Lisinopril for Non-Alcoholic Fatty Liver Disease

Recruiting at5 trial locations

Overseen by Ju Dong Yang

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: ACE inhibitors, ARBs, Lithium

Disqualifiers: Decompensated liver disease, Alcoholic liver disease, Hepatitis B, Hepatitis C, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase II trial investigates how well lisinopril may work in preventing the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD is a condition where there is an accumulation of fatty cells in the liver. NAFLD increases a person's risk of developing liver cancer. Liver fibrosis is the common finding of chronic liver diseases leading to reduced liver function. Lisinopril is a medication that is commonly used to treat high blood pressure. Lisinopril may help to decrease liver fibrosis. The purpose of this trial is to find out what effect, if any, lisinopril has on a patient's risk of developing liver cancer.

Will I have to stop taking my current medications?

The trial requires that you have not used an ACE inhibitor or ARB within 24 weeks before joining. If you're taking vitamin E or anti-diabetic medications, you must be on a stable dose for a certain period before and during the study. If you're taking lithium, you cannot participate.

What data supports the effectiveness of the drug Lisinopril for treating non-alcoholic fatty liver disease (NAFLD)?

Some studies suggest that drugs like Lisinopril, which are angiotensin-converting enzyme inhibitors (ACE-I), might help with NAFLD because they target the renin-angiotensin system, which is involved in the disease. However, more research is needed to confirm their effectiveness in humans. ^{1 2 3 4 5}

Is Lisinopril safe for humans?

Lisinopril is generally well tolerated, but there have been rare reports of serious liver injury, including a case of liver damage in a woman with diabetes and high blood pressure. Most people do not experience these severe side effects, but it's important to be aware of the potential risks. ^{3 4 6 7 8}

How does the drug Lisinopril differ from other treatments for non-alcoholic fatty liver disease?

Lisinopril, an ACE inhibitor, is unique for non-alcoholic fatty liver disease (NAFLD) because it targets the renin-angiotensin system, which is thought to play a role in the disease's development. Unlike other treatments that focus on lifestyle changes, Lisinopril may offer a pharmacological approach, although more human studies are needed to confirm its effectiveness. ^{1 2 3 4 9}

Research Team

Ju Dong Yang

Principal Investigator

Northwestern University

Eligibility Criteria

Adults diagnosed with nonalcoholic steatohepatitis (NASH) and liver fibrosis, who have not used certain blood pressure medications recently, can join this trial. They must have a stable blood count, kidney function, and be willing to use contraception if of childbearing potential. Exclusions include pregnant or breastfeeding women, those with severe liver disease or recent weight reduction surgery, heavy drinkers, and individuals on unstable doses of certain supplements or diabetes medication.

Inclusion Criteria

Male and female subjects >= 18 years of age

Clinical diagnosis of nonalcoholic steatohepatitis (NASH) assessed by the presence of body imaging criteria (ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]), or liver biopsy up to six months prior to enrollment without suspicious nodules or cancer

Absolute neutrophil count >= 1,500/microliter

Exclusion Criteria

You have had allergic reactions to drugs that are similar to lisinopril.

You have a history of serious liver problems, such as fluid buildup in the abdomen (ascites), confusion caused by liver damage (hepatic encephalopathy), or bleeding from swollen blood vessels in the esophagus (variceal bleeding).

You are currently taking lithium medication.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive lisinopril orally once daily for 24 weeks. Patients undergo transient elastography and blood sample collection on study. Optional PDFF MRI and MRE may be conducted.

24 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

1-2 visits (in-person)

Treatment Details

Interventions

• Lisinopril (ACE Inhibitor)

Trial Overview The RELIEF-NAFLD study is testing whether the blood pressure medication Lisinopril can prevent worsening of non-alcoholic fatty liver disease (NAFLD) and reduce the risk of developing liver cancer. Participants will undergo various assessments including questionnaires, imaging tests like MRI and ultrasonography for fat in the liver as well as biospecimen collection to monitor effects.

Participant Groups

Group I: Prevention (lisinopril) Experimental Treatment 7 Interventions

Patients receive lisinopril PO QD for 24 weeks in absence of unacceptable toxicity. Patients undergo transient elastography during screening and on study. Patients also undergo blood sample collection on study and may undergo a PDFF MRI and MRE on study.

Lisinopril is already approved in Canada for the following indications:

Approved in Canada as Lisinopril for:

• Hypertension
• Heart failure
• Post-myocardial infarction

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, and currently, there are no effective pharmacologic treatments available, with management primarily focused on lifestyle changes.

Emerging evidence suggests that targeting the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may be a promising therapeutic approach for NAFLD, but more robust randomized controlled trials are needed to confirm their efficacy in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. Paschos, P., Tziomalos, K.[2022]

In a study of over 7.7 million patients, those with non-alcoholic fatty liver disease (NAFLD) were more likely to be prescribed specific antidiabetic drugs, such as SGLT2 inhibitors and thiazolidinediones, compared to those without NAFLD, indicating a targeted approach in managing diabetes in these patients.

