtvDTpGTzJxQwSz9IkGAye4dRicJiNgZnHQCJxg3SOmTQPD3Nig8QZYwOgOGEt82eeAWmpJ0FLww0ekJbDiQ38PYYP8GmRBGo5DPbLmbxkax6e48VsEmyJDxLwaOE7f4zxccEfmzz59rMHb/P2VOfx8x8+cODDH9xaQAAqy8PAwNjDwMAGiqAEvBoYGJjhWhh+ADH/AQLqR8EoGAWjYKQBAO76SwZ24JMeAAAAAElFTkSuQmCC","orcid":"","institution":"Post Graduate Institute of Medical Education and Research","correspondingAuthor":true,"prefix":"","firstName":"Virendra","middleName":"","lastName":"Singh","suffix":""},{"id":338587345,"identity":"79333367-a4ca-409b-ab7e-fb9610a6508e","order_by":1,"name":"Arka De","email":"","orcid":"","institution":"Post Graduate Institute of Medical Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Arka","middleName":"","lastName":"De","suffix":""},{"id":338587346,"identity":"e7345631-9003-4448-ae52-b3e2d2d928c7","order_by":2,"name":"Rishav Aggrawal","email":"","orcid":"","institution":"Post Graduate Institute of Medical Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Rishav","middleName":"","lastName":"Aggrawal","suffix":""},{"id":338587347,"identity":"0df094bc-1eb1-4c51-8061-d39c22367460","order_by":3,"name":"Akash Singh","email":"","orcid":"","institution":"Albert Einstein College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akash","middleName":"","lastName":"Singh","suffix":""},{"id":338587348,"identity":"eb3e8617-02f9-40ef-b6df-e026da7446a3","order_by":4,"name":"Swati Charak","email":"","orcid":"","institution":"Post Graduate Institute of Medical Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Swati","middleName":"","lastName":"Charak","suffix":""},{"id":338587349,"identity":"316ba924-9674-4dd6-92c0-e64799825561","order_by":5,"name":"Naveen Bhagat","email":"","orcid":"","institution":"Post Graduate Institute of Medical Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Naveen","middleName":"","lastName":"Bhagat","suffix":""}],"badges":[],"createdAt":"2024-07-14 19:26:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4739647/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4739647/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-024-08667-4","type":"published","date":"2024-10-09T15:57:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62657868,"identity":"76672e92-5d27-48e0-91f2-f14c74abdc6b","added_by":"auto","created_at":"2024-08-17 02:12:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":89497,"visible":true,"origin":"","legend":"\u003cp\u003eConsort diagram of study\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4739647/v1/1628339dd90c57e28d5c7ca2.png"},{"id":62657869,"identity":"c88e070b-99a2-4aeb-8729-7e53ceebc474","added_by":"auto","created_at":"2024-08-17 02:12:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":166027,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier curve showing survival at 6-months in Groups A and B\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4739647/v1/4636f104ce14c02366f87d85.png"},{"id":66597256,"identity":"0edb0ea7-e70a-420f-98d9-d49c212e07d2","added_by":"auto","created_at":"2024-10-14 16:09:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":761825,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4739647/v1/46b05353-63fd-4b1e-b70f-2b5618f81d5a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety and efficacy of dapagliflozin in recurrent ascites: a pilot study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe development of ascites is a landmark event in the natural history of cirrhosis and signifies a grim prognosis. Portal hypertension and splanchnic arterial vasodilatation are the major contributors in the development of ascites. Vasodilatation with the consequential decrease in effective circulating volume leads to the activation of sympathetic nervous system and renin angiotensin aldosterone system (RAAS), leading to antinatriuretic effects and retention of sodium and water thereby causing ascites (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Management of ascites primarily consists of salt restriction, diuretics, large volume paracentesis (LVP) or transjugular intrahepatic portosystemic shunt (TIPS) with liver transplant being the ultimate panacea (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDapagliflozin, a Sodium glucose linked transporter-2(SGLT-2) inhibitor, is a part of the routine armamentarium for treatment of patients with Type 2 Diabetes Mellitus. Its safety is well established in non-diabetic patients too where it has been shown to improve cardiovascular outcomes. The risk of hypoglycemia is negligible as its action is independent of insulin (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). By virtue of its natriuretic effect, it has been shown to reduce hospitalizations in patients with heart failure irrespective of the presence of diabetes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe hypothesized that a similar natriuretic effect may help in suppressing the renin-angiotensin axis with improved mobilization of ascites in patients with cirrhosis. Pharmacokinetic data on the use of Dapagliflozin suggest that there is no need for dose modification in cirrhosis. The AUC and C\u003csub\u003emax\u003c/sub\u003e for Dapagliflozin in Child Pugh C cirrhosis is 67% and 40%, respectively (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). SGLT-2 inhibitors including dapagliflozin have been shown to improve fluid retention and serum sodium in patients with cirrhosis in case reports and small case series (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, SGLT-2 inhibitors have not been evaluated in randomized controlled trials. