L-Citrulline + BH4 + Atorvastatin for Heart Failure

Overseen By Misti Seppi

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: D. Walter Wray

Must not be taking: Antioxidants, Nitrates, PDE-5 inhibitors, Statins

Disqualifiers: Hypersensitivity to statins, NYHA Class IV, Active liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 90 days

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This project will evaluate the impact of L-Citrulline, tetrahydrobiopterin (BH4), and atorvastatin administration on physical capacity and vascular function in Veterans with heart failure with preserved ejection fraction (HFpEF).

Will I have to stop taking my current medications?

Yes, you will need to stop taking any antioxidants, nitrates, PDE-5 inhibitors, or statins to participate in this trial.

Is the combination of L-Citrulline, BH4, and Atorvastatin safe for humans?

Atorvastatin, also known as Lipitor, is generally considered safe and well-tolerated in humans, with mild side effects like gastrointestinal disturbances and muscle pain. It has been extensively studied and is not associated with serious adverse effects on the liver, muscles, or kidneys. However, specific safety data for the combination with L-Citrulline and BH4 is not available. ^{1 2 3 4 5}

What makes the drug L-Citrulline + BH4 + Atorvastatin unique for heart failure?

This drug combination is unique because it combines L-Citrulline, which may help improve blood flow, with Tetrahydrobiopterin (BH4), known for its antioxidant properties and ability to enhance nitric oxide production, and Atorvastatin, a statin that can lower cholesterol. Together, they may address multiple aspects of heart failure, such as improving endothelial function and reducing oxidative stress, which are not typically targeted simultaneously by standard treatments. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for veterans with heart failure where the heart's lower chambers are still pumping well (HFpEF). Participants should have signs of inflammation or diagnosed heart failure. Specific eligibility details aren't provided, but typically, participants must be in stable health and meet certain medical criteria.

Inclusion Criteria

Left Ventricular Ejection Fraction (LVEF) > 50%

Plasma Brain Natriuretic Peptide (BNP) ≥150 pg/mL or NT-proBNP ≥600 pg/mL at Visit 1, or a BNP ≥100 pg/mL (or NT-proBNP ≥400 pg/mL) and a hospitalization for heart failure within the last 12 months

My heart condition allows me to perform daily activities with minimal to moderate difficulty.

Exclusion Criteria

History of hypersensitivity or allergy to any lipophilic statin

I am currently taking antioxidants, nitrates, PDE-5 inhibitors, or statins.

Prior EF <50%

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 90-day supply of either Placebo, L-Citrulline, BH4, or Atorvastatin, with baseline and follow-up assessments of vascular function and exercise tolerance

90 days

6 visits (in-person)

Washout

A two-week washout period between treatment phases

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Atorvastatin
• L-Citrulline
• Tetrahydrobiopterin (BH4)

Trial Overview The study tests if L-Citrulline, BH4 (tetrahydrobiopterin), or atorvastatin can improve how far veterans with HFpEF can walk and their blood vessel function. Each participant will receive one treatment followed by a placebo in different periods to compare effects.

Participant Groups

Group I: Placebo, Then L-Citrulline Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of L-Citrulline and perform baseline and follow-up assessments as above.

Group II: Placebo, Then BH4 Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of BH4 and perform baseline and follow-up assessments as above.

Group III: Placebo, Then Atorvastatin Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Atorvastatin and perform baseline and follow-up assessments as above.

Group IV: L-Citrulline, Then Placebo Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of L-Citrulline and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

Group V: BH4, Then Placebo Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of BH4 and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

Group VI: Atorvastatin, Then Placebo Experimental Treatment 2 Interventions

Participants will receive a 90-day supply of Atorvastatin and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.

Atorvastatin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

D. Walter Wray

Lead Sponsor

Trials

1

Recruited

90+

US Department of Veterans Affairs

Collaborator

Trials

881

Recruited

502,000+

Findings from Research

Atorvastatin is generally well tolerated across various dosages, with only a slight increase in liver enzyme elevations at the highest dose (80 mg/day), but no significant risk of serious adverse events.

Unlike some other statins, atorvastatin has a low incidence of muscular toxicity and does not require dosage adjustments for patients with renal dysfunction, making it a safe option for older adults (65 years and older) as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin: a safety and tolerability profile. Arca, M.[2021]

Atorvastatin effectively lowers elevated levels of LDL cholesterol and triglycerides in patients with various dyslipidemic disorders, showing tailored efficacy based on the specific lipid abnormalities present in each patient group.

The drug was well-tolerated among 231 patients in the study, with a safety profile comparable to other medications in the same class, indicating it is a safe option for managing cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. Bakker-Arkema, RG., Best, J., Fayyad, R., et al.[2019]

Atorvastatin is a highly effective statin that significantly lowers LDL and total cholesterol levels, and it is the first statin proven to reduce triglycerides in patients with high triglyceride levels.

