Sacubitril/Valsartan for Metabolic Health in Black Individuals

Overseen By Nehal Vekariya, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must be taking: Sacubitril/valsartan

Disqualifiers: Cardiovascular diseases, Diabetes, Smoking, others

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

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

Compensation: Varies

Number of Visits: 12

Duration: 12 weeks

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how sacubitril/valsartan (known as Entresto when combined with valsartan) can improve metabolic health in Black individuals by enhancing hormone levels that may reduce diabetes risk. Researchers compare two treatment approaches to determine which more effectively boosts insulin sensitivity and energy use. The trial targets Black adults with blood pressure between 120-160/80-100 mmHg, without diabetes or heart issues. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that sacubitril/valsartan, a combination drug, has received FDA approval for treating heart failure, indicating it has undergone safety testing in people. Studies have found that this medication can improve sugar and insulin management in some patients.

Patients taking sacubitril/valsartan for heart issues have reported common side effects, such as low blood pressure, high potassium levels, and cough. However, most tolerate it well.

For the trial group using only valsartan, this drug is often prescribed for high blood pressure and heart failure. It is known to be safe, with side effects that can include dizziness, high potassium levels, and fatigue.

Both treatments have been used by many patients, providing reassurance about their safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Sacubitril/Valsartan for improving metabolic health in Black individuals because it combines two active ingredients, sacubitril and valsartan, which work together to enhance insulin sensitivity. Unlike standard treatments that often focus solely on blood pressure management or glucose control, Sacubitril/Valsartan targets a dual mechanism: it helps relax blood vessels and improves heart function while potentially boosting metabolism. This dual action offers a promising new approach for addressing metabolic issues more comprehensively. Additionally, Valsartan, used as an active comparator, allows researchers to directly assess the added benefits of the combination with sacubitril, sparking interest in its potential to outperform existing therapies.

What evidence suggests that sacubitril/valsartan might be an effective treatment for metabolic health in Black individuals?

Research has shown that sacubitril/valsartan, a combination drug, can improve metabolic health by enhancing insulin sensitivity and energy efficiency. Studies have found that this drug lowers insulin resistance in prediabetic individuals, helping to prevent diabetes. In this trial, some participants will receive sacubitril/valsartan, which has demonstrated better protection for metabolism and the heart compared to valsartan alone. This combination drug increases levels of certain hormones called natriuretic peptides, which are important for heart and metabolic health. Overall, sacubitril/valsartan appears promising in improving metabolic health, especially for those at risk of diabetes. ^{2 6 7 8 9}

Who Is on the Research Team?

Pankaj Arora, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for African-American or Black adults with blood pressure between 120-160/80-100 mmHg, who are not pregnant, don't smoke, and have no history of significant heart disease or diabetes. They must be able to exercise on a treadmill and not consume more than two alcoholic drinks daily.

Inclusion Criteria

You identify yourself as African-American or Black.

You identify as African-American or Black.

You have a blood pressure of 120-160/80-100 mmHg.

Exclusion Criteria

You are unable to walk or run on a treadmill.

Anemia (men, Hct < 38%, Hb<13 g/dL; women, Hct <36%, Hb <12 g/dL)

I have diabetes or my blood sugar/HbA1C levels are high.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sacubitril/valsartan or valsartan alone for 12 weeks to assess changes in insulin sensitivity and energy expenditure

12 weeks

Baseline and after 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Sacubitril
• Valsartan

Trial Overview The study tests if increasing Natriuretic Peptide levels using sacubitril/valsartan can improve metabolic health in Black individuals. It measures insulin sensitivity & energy expenditure to understand the role of NPs in cardiometabolic risk.

How Is the Trial Designed?

Group I: Sacubitril/Valsartan Experimental Treatment 4 Interventions

We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.

Group II: Valsartan Active Control 4 Interventions

We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.

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

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction

Approved in United States as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Canada as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Japan as Entresto for:

• Heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Sacubitril/valsartan (Entresto) significantly reduces the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction, outperforming enalapril in clinical studies.

While effective, sacubitril/valsartan can cause side effects such as low blood pressure, angioedema, and impaired kidney function, and it is contraindicated in pregnant or breastfeeding women and patients with severe liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. Bruhn, C.[2021]

In a rat model of hypertension and obesity, low-dose sacubitril/valsartan showed a reduction in cardiac hypertrophy and pulmonary edema compared to a vehicle, but not when compared to valsartan alone, indicating potential benefits in specific conditions.

