Sodium-glucose Linked Transporter 2 (SGLT-2) Inhibitors in Recurrent Ascites: a Pilot RCT

Post Graduate Institute of Medical Education and Research, Chandigarh

Status and phase: Unknown; Phase 2

Conditions: Cirrhosis; Ascites Hepatic

Treatments: Drug: Dapagliflozin (10Mg Tab) along with standard medical therapy; Drug: Placebo of dapaglifozin along with standard medical therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT05014594

Dapa recurrent ascites

Details and patient eligibility

About

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. This results in the formation of ascites. Management of ascites primarily consists of salt restrictrion and diuretics. Liver transplant is the ultimate panacea.

Dapaglifozin, a Sodium glucose linked transporter-2(SGLT-2) inhibitor, is a part of the routine armamentarium for treatment of patients with Diabetes Mellitus type-2. 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. By virtue of its natriuretic effect, it has been shown to reduce hospitalisations in patients with heart failure irrespective of the presence of diabetes. We hypothesise 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 Dapaglifozin suggest that there is no need for dose modification in cirrhosis. The AUC and Cmax for Dapaglifozin in Child Pugh C cirrhosis is 67% and 40%, respectively. In a recent small case series, SGLT-2 inhibitors including dapaglifozin led to improvement in fluid retention and serum sodium, without acute kidney injury or encephalopathy, in patients with cirrhosis. However, SGLT-2 inhibitors have not been evaluated in randomized controlled trials. In this pilot study, we plan to evaluate the efficacy and safety of dapaglifozin in cirrhotics patients with recurrent ascites.

Enrollment: 44 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age 18-70 years
2. Cirrhosis as determined by clinical findings, hemogram and liver function tests, endoscopic findings and imaging
3. Recurrent ascites: Recurrent ascites will be defined as tense ascites recurring at least thrice within the last 1-year despite optimal standard medical treatment including large volume paracentesis and diuretics

Exclusion criteria

1. Presence of chronic kidney disease as defined by an estimated glomerular filtration rate of <60 ml/min for more than 3 months. The MDRD-6 equation will be used for estimating GFR.
2. Portal vein thrombosis
3. Hepatocellular carcinoma.
4. Gastrointestinal bleed in the preceding 2-weeks
5. Overt hepatic encephalopathy in the preceding 1-month
6. Documented hypoglycemia in the preceding 1-month
7. Serum sodium < 125 meq/l
8. History of skeletal fracture in the preceding year or any past history of fragility fracture
9. History of peripheral vascular disease
10. Acute kidney injury as defined by the International Club of Ascites criteria
11. Infection within 1-month preceding the study
12. Anatomic urologic defects that predispose to urinary tract infection
13. Mixed ascites (additional etiology of ascites apart from portal hypertension)
14. Any severe extra hepatic condition including respiratory and cardiac failure
15. Acute-on-chronic liver failure as per the APASL or CANONIC criteria
16. Treatment with drug with known effects on systemic and renal hemodynamics within 7 days of inclusion excepting beta-blockers
17. Patients opting for liver transplant or TIPS
18. Refusal to give consent

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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44 participants in 2 patient groups, including a placebo group

Group A (Dapaglifozin)

Active Comparator group

Description:

Group A will receive oral Dapaglifozin (10 mg/day) along with standard medical therapy for 6 months

Treatment:

Drug: Dapagliflozin (10Mg Tab) along with standard medical therapy

Group B (Placebo)

Placebo Comparator group

Description:

Group B will receive placebo of Dapaglifozin along with standard medical therapy for 6 months

Treatment:

Drug: Placebo of dapaglifozin along with standard medical therapy