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in cirrhotic patients with recurrent ascites.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis pilot, double-blind, randomized, placebo-controlled trial was conducted at a tertiary center from September 2021 till February 2023. Institutional Ethical approval was obtained, and the trial was registered at clinicaltrials.gov (NCT05014594). The study was compliant with the Declaration of Helsinki and has been reported according to CONSORT guidelines. Written informed consent was obtained from all patients. The consort diagram of the study is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eAdult patients\u0026thinsp;\u0026lt;\u0026thinsp;70 years of age with recurrent ascites (defined as tense ascites recurring at least thrice within the last 1-year despite optimal standard medical treatment including LVP and diuretics) and cirrhosis (determined by clinical findings, hemogram, liver function tests, endoscopic findings and imaging) were included in the trial. Patients with chronic kidney disease (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min (by MDRD-6) for \u0026gt;\u0026thinsp;3 months, portal vein thrombosis, hepatocellular carcinoma(HCC), gastrointestinal bleed in the preceding 2-weeks, overt hepatic encephalopathy in the preceding 1-month, documented hypoglycemia in the preceding 1-month, serum sodium\u0026thinsp;\u0026lt;\u0026thinsp;125 mEq/L, history of skeletal fracture in the preceding year or any past history of fragility fracture, history of peripheral vascular disease, acute kidney injury as defined by the International Club of Ascites criteria, infections within past 1-month, anatomic urologic defects that predispose to urinary tract infection, acute-on-chronic liver failure as per the APASL or CANONIC criteria, treatment with drug with known effects on systemic and renal hemodynamics within 7-days of assesment (excepting non-selective β-blockers) were excluded from the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eGroups and randomization\u003c/h2\u003e \u003cp\u003e Recruited patients were randomized into two groups in a 1:1 allocation ratio using computer-generated random number table provided by an independent statistician. Allocation concealment was done by serially numbered opaque sealed envelopes. Patients and clinicians responsible for treatment were blinded to the group allocated. Only an independent research scholar who was not involved in patient care was aware about patient allocation and was involved in drug dispensation. The specified intervention was started within 1-week of randomization.\u003c/p\u003e \u003cp\u003eGroup A patients (n\u0026thinsp;=\u0026thinsp;20) received Dapagliflozin (10 mg/day) along with standard medical therapy (SMT) while Group B patients (n\u0026thinsp;=\u0026thinsp;20) received placebo of Dapagliflozin along with SMT.\u003c/p\u003e \u003cp\u003eSMT included dietary sodium restriction, treatment with diuretics and LVP as needed. A combination of a loop-acting diuretic (furosemide 40\u0026ndash;160 mg/day) and a distal-acting diuretic (spironolactone 100\u0026ndash;400 mg/day) was given with dose escalation by one step at a time to target a reduction in body weight of \u0026lt;\u0026thinsp;1kg/day in patients with pedal edema and \u0026lt;\u0026thinsp;500 mg/day in those without pedal edema. Repeat LVP with albumin infusion was done for tense, symptomatic ascites with weight gain\u0026thinsp;\u0026gt;\u0026thinsp;4.5 kg from immediately previous nadir weight despite maximal diuretic therapy or inability to use an effective dose of diuretics due to diuretic-related side effects. Patients on non-selective beta blockers (NSBB) were allowed to continue to do so with dose modifications/withdrawal as per Baveno guidelines. Adequate etiology specific intervention like alcohol abstinence in alcoholic liver disease and initiation of antivirals in chronic viral hepatitis were ensured in all patients prior to enrolment. Patients were counseled to stay adequately hydrated and avoid alcohol intake at baseline and at every follow-up visit. All patients with chronic viral hepatitis had received antivirals and had undetectable viral load at baseline. Patients requiring fasting for \u0026gt;\u0026thinsp;6 hours (in order to perform endoscopy or other procedures), Dapaglifozin or placebo was discontinued 1-day prior to the procedure and was reinstituted once normal diet was resumed. Dapagliflozin or placebo was also temporarily discontinued in patients who developed AKI, infections, dyselectrolytemia, shock or hepatic encephalopathy and was resumed after control of the same.