Empagliflozin for Cirrhosis with Ascites

(EMPA Liver Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Jeffrey Testani, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Yale University

Must be taking: Diuretics

Must not be taking: SGLT-2 inhibitors

Disqualifiers: Active malignancy, Type 1 diabetes, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

A proof-of-concept placebo-controlled trial to explore the acute and 14-day effects of empagliflozin on natriuresis and total body water in patients with cirrhosis and ascites. We will additionally investigate its effect on neurohumoral activation, and renal hemodynamics.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable dose of certain diuretics (water pills) like spironolactone. If you are using SGLT-2 inhibitors, you must stop them at least 10 days before joining the trial.

What data supports the effectiveness of the drug empagliflozin for cirrhosis with ascites?

Empagliflozin has been shown to reduce the risk of death in patients with cirrhosis and diabetes, although it did not significantly reduce the risk of ascites (fluid build-up in the abdomen). Additionally, empagliflozin has been effective in reducing liver fat content in patients with non-alcoholic fatty liver disease, which may suggest potential benefits for liver-related conditions. ^{1 2 3 4 5}

Is empagliflozin generally safe for humans?

Empagliflozin, also known as Jardiance, has been studied for safety in various conditions, including diabetes and heart failure. It is generally considered safe, but patients should be monitored for side effects like fluid deficits. ^{1 2 6 7 8}

How does the drug empagliflozin differ from other treatments for cirrhosis with ascites?

Empagliflozin is unique because it is primarily used to manage type 2 diabetes by helping the body excrete excess glucose through urine, and it has shown potential in reducing liver fat and improving liver function in patients with non-alcoholic fatty liver disease. This mechanism of action is different from traditional treatments for cirrhosis, which often focus on managing symptoms rather than addressing underlying metabolic issues. ^{2 9 10 11 12}

Research Team

Jeffrey Testani, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults over 18 with cirrhosis and ascites who are on stable diuretic therapy, have an eGFR of at least 30 mL/min/1.73 m2, and haven't been hospitalized for cirrhosis complications in the last 8 weeks. People with direct bilirubin >=3 mg/dL, low blood pressure, active cancers, certain urinary issues, type 1 diabetes or those pregnant/breastfeeding cannot join.

Inclusion Criteria

eGFR >= 30mL/min/1.73 m2

I am 18 years old or older.

I have cirrhosis with ascites, manage it with stable diuretics, and don't need frequent fluid removal.

Exclusion Criteria

I was hospitalized for a liver-related complication within the last 8 weeks.

Direct bilirubin >=3 mg/dL

Type 1 diabetes

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive empagliflozin or placebo for 14 days to assess effects on natriuresis and total body water

14 days

Daily administration

Washout

A 14-day washout period before crossing over to the alternate drug

14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Empagliflozin 10 MG (Sodium-glucose cotransporter 2 (SGLT2) inhibitor)
• Matching Placebo (Drug)

Trial Overview The study tests Empagliflozin's effects on salt excretion and body water in patients with liver scarring (cirrhosis) and fluid accumulation (ascites). It compares Empagliflozin to a placebo over two weeks to see if it changes hormone levels affecting the kidneys.

Participant Groups

Group I: Empagliflozin Active Control 1 Intervention

Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug.

Group II: Placebo Placebo Group 1 Intervention

Empagliflozin vs placebo for 14 days, followed by 14 day washout period, before crossing over to the alternate drug.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Findings from Research

In the EMPEROR-Reduced study involving over 3700 participants with chronic heart failure and reduced ejection fraction, empagliflozin significantly reduced the risk of hospitalization for heart failure complications (13.2% vs. 18.3% for placebo) over an average of 16 months.

Empagliflozin also showed a lower incidence of serious kidney problems (1.6% vs. 3.1% for placebo), indicating its potential safety and efficacy in managing heart failure, although it was associated with a higher rate of genital tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. Zannad, F., Macari, S.[2023]

Empagliflozin was well tolerated in patients with varying degrees of hepatic impairment, with only mild to moderate adverse events reported, indicating its safety for these populations.

The study found that empagliflozin exposure increased in patients with hepatic impairment, but the increases were less than twofold, suggesting that no dose adjustment is necessary for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Macha, S., Rose, P., Mattheus, M., et al.[2019]

A study involving 60 healthy Chinese subjects demonstrated that the test formulation of empagliflozin is bioequivalent to the brand-name drug Jardiance, showing similar pharmacokinetic properties under both fasting and fed conditions.

Both formulations of empagliflozin were generally well tolerated, indicating a good safety profile for the drug in the tested populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. Chen, G., Zhang, D., Du, A., et al.[2021]

In a one-year study involving 24 patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, treatment with empagliflozin significantly improved markers of liver inflammation, function, and fibrosis.

Key improvements included reductions in liver enzymes and insulin resistance, as well as enhanced liver function as indicated by the ALBI score, demonstrating empagliflozin's potential as an effective therapy for managing NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus. Shinozaki, S., Tahara, T., Lefor, AK., et al.[2021]

In a study of patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), empagliflozin significantly reduced liver fat content and improved liver function markers after six months of treatment.

The therapy also resulted in weight loss and reductions in blood pressure and liver enzymes, with manageable side effects, suggesting empagliflozin is a safe and effective option for treating these coexisting conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Empagliflozin on Liver Fat in Type 2 Diabetes Mellitus Patients With Non-Alcoholic Fatty Liver Disease. Pokharel, A., Kc, S., Thapa, P., et al.[2021]

Empagliflozin is an effective oral medication for type 2 diabetes that works independently of insulin, showing improvements in blood glucose levels, body weight, and blood pressure across various patient populations.

It has been found to be well tolerated with no increased risk of hypoglycemia compared to placebo, making it a safe option for managing diabetes either alone or in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. White, JR.[2018]

In a study of 63 type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD), the combination therapy of empagliflozin and metformin significantly improved liver health markers, including reduced liver steatosis and ALT levels, compared to metformin alone after 6 months.

Patients receiving the combination therapy also experienced notable reductions in body mass index (BMI) and glycated hemoglobin, indicating improved overall metabolic control and liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study. Caturano, A., Galiero, R., Loffredo, G., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

The Impact of an SGLT2 Inhibitor versus Ursodeoxycholic Acid on Liver Steatosis in Diabetic Patients. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Impact of SGLT2 inhibitors in comparison with DPP4 inhibitors on ascites and death in veterans with cirrhosis on metformin. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

The Effect of Empagliflozin on Liver Fat in Type 2 Diabetes Mellitus Patients With Non-Alcoholic Fatty Liver Disease. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus: a review of the evidence. [2018]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study. [2023]