Empagliflozin for Cirrhosis with Ascites

(EMPA Liver Trial)

Overseen By Kara Otis

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yale University

Must be taking: Diuretics

Must not be taking: SGLT-2 inhibitors

Disqualifiers: Active malignancy, Type 1 diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called empagliflozin, an SGLT2 inhibitor, to determine its effectiveness for people with cirrhosis and ascites, a condition where fluid accumulates in the abdomen due to liver damage. Researchers aim to discover if empagliflozin can remove excess water from the body and will study its short-term effects over 14 days. The trial will also examine the medication's impact on hormones and kidney function. Suitable participants have cirrhosis with fluid retention, are on a stable dose of specific diuretics, and do not require regular abdominal fluid drainage. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that four weeks of treatment with empagliflozin was safe and well-tolerated in patients with advanced chronic liver disease. Research also shows that empagliflozin, an SGLT-2 inhibitor, may reduce the risk of serious liver problems compared to traditional water pill therapy. These findings suggest that empagliflozin is generally safe for people with liver issues. However, further research is ongoing to fully understand its effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cirrhosis with ascites?

Researchers are excited about empagliflozin for cirrhosis with ascites because it targets the condition in a way that's different from current standard treatments like diuretics or beta-blockers. Empagliflozin is an SGLT2 inhibitor, which is primarily used in diabetes care to help lower blood sugar by removing excess glucose through urine. However, this mechanism might also help reduce fluid retention in patients with cirrhosis and ascites, offering a new approach to managing these symptoms. Unlike traditional options, empagliflozin could potentially address fluid buildup more efficiently and with fewer side effects.

What evidence suggests that empagliflozin might be an effective treatment for cirrhosis with ascites?

Research has shown that empagliflozin might be a helpful treatment for cirrhosis with fluid buildup in the abdomen, known as ascites. In this trial, participants will receive either empagliflozin or a matching placebo for 14 days, followed by a 14-day washout period before switching to the alternate treatment. Earlier studies found that people with long-term liver disease who took empagliflozin considered it safe and easy to handle. The drug was linked to fewer serious liver problems compared to traditional water pills. It may also help the body eliminate extra salt, which is important for managing fluid buildup. These encouraging findings suggest that empagliflozin could be a useful additional treatment for people with difficult-to-treat ascites. ^{1 2 3 6 7}

Who Is on the Research Team?

Jeffrey Testani, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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

Exclusion Criteria

Direct bilirubin >=3 mg/dL

Systolic blood pressure < 100 mmHg

Type 1 diabetes

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin 10 MG
• Matching Placebo

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.

How Is the Trial Designed?

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.

Empagliflozin 10 MG is already approved in United States, European Union for the following indications:

Approved in United States as Jardiance for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in European Union as Jardiance for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Published Research Related to This Trial

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]

Empagliflozin (Jardiance) is now approved for reducing the risk of cardiovascular death and hospitalization in adults with heart failure, even in those without diabetes, highlighting its expanded therapeutic use.

Healthcare providers, including nurses and nurse practitioners, should closely monitor patients for potential adverse effects, particularly fluid deficits, to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. Aschenbrenner, DS.[2023]

Empagliflozin (10 mg and 25 mg) is well tolerated in patients with type 2 diabetes mellitus (T2DM), showing similar rates of adverse events compared to placebo across a pooled analysis of 20 clinical trials involving over 14,000 participants.

While empagliflozin did not significantly increase the risk of hypoglycemia or urinary tract infections compared to placebo, it was associated with a higher incidence of genital infections, highlighting the need for monitoring in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus. Kinduryte Schorling, O., Clark, D., Zwiener, I., et al.[2022]

In a study involving 846 patients with cirrhosis and diabetes, SGLT2 inhibitors (SGLT2i) did not significantly reduce the risk of developing ascites compared to dipeptidyl peptidase-4 inhibitors.

However, SGLT2i users showed a significantly lower risk of death, suggesting that these medications may improve survival in patients with cirrhosis who are also managing diabetes, although further confirmatory studies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of SGLT2 inhibitors in comparison with DPP4 inhibitors on ascites and death in veterans with cirrhosis on metformin. Saffo, S., Kaplan, DE., Mahmud, N., et al.[2022]

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]

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]

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 240 NAFLD patients with type 2 diabetes, empagliflozin (EMPA) significantly reduced liver fat content by 8.73%, outperforming both ursodeoxycholic acid (UDCA) and placebo, indicating its efficacy in managing liver steatosis.

While EMPA improved liver fat reduction and beta-cell function, UDCA was more effective in reducing liver fibrosis scores and insulin resistance, suggesting that both treatments have unique benefits in managing NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Impact of an SGLT2 Inhibitor versus Ursodeoxycholic Acid on Liver Steatosis in Diabetic Patients. Elhini, SH., Wahsh, EA., Elberry, AA., et al.[2023]

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]

In a study involving 333 patients with type 2 diabetes, empagliflozin significantly reduced HbA1c levels compared to placebo after 24 weeks, indicating improved glycemic control when used alongside linagliptin and metformin.

Empagliflozin also led to significant reductions in fasting plasma glucose and body weight, and it was well tolerated, with fewer adverse events reported compared to the placebo group.

NCBI (Pubmed)

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. Søfteland, E., Meier, JJ., Vangen, B., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12576750/

Effect of empagliflozin on fractional excretion of sodium in ... A total of 70 patients with refractory ascites secondary to cirrhosis will be enrolled and randomly assigned to receive either empagliflozin 10 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38881155/

A potential novel treatment for cirrhosis-related ascites Conclusions: Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support ...

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2835700

SGLT-2 Inhibitors and Serious Liver Events in Patients With ... Use of SGLT-2 inhibitors was associated with a significantly reduced risk of serious liver events compared with diuretic therapy alone.

4. eglj.springeropen.com eglj.springeropen.com/articles/10.1186/s43066-024-00383-y

Empagliflozin as a novel therapy for cirrhotic refractory ascites Conclusions. Empagliflozin may be an effective option for use as an add-on therapy in the management of RA, with an accepted safety profile.

5. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.16139

A potential novel treatment for cirrhosis‐related ascites ... Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data ...

6. journals.lww.com journals.lww.com/10.14309/01.ajg.0001139060.76824.1f

S2900 Comparative Outcomes of Empagliflozin vs... This study evaluated real-world clinical outcomes, hepatic decompensation events, and safety profiles of empagliflozin vs dapagliflozin in cirrhosis patients.

7. wjgnet.com wjgnet.com/1948-5182/full/v17/i10/110247.htm

Effect of empagliflozin on fractional excretion of sodium in ... A total of 70 patients with refractory ascites secondary to cirrhosis will be enrolled and randomly assigned to receive either empagliflozin 10 ...