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInvestigations and monitoring\u003c/h2\u003e \u003cp\u003eAll patients were followed up every 1\u0026ndash;2 weeks in the 1st month and monthly thereafter (or more frequently if clinically indicated) for 6-months. At every follow-up visit, specific enquiry was made about urine output and lower urinary tract symptoms, and the body weight and abdominal girth was measured. Complete hemogram, serum bilirubin, AST, ALT, total proteins, albumin, prothrombin time and International normalized ratio were performed at baseline and monthly (or more frequently if indicated). Serum urea, creatinine, sodium and potassium was measured at baseline and every week in the 1st month, once every 2 weeks in the second month and monthly thereafter. Glycaemic control and lipid profile, 24-hour urine sodium, alpha fetoprotein and ultrasound abdomen were performed at baseline, 3-months and 6-months.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome of the study was control of ascites at 6-months (complete response: total absence of ascites; partial response: presence of ascites not requiring paracentesis; non response: persistence of grade 3 ascites requiring paracentesis).\u003c/p\u003e \u003cp\u003eSecondary outcomes included change in (Δ) urine output, 24-hour urinary sodium, HbA1c, mean arterial pressure, Child Turcotte Pugh (CTP) and Model for end stage liver disease- sodium (MELD-Na) scores, the incidence of AKI, infections, overt hepatic encephalopathy, hyponatremia (serum sodium\u0026thinsp;\u0026lt;\u0026thinsp;130 mEq/l), hypokalemia (serum potassium\u0026thinsp;\u0026lt;\u0026thinsp;3.5 mEq/l) and hyperkalemia (\u0026gt;\u0026thinsp;6 mEq/l), HCC, ketoacidosis (including euglycemic ketoacidosis), hyperosmolar nonketotic coma, skeletal fractures and survival at 6-months.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSample size and statistical analysis\u003c/h2\u003e \u003cp\u003eAs this was a pilot study with no substantial prior data available on the use of Dapagliflozin in ascites, no formal sample size and power calculations were performed a-priori. A convenient sample size of twenty patients in each arm was taken.\u003c/p\u003e \u003cp\u003eData recorded in a clinical record form was entered into Microsoft Excel and was analysed on an intention-to-treat basis using MedCalc\u0026reg; Statistical Software version 22.014 (MedCalc Software Ltd, Ostend, Belgium; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.medcalc.org\u003c/span\u003e\u003cspan address=\"https://www.medcalc.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; 2023). Quantitative data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (interquartile range), and was compared using student\u003c/p\u003e \u003cp\u003et-test for normally distributed data, Mann\u0026ndash;Whitney U test for unpaired skewed data, and Wilcoxon signed rank tests for paired skewed data. For categoric data, the Fisher exact test was used for comparisons involving single degree of freedom while chi-square test was used for comparisons with higher degrees of freedom. Missing data due to death or loss to follow-up was imputed by carrying forward the last recorded value. Survival analysis was performed by the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Patients who were lost to follow-up evaluation or withdrawn from the study were censored. All statistical analyses were performed 2-sided with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 being considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline characteristics of the two groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Both groups were comparable at baseline. Alcoholic liver disease was the commonest etiology in both groups. All patients had grade 3 ascites at baseline. There was no difference in the number of LVPs in the preceding 6-months between the two groups [4 (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) vs 4 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), p\u0026thinsp;=\u0026thinsp;0.63].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.1 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.7 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender (Males: Females)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18:2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEtiology of cirrhosis [n (%)]\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-Hepatitis B\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-Hepatitis C\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-MASLD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-ALD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e-ALD\u0026thinsp;+\u0026thinsp;Hepatitis C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003cp\u003e5 (25%)\u003c/p\u003e \u003cp\u003e10 (50%)\u003c/p\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003cp\u003e5 (25%)\u003c/p\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003cp\u003e9 (45%)\u003c/p\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemoglobin (g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlatelets (X10\u003c/b\u003e\u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (60\u0026ndash;110)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (70\u0026ndash;134)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal Bilirubin (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.6 (2.1\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8 (2.1\u0026ndash;3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eINR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum albumin (g/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum Creatinine (mg/dL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2 (0.8\u0026ndash;1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1 (0.7\u0026ndash;1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHbA1c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType 2 Diabetes mellitus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCTP score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMELD Na score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e24-hour urine volume (mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e800 (600\u0026ndash;1080)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e850 (630\u0026ndash;1050)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e24-hour urinary sodium (mEq)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.5\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean Arterial Pressure (mm of Hg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceiving non-selective β blockers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCTP- Child-Turcotte-Pugh, MELD- Model for end-stage liver disease, MASLD: Metabolic-dysfunction associated steatotic liver disease; ALD: alcohol associated liver disease\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePrimary outcome\u003c/p\u003e \u003cp\u003eAt 6-months, complete and partial control of ascites was seen in 3 (15%) and 11 (55%) patients, respectively, in Group A. This was significantly better than that in Group B where none of the patients had complete response while 7 (35%) patients had partial response (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003eSecondary outcomes\u003c/p\u003e \u003cp\u003eThere was significant improvement in natriuresis in Group A with the median change in 24-hour urinary sodium at 6-months from baseline (Δ 24-hours urinary sodium) being significantly higher than that in Group B [13.3 (-10.9 to 30.1) mEq vs -4.4 (-16.4 to 5.6) mEq, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001]. However, there was no difference in change in urine output, HbA1c, MAP, CTP or MELD-Na scores between the groups at 6-months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of outcomes between the two groups at 6-months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B (n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl of ascites\u003c/p\u003e \u003cp\u003e-Complete response\u003c/p\u003e \u003cp\u003e-Partial response\u003c/p\u003e \u003cp\u003e- No response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003cp\u003e11 (55%)\u003c/p\u003e \u003cp\u003e6 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e7 (35%)\u003c/p\u003e \u003cp\u003e13 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ 24-hour urinary sodium (mEq)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.3 (-10.9 to 30.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4.4 (-16.4 to 5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔ 24-hour urinary volume (mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (-20 to 150)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (-90 to 50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e∆ CTP Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1 (-2 to +\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (-1 to 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e∆ MELD-Na Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (-3 to 8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (-4 to 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e∆ MAP (mm of Hg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (-6 to 8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2 (-8 to 6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfections\u003c/p\u003e \u003cp\u003e- urinary tract infection\u003c/p\u003e \u003cp\u003e- pneumonia\u003c/p\u003e \u003cp\u003e- spontaneous bacterial peritonitis\u003c/p\u003e \u003cp\u003e- blood stream infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (55%)\u003c/p\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003cp\u003e4 (20%)\u003c/p\u003e \u003cp\u003e4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (20%)*\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003cp\u003e2 (10%)*\u003c/p\u003e \u003cp\u003e2 (10%)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003cp\u003e0.24\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003cp\u003e0.66\u003c/p\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypokalemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperkalemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatocellular carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKetoacidosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperosmolar non-ketotic coma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkeletal fractures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e* One patient in Group B had concomitant spontaneous bacterial peritonitis and blood stream infection which was counted as a single episode of infection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eInfections were