Patients with NAFLD also showed higher prescription rates for certain antihypertensive and lipid-lowering medications, such as angiotensin II receptor antagonists and fibrates, suggesting that comorbid conditions influence treatment choices, although the differences in prescription rates were not substantial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. Machida, T., Obara, T., Miyazaki, M., et al.[2022]

A 6-month study involving 20 patients with metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) showed that the combination of amlodipine, lisinopril, and rosuvastatin significantly reduced blood pressure and improved liver enzyme levels, indicating effective management of both hypertension and liver health.

The therapy led to normalization of liver enzymes (ALT and AST) in all patients, and significant reductions in LDL cholesterol and insulin resistance, demonstrating both safety and efficacy in this high cardiovascular risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Efficacy of Amlodipine, Lisinopril and Rosuvastatin Therapy in Patients With Metabolic Syndrome and Nonalcoholic Fatty Liver Disease]. Baranova, EI., Berezina, AV., Melioranskaya, EI., et al.[2019]

In a study involving 29 rabbits, the ACE-inhibitor ramipril significantly reduced the development of key features of non-alcoholic fatty liver disease (NAFLD), including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, compared to a placebo.

Ramipril also significantly decreased the progression to non-alcoholic steatohepatitis (NASH), indicating its potential as a preventive treatment for NAFLD in conditions associated with high cholesterol diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits. Sturzeneker, MCS., de Noronha, L., Olandoski, M., et al.[2020]

Telmisartan and olmesartan, both angiotensin II receptor blockers, significantly improved insulin resistance and liver injury markers in patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CH-C), suggesting their potential as therapeutic options.

The study found that telmisartan had more pronounced effects on improving insulin sensitivity and liver function compared to olmesartan, indicating that it may be particularly beneficial for patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. Enjoji, M., Kotoh, K., Kato, M., et al.[2022]

A 61-year-old woman developed acute liver injury after starting aliskiren, an antihypertensive medication, with significant increases in liver enzymes indicating hepatocellular damage.

Upon stopping aliskiren, the patient's liver enzyme levels rapidly normalized, suggesting a direct link between the drug and the liver injury, which is supported by reports of 117 suspected cases of aliskiren-related hepatotoxicity in pharmacovigilance databases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases. Crepin, S., Godet, B., Carrier, P., et al.[2019]

Three middle-aged men developed hepatitis after taking ramipril, with symptoms appearing between 3 to 8 weeks after starting the medication, indicating a potential risk of liver injury associated with this drug.

Liver biopsies revealed unique findings such as duct necrosis and bile extravasation, and prolonged cholestasis was observed in one patient, suggesting that liver function should be monitored in patients prescribed ramipril.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ramipril-associated hepatotoxicity. Yeung, E., Wong, FS., Wanless, IR., et al.[2021]

Lisinopril, an ACE inhibitor commonly used for hypertension and diabetic nephropathy, can cause rare but severe liver injury, as demonstrated in a case of fulminant hepatic cholestasis in a 59-year-old woman.

Despite being well-tolerated in most patients, this case highlights that lisinopril can lead to life-threatening hepatotoxicity, emphasizing the need for monitoring liver function in patients taking this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisinopril-Induced Liver Injury: An Unusual Presentation and Literature Review. Al-Rifaie, A., Khan, MA., Ali, A., et al.[2022]

Patients with metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) require careful selection of antihypertensive medications due to the liver's role in drug metabolism.

The article highlights the importance of angiotensin-converting enzyme (ACE) inhibitors, discussing their pharmacological properties and potential benefits for patients with these comorbid conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CURRENT ISSUES IN THE CHOICE OF ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH METABOLIC SYNDROME AND RELATED NON-ALCOHOLIC FATTY LIVER DISEASE]. Morozova, TE., Rykova, SM., Shmarova, DG.[2018]

References

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

Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. [2022]

2. Mexico pubmed.ncbi.nlm.nih.gov

Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. [2022]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Safety and Efficacy of Amlodipine, Lisinopril and Rosuvastatin Therapy in Patients With Metabolic Syndrome and Nonalcoholic Fatty Liver Disease]. [2019]

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

Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits. [2020]

5. Greece pubmed.ncbi.nlm.nih.gov

Therapeutic effect of ARBs on insulin resistance and liver injury in patients with NAFLD and chronic hepatitis C: a pilot study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases. [2019]

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

Ramipril-associated hepatotoxicity. [2021]

8. Italy pubmed.ncbi.nlm.nih.gov

Lisinopril-Induced Liver Injury: An Unusual Presentation and Literature Review. [2022]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[CURRENT ISSUES IN THE CHOICE OF ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH METABOLIC SYNDROME AND RELATED NON-ALCOHOLIC FATTY LIVER DISEASE]. [2018]