DICE Study- Diastolic Improvement With Carvedilol & Empagliflozin in Patients With Cirrhosis (DICE)

Empagliflozin + Carvedilol vs. Carvedilol Alone for Patients With Cirrhosis and Left Ventricular Diastolic Dysfunction and Impact on Hepatic Decompensation and Survival: A Double-Blind Placebo-Controlled Randomized Controlled Trial

1. This proposed double-blind placebo controlled randomized controlled trial incorporates recent advances in management of heart failure and portal hypertension using the SGLT-2 inhibitor i.e. EMPAGLIFLOZIN. The drug has been found to be useful in large trials on heart failure with preserved ejection fraction in the general population with improvement in MASLD progression, with improvement in body weight and hepatic steatosis but no change in liver fibrosis.
2. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the development and progression of heart failure in patients with type 2 diabetes and in those with heart failure and a reduced and preserved ejection fraction. In patients with cirrhosis safety of empagliflozin in a dose of 10 mg has been demonstrated.
3. Prevention of decompensation related events in cirrhosis is the key endpoint of any liver-directed therapy as the median survival in the compensated state exceeds 10 years but median survival in the decompensated state approximates 1.5 years. Previous data has demonstrated the risk of hepatic decompensation acute kidney injury and poor survival in patients with cirrhosis and heart failure with preserved ejection fraction (HFpEF) i.e. LVDD a large subset of whom meet criteria for CCM.

Study Overview

• Status: Recruiting
• Conditions: Cirrhosis; Empagliflozin; Cirrhotic Cardiomyopathy; Cardiometabolic Risk Factors
• Intervention / Treatment: Drug: Empagliflozin + Carvedilol; Drug: Carvedilol

Detailed Description

New diagnostic criteria for cirrhotic cardiomyopathy For the diagnosis of cirrhotic cardiomyopathy (CCM) we will use criteria proposed by the CCM consortium in 2020 with modification to take septal e' and E/e' readings. In accordance with the recent CCM criteria 'systolic dysfunction is defined as an ejection fraction (EF) of 50% or less or an absolute value of GLS <18%. LVDD grade will be determined if 3 of the following 4 criteria are met: early diastolic trans mitral flow to early diastolic mitral annular velocity (E/e') ≥15 left atrial volume index (LAVI) >34 mL/m2 septal early diastolic mitral annular velocity (e') <7 cm/second or tricuspid regurgitation (TR) maximum velocity >2.8 m/second in the absence of pulmonary hypertension (HTN) and the presence of measurable early to late diastolic trans mitral flow velocity (E/A) ratio (E/A >2 = grade 3 E/A 0.8-2 = grade 2)'. LVDD will be classified as "of indeterminate grade" when only 2 of the 4 criteria are met. The supporting criteria for diagnosis of LVDD are changes in cardiac chamber sizes electrophysiological abnormalities increased biomarkers like N terminal pro-brain natriuretic peptide (NT-Pro BNP) and troponin I.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Madhumita Premkumar, MD DM; Phone Number: 01722754777; Email: drmadhumitap@gmail.com
• Study Contact Backup: Name: Madumita Premkumar; Phone Number: 01722754777

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • PGIMER Chandigarh
    • Contact: Prerna Sharma; Phone Number: 01722754777; Email: hepatology.mpk@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Age range of 18-65 years
• Cirrhosis as diagnosed by histology or clinical laboratory and USG findings
• LVDD (with EF>50%) on 2D echocardiography with TDI
• Written informed consent.