significantly more common in Group A (55%) compared to Group B (20%, p\u0026thinsp;=\u0026thinsp;0.04) with a relative risk of 2.7 (1.1\u0026ndash;7.3). However, there was no difference in the specific sites of sepsis including urinary tract infection (UTI) between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was a significantly higher incidence of AKI in Group A [10 (50%) vs 3 (15%), p\u0026thinsp;=\u0026thinsp;0.04) with a relative risk of 3.3 (1.3\u0026ndash;10.2). AKI was precipitated by sepsis in 12 of these patients and one episode was precipitated by variceal bleed. The trial intervention (Dapagliflozin or placebo) was temporarily halted in all these patients. All episodes were volume unresponsive and were diagnosed as HRS-AKI in all except one instance. Complete resolution of AKI with albumin and terlipressin was documented in 5 patients (4 patients in Group A and 1 patient in Group B) in whom the allocated trial intervention was re-initiated. Among the remaining 8 patients, 6 patients (5 patients in Group A and 1 patient in Group B) died. Two patients (1 patient in each Group) had incomplete response of AKI and were permanently discontinued from subsequent trial interventions. There was no difference in the incidence of hepatic encephalopathy [2 (10%) vs 1 (5%), p\u0026thinsp;=\u0026thinsp;0.61] between the two groups. None of the patients developed hepatocellular carcinoma, skeletal fracture, ketoacidosis or hyperosmolar coma.\u003c/p\u003e \u003cp\u003eAt trial completion, 7 patients died while the trial intervention had been prematurely withdrawn due to non-resolution of AKI in 1 patient in Group A. In Group B, 5 patients died, 2 patients were lost to follow-up and 1 patient was prematurely withdrawn from trial intervention. Among the 12 deaths observed in the trial, 11 were attributed to acute-on-chronic liver failure while intracranial bleed accounted for the demise of 1 patient in Group B. None of the patients underwent liver transplantation or TIPS. Survival at 6-months was similar between the two groups [65% vs 72.2%; Hazard ratio: 0.83 (0.26\u0026ndash;2.63), p\u0026thinsp;=\u0026thinsp;0.75] (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTherapeutic options for ascites in cirrhosis short of liver transplantation, are limited to diuretics, neurohormonal modulators, vasoconstrictors, LVP and TIPS (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Among the non-invasive pharmacologic modalities, the largest body of evidence is with the use of mineralocorticoid antagonists like aldosterone which inhibit the RAAS pathway, prevents distal absorption of sodium in the renal tubule and leads to net natriuresis. However, spironolactone with or without loop diuretics may lead to various adverse effects including dyselectrolytemia, renal dysfunction, volume depletion, hypotension and hepatic encephalopathy. The hemodynamic perturbations associated with other neurohormonal modulators of RAAS like ACE inhibitors and angiotensin receptor blockers are likely to be more severe than that with mineralocorticoid antagonists and they are not used for managing ascites in cirrhosis. Tolvaptan, a vasopressin (V2) receptor antagonist, promotes free water excretion, and is commonly used for management of ascites in some countries like Japan (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, this is not widely practiced elsewhere due to concerns of dehydration, hypernatremia, renal dysfunction and rebound hyponatremia on withdrawal (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Since vasodilation lies at the root of ascites pathogenesis in cirrhosis, vasoconstrictors like midodrine have also been used in the management of recurrent and refractory ascites and may be particularly useful in those with low MAP (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). As such, the development of alternate pharmacologic therapies for ascites in cirrhosis remains an unmet need. The effectiveness of SGLT-2 inhibitors for safely controlling ascites have been recently described in small case series and case reports (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In this pilot double-blind, randomized controlled trial, we showed that Dapagliflozin led to significantly better control of ascites and higher natriuresis. The mechanism of action involves the blockage of glucose and sodium reabsorption in the proximal tubule leading to osmotic diuresis and increased urinary sodium excretion. A second plausible mechanism involves neurohormonal modulation with inhibition of renin secretion and RAAS suppression via tubuloglomerular feedback due to increased sodium delivery to the macula densa (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). We could not look at the plasma renin activity due to logistical difficulties during the COVID-19 pandemic.