In addition to its cholesterol-lowering effects, atorvastatin has beneficial non-lipid effects, such as improving blood vessel function and reducing inflammation, although clinical trial evidence is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin. Wierzbicki, AS.[2019]

Atorvastatin is a highly effective statin that significantly reduces low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels in patients with high cholesterol, achieving better results than other statins.

While atorvastatin is generally safe, it can cause mild side effects like gastrointestinal issues and muscle pain, and it may require monitoring for liver enzyme levels, especially due to its metabolism through the CYP3A4 pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. Malinowski, JM.[2022]

A review of 1,644,220 adverse event reports from 2004 to 2009 revealed that rosuvastatin is more strongly associated with muscular adverse events like myalgia and rhabdomyolysis compared to pravastatin and atorvastatin.

The analysis also found signals for acute renal failure associated with statin use, particularly with atorvastatin, although the association was weaker and no significant link was found for non-acute renal failure or increased blood creatinine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. Sakaeda, T., Kadoyama, K., Okuno, Y.[2021]

Tetrahydrobiopterin (BH(4)) is crucial for the function of nitric oxide synthase and has antioxidant properties, playing a protective role against conditions like endothelial dysfunction and hypertension.

While synthetic BH(4) is approved for treating phenylketonuria and shows promise in improving cardiovascular issues, its effectiveness in human patients is still uncertain, with mixed early results from studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin. Moens, AL., Kietadisorn, R., Lin, JY., et al.[2023]

Statins, such as cerivastatin and fluvastatin, significantly increase the mRNA levels of GTP cyclohydrolase I (GTPCH) and endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells, enhancing the synthesis of tetrahydrobiopterin (BH4) which is crucial for nitric oxide production.

The study shows that statins not only boost eNOS expression but also improve GTPCH gene expression and BH4 levels, which helps prevent shortages of BH4 and supports better endothelial function by increasing nitric oxide production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Hattori, Y., Nakanishi, N., Akimoto, K., et al.[2023]

In a 12-week trial involving 36 patients with chronic kidney disease (CKD) and hypertension, treatment with sapropterin dihydrochloride (6R-BH4) significantly reduced muscle sympathetic nerve activity (MSNA), indicating a decrease in sympathetic nervous system overactivity.

The 6R-BH4 treatment also improved arterial stiffness and endothelial function, suggesting potential cardiovascular benefits for hypertensive patients with CKD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetrahydrobiopterin lowers muscle sympathetic nerve activity and improves augmentation index in patients with chronic kidney disease. Park, J., Liao, P., Sher, S., et al.[2023]

In a porcine model of left ventricular hypertrophy (LVH), treatment with atorvastatin did not prevent the development of LVH or improve endothelial dysfunction in coronary arteries, indicating a lack of efficacy in this context.

Atorvastatin treatment led to worsening left ventricular diastolic dysfunction and increased oxidative stress, as evidenced by elevated angiotensin II levels, suggesting potential adverse effects despite its known benefits in other settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin worsens left ventricular diastolic dysfunction and endothelial dysfunction of epicardial coronary arteries in normocholesterolemic porcine with left ventricular hypertrophy. Forcillo, J., Maltais, S., Aubin, MC., et al.[2018]

Tetrahydrobiopterin (BPH4) effectively inhibits the oxidation of low-density lipoprotein (LDL) induced by copper ions (Cu2+) in a dose-dependent manner, showing potential as a protective agent against LDL modification.

BPH4's ability to suppress the formation of harmful substances and changes in LDL mobility is comparable to or even stronger than well-known antioxidants like ascorbic acid and alpha-tocopherol, suggesting it could be a powerful endogenous inhibitor of atherogenic LDL oxidation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetrahydrobiopterin inhibits copper-induced oxidation of low density lipoprotein. Sakuma, S., Fujimoto, Y., Gohda, Y., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Atorvastatin: a safety and tolerability profile. [2021]

2. Ireland pubmed.ncbi.nlm.nih.gov

A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Atorvastatin. [2019]

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

Atorvastatin: a hydroxymethylglutaryl-coenzyme A reductase inhibitor. [2022]

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

Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. [2021]

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

Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin. [2023]

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

HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. [2023]

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

Tetrahydrobiopterin lowers muscle sympathetic nerve activity and improves augmentation index in patients with chronic kidney disease. [2023]

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

Atorvastatin worsens left ventricular diastolic dysfunction and endothelial dysfunction of epicardial coronary arteries in normocholesterolemic porcine with left ventricular hypertrophy. [2018]

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

Tetrahydrobiopterin inhibits copper-induced oxidation of low density lipoprotein. [2023]