Exclusion criteria

• Age >65 years
• Serum Creatinine>2 mg/dl
• History of urinary tract /genital infections in last 3 months
• Patient on treatment with statin (one month before the study)
• Advanced Cirrhosis (MELD>20)
• Coronary artery disease
• Sick sinus syndrome/ Pacemaker valvular heart disease
• Cardiac rhythm disorder Peripartum cardiomyopathy
• Portopulmonary hypertension/ hepatopulmonary syndrome
• Transjugular intrahepatic porto systemic shunt (TIPS) insertion
• Hepatocellular carcinoma
• Pregnancy or lactation
• Patients with HIV or retroviral therapy
• Anemia Hb < 8gm/dl in females and < 9 gm/dl in males
• Acute variceal bleeding in last 6months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Experimental: Empagliflozin + Carvedilol-arm; Experimental: Empagliflozin + Carvedilol-arm; Empagliflozin fixed dose of 10 mg per day in patients with or without diabetes for 1 year from randomization; Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate; Standard Medical Therapy for liver disease as per clinician decision	Drug: Empagliflozin + Carvedilol; Patient Recruitment: The study participants are all cirrhosis patients receiving treatment at PGIMER Chandigarh. Eligible participants meeting LVDD criteria per the CCM Consortium 2020 consensus. Carvedilol Dosing protocol in this study Patients will be given carvedilol in a starting dose of 3.125 mg twice daily. The dose will be titrated weekly to achieve a target heart rate of 50-60/ min taking care that side effects such as hypotension bronchospasm excessive bradycardia are not seen. The maximum dosage allowed as per prior trial data is 25 mg per day. Empagliflozin Dosing protocol in this Study: • All patients will receive a standard dose of Empagliflozin fixed dose of 10 mg per day in patients with or without diabetes.
Active Comparator: Active Comparator: Carvedilol arm; Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate 10 mg placebo administered once daily.; Standard Medical Therapy prescribed as per clinician decision	Drug: Carvedilol; Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate 10 mg placebo pill; Standard Medical Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite end point of decompensation event and/or death	The primary outcome measure is defined as a composite end point of acute decompensation event (acute variceal bleeding new ascites or recurrence of previously controlled ascites episode of hepatic encephalopathy or acute kidney injury) OR all-cause death in patients with cirrhosis and LVDD	From enrolment through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Cardiac Diastolic Function	Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging Septal E/e' ratio	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Diastolic Function	Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging Septal e' velocity	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Diastolic Function	Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging Left atrial volume index	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Diastolic Function	Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging Tricuspid regurgitant Velocity	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Systolic Function	Improvement in Cardiac systolic function (Cardiac Index) in either arm based on Echocardiography and Cardiac Imaging	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Systolic Function	Improvement in Cardiac systolic function (Ejection Fraction) in either arm based on Echocardiography and Cardiac Imaging	From enrolment through study completion, an average of 1 year
Improvement in Cardiac Systolic Function	Improvement in Cardiac systolic function (Global Longitudinal Strain) in either arm based on Echocardiography and Cardiac Imaging	From enrolment through study completion, an average of 1 year
Hospitalization events	• Episodes warranting hospitalization	From enrolment through study completion, an average of 1 year
• Serum level of NT-proBNP	Cardiac biomarkers	At enrolment
• Serum level of NT-proBNP	Cardiac biomarkers	At 6 months from enrolment
• Serum level of NT-proBNP	Cardiac biomarkers	At 12 months from enrolment
• Serum level of Galectin-3	Cardiac biomarkers	At enrolment
• Serum level of Galectin 3	Cardiac biomarkers	At 6 months from enrolment
• Serum level of Galectin 3	Cardiac biomarkers	At 12 months from enrolment
• Serum level of Aldosterone	Cardiac biomarkers	At enrolment
• Serum level of Aldosterone	Cardiac biomarkers- Renin angiotensin aldosterone system	At 6 months from enrolment
• Serum level of Aldosterone	Cardiac biomarkers- Renin angiotensin aldosterone system	At 12 months from enrolment

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): January 30, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: November 30, 2025
• First Submitted That Met QC Criteria: December 22, 2025
• First Posted (Actual): January 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Ascites; Diastolic heart failure; heart failure with preserved ejection fraction; SGLT-2 inhibitor; Empagliflozin in cirrhosis; Carvedilol in Cirrhosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Heart Failure; Pathological Conditions, Signs and Symptoms; Fibrosis; Ascites; Heart Failure, Diastolic; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Alcohols; Propanolamines; Amino Alcohols; Propanols; Heterocyclic Compounds, 3-Ring; Carbazoles; Carvedilol; empagliflozin
• Other Study ID Numbers: PGI/IEC/2025/SPL-865

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This database has identifier information

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No