\u003c/p\u003e \u003cp\u003eThe main concern with the use of SGLT-2inhibitors is the risk of UTI (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Although Dapagliflozin was associated with an increased risk of infections, there was no difference in the incidence of UTI or other specific sites of infection. These observations are difficult to explain. Indeed, there is evidence to suggest that Dapagliflozin may be protective against severe pneumonia and septic shock in diabetic patients (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It should be noted that patients with decompensated cirrhosis are extremely prone to infections with 4\u0026ndash;5 times higher risk than in non-cirrhotics patients (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). We admit that given the small sample size of our study and the extremely high risk of infections in patients with decompensated cirrhosis, our finding of increased incidence of infections in the Dapagliflozin arm may well have been a random \u0026ldquo;chance\u0026rdquo; observation.\u003c/p\u003e \u003cp\u003eThere was also a significantly higher risk of AKI among patients on Dapagliflozin. All episodes of AKI in our study were volume unresponsive and all except one patient had sepsis. The relative contribution of sepsis, Dapagliflozin and diuretics to the development of AKI in these patients is speculative. Insights from patients with diabetic kidney disease suggests that unlike loop diuretics or vaptans, Dapagliflozin decreases extracellular water only when the extracellular water to total body water ratio is high and thus, Dapagliflozin may have a lower propensity to cause dehydration (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). SGLT-2 inhibitors like Dapagliflozin may also have a differential effect on extracellular water with more of the water being lost from the interstitial space compared to the intravascular compartment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). As such, in non-cirrhotic patients, Dapagliflozin has been described to have a renal protective effect (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and it is possible that the finding of higher risk of AKI in our study may be attributable to sepsis and not to alteration of renal hemodynamics by Dapagliflozin per se.\u003c/p\u003e \u003cp\u003eIn conclusion, Dapagliflozin was shown to improve ascites control and increase natriuresis with no effect on disease severity scores or survival in this pilot, double-blind, randomized, placebo-controlled trial. However, there are substantial concerns over the risk of AKI and infections. It is difficult to attribute causality to these adverse events due to the small sample size of this pilot trial. Our findings need to be corroborated in further larger studies with due precautions regarding these concerns including pre-specified endpoints for trial termination based on the development of these adverse events.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRAAS: renin angiotensin aldosterone system\u003c/p\u003e\n\u003cp\u003eLVP:large volume paracentesis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTIPS: transjugular intrahepatic portosystemic shunt\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGLT-2:Sodium glucose linked transporter-2\u003c/p\u003e\n\u003cp\u003eHCC: hepatocellular carcinoma\u003c/p\u003e\n\u003cp\u003eCTP: Child Turcotte Pugh\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMELD-Na: Model for end stage liver disease- sodium\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;UTI: urinary tract infection\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eWe declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial disclosures:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e Partially funded by Society for the study of Liver Diseases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe paper was presented as an oral abstract at The Liver Meeting 2023,\u0026nbsp;AASLD\u0026rsquo;s 74 th annual meeting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eVS: conceptualization and design of the study, patient recruitment, data interpretation and critical revision of manuscript, study coordinator; AD: study design, patient recruitment, data analysis and manuscript writing; RA: patient enrollment and revision of manuscript; AS: revision of manuscript: SC: drug dispensation and revision of manuscript; NB: patient enrollment and manuscript writing\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rod\u0026eacute;s J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8(5):1151-7.\u003c/li\u003e\n\u003cli\u003eBernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. Journal of hepatology. 2015;63(5):1272-84.\u003c/li\u003e\n\u003cli\u003eSingh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, et al. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatology international. 2023;17(4):792-826.\u003c/li\u003e\n\u003cli\u003eAithal GP, Palaniyappan N, China L, H\u0026auml;rm\u0026auml;l\u0026auml; S, Macken L, Ryan JM, et al. Guidelines on the management of ascites in cirrhosis. Gut. 2021;70(1):9-29.\u003c/li\u003e\n\u003cli\u003eEASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. 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Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2020;18(10):2168-72 e2.\u003c/li\u003e\n\u003cli\u003eMiyamoto Y, Honda A, Yokose S, Nagata M, Miyamoto J. The Effects of SGLT2 Inhibitors on Liver Cirrhosis Patients with Refractory Ascites: A Literature Review. J Clin Med. 2023;12(6).\u003c/li\u003e\n\u003cli\u003eMontalvo-Gordon I, Chi-Cervera LA, Garc\u0026iacute;a-Tsao G. Sodium-Glucose Cotransporter 2 Inhibitors Ameliorate Ascites and Peripheral Edema in Patients With Cirrhosis and Diabetes. Hepatology. 2020;72(5):1880-2.\u003c/li\u003e\n\u003cli\u003eMiyamoto Y, Honda A, Yokose S, Nagata M, Miyamoto J. Weaning from concentrated ascites reinfusion therapy for refractory ascites by SGLT2 inhibitor. Clin Kidney J. 2022;15(4):831-3.\u003c/li\u003e\n\u003cli\u003eKalambokis GN, Tsiakas I, Filippas-Ntekuan S, Christaki M, Despotis G, Milionis H. 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J Clin Endocrinol Metab. 2022;107(12):3442-51.\u003c/li\u003e\n\u003cli\u003eEkpanyapong S, Reddy KR. Infections in Cirrhosis. Curr Treat Options Gastroenterol. 2019;17(2):254-70.\u003c/li\u003e\n\u003cli\u003eBajaj JS, Kamath PS, Reddy KR. The Evolving Challenge of Infections in Cirrhosis. The New England journal of medicine. 2021;384(24):2317-30.\u003c/li\u003e\n\u003cli\u003ePiano S, Singh V, Caraceni P, Maiwall R, Alessandria C, Fernandez J, et al. Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide. Gastroenterology. 2019;156(5):1368-80.e10.\u003c/li\u003e\n\u003cli\u003eOhara K, Masuda T, Morinari M, Okada M, Miki A, Nakagawa S, et al. The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease. Diabetol Metab Syndr. 2020;12:37.\u003c/li\u003e\n\u003cli\u003eHallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20(3):479-87.\u003c/li\u003e\n\u003cli\u003eTang L, Wu Y, Tian M, Sj\u0026ouml;str\u0026ouml;m CD, Johansson U, Peng XR, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab. 2017;313(5):E563-e76.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"SGLT-2 inhibitor, Gliflozin, cirrhosis, decompensated cirrhosis, natriuresis","lastPublishedDoi":"10.21203/rs.3.rs-4739647/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4739647/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn cirrhosis, activation of renin-angiotensin-aldosterone system leads to sodium and water retention causing ascites. Dapagliflozin, a sodium glucose linked transporter-2 inhibitor, induces natriuresis in patients with heart failure. A similar natriuretic effect may improve ascites in patients with cirrhosis. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in patients with cirrhosis with recurrent ascites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty patients with recurrent ascites and cirrhosis were randomized to 1:1 in a double blinded fashion to receive either dapagliflozin (10 mg/day) with standard medical therapy (Group A) or placebo with standard medical therapy (Group B). The primary outcome was control of ascites at 6-months. Secondary outcomes were urine output, 24-hour urinary sodium, Child Turcotte Pugh (CTP), model for end stage liver disease (MELD) scores, survival at 6-months, incidence of acute kidney injury (AKI) and infections.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 2 groups were comparable at baseline. Control of ascites at 6-months was significantly better in group A than that in Group B (p = 0.04). Change in urinary sodium was significantly higher in Group A (p \u0026lt; 0.001]. However, there was no difference in change in urine output, CTP or MELD scores and survival (65% vs 72.2%, p = 0.75) between the groups at 6-months. Incidence of AKI (50% vs 15%, p = 0.04) and infections (55% vs 20%, p = 0.04) were significantly higher in Group A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificantly better control of ascites and higher natriuresis are observed with dapagliflozin. However, it does not improve disease severity scores or survival, and is associated with increased AKI and infections (NCT05014594).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration Number- \u003c/strong\u003eclinical trials.gov (NCT05014594)\u003c/p\u003e","manuscriptTitle":"Safety and efficacy of dapagliflozin in recurrent ascites: a pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 02:12:44","doi":"10.21203/rs.3.rs-4739647/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-02T16:42:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-17T23:06:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"69601992095287306609333268896530184378","date":"2024-07-31T10:29:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-29T05:19:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-28T23:12:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-18T10:43:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2024-07-14T19:25:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b36c1659-73a6-400d-85d2-ada7c93263ed","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T16:03:07+00:00","versionOfRecord":{"articleIdentity":"rs-4739647","link":"https://doi.org/10.1007/s10620-024-08667-4","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2024-10-09 15:57:58","publishedOnDateReadable":"October 9th, 2024"},"versionCreatedAt":"2024-08-17 02:12:44","video":"","vorDoi":"10.1007/s10620-024-08667-4","vorDoiUrl":"https://doi.org/10.1007/s10620-024-08667-4","workflowStages":[]},"version":"v1","identity":"rs-4739647","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4739647","identity":"rs-4739647","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}