The study suggests that the effects of sacubitril/valsartan on cardiac health may vary depending on the stage of cardiac hypertrophy, as gene markers of cardiac dysfunction were upregulated in rats treated with sacubitril/valsartan after prolonged high-salt feeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Low-Dose Sacubitril/Valsartan on Different Stages of Cardiac Hypertrophy in Salt-Loaded Hypertensive Rats. Hamano, G., Yamamoto, K., Takami, Y., et al.[2021]

This case report describes the first instance of severe liver injury associated with sacubitril/valsartan (Entresto) in a 90-year-old female patient, highlighting a potential risk of hepatotoxicity despite the drug's established safety profile.

After discontinuing sacubitril/valsartan, the patient's liver function improved, suggesting that while liver injury from this medication is rare, clinicians should remain vigilant for signs of hepatotoxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan-induced liver injury: A case report and literature review. Zhang, T., Cai, JL., Yu, J.[2023]

In a study of 224 patients with heart failure and reduced ejection fraction, approximately 38.4% were eligible for sacubitril/valsartan treatment after being on optimized guideline-directed medical therapy.

The analysis revealed that many patients remained symptomatic despite optimal treatment, highlighting the potential need for additional therapies like sacubitril/valsartan in managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. Pinto, G., Tondi, L., Gemma, M., et al.[2021]

A case study of a 58-year-old male revealed that co-administration of atorvastatin and sacubitril/valsartan can lead to life-threatening rhabdomyolysis, highlighting the need for careful monitoring of muscle-related toxicity in patients taking these medications together.

The mechanism behind this adverse effect is that sacubitril inhibits the excretion of atorvastatin, increasing its concentration in the body and the risk of muscle damage; therefore, starting with a lower dose of atorvastatin or considering alternatives like rosuvastatin may be safer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to management of rhabdomyolysis as the adverse effect of drug interaction between atorvastatin and sacubitril/valsartan: a case report. Siew, KSW., Abdul Hafidz, MI., Mohd Zaidan, FZB., et al.[2022]

In a study of 59 prediabetic patients with heart failure and reduced ejection fraction, treatment with sacubitril/valsartan for 24 weeks significantly improved metabolic parameters, including reductions in fasting plasma glucose, insulin levels, and hemoglobin A1c, indicating better glycemic control.

The treatment also led to significant improvements in heart function, as evidenced by reductions in left ventricular volumes and an increase in ejection fraction, suggesting that sacubitril/valsartan may enhance both metabolic control and cardiac function in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sacubitril/valsartan on both metabolic parameters and insulin resistance in prediabetic non-obese patients with heart failure and reduced ejection fraction. Cloro, C., Zaffina, I., Sacchetta, L., et al.[2022]

In a review of 14 studies with 20,261 patients, sacubitril/valsartan showed no significant difference in total adverse events compared to ACE inhibitors or ARBs, but it was associated with a lower risk of death and renal dysfunction.

While sacubitril/valsartan reduced the risk of discontinuation due to adverse events, it did increase the risk of hypotension, particularly in patients with heart failure, indicating a need for careful monitoring in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Sacubitril/Valsartan: A Meta-analysis of Randomized Controlled Trials. Huang, Y., Zhang, Y., Ma, L., et al.[2022]

Sacubitril/valsartan (Entresto®) is the first angiotensin receptor neprilysin inhibitor (ARNI) approved for heart failure patients with reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor blocker.

A case report highlighted a probable instance of ARNI-induced hyponatremia in an elderly woman, suggesting a likely association between the drug and her low sodium levels, as assessed by the Naranjo Adverse Drug Reaction Assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. Fuzaylova, I., Lam, C., Talreja, O., et al.[2021]

In a study of 83 patients with heart failure, sacubitril/valsartan significantly improved left ventricular ejection fraction (LVEF) from 28.8% to 32.0%, indicating its efficacy in enhancing heart function.

The improvement in LVEF was primarily observed in white patients, while black patients did not show significant changes, suggesting that the response to sacubitril/valsartan may vary by race and highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between ethnicity and degree of improvement in cardiac function following initiation of sacubitril/valsartan. Holm, N., Bromage, DI., Cannata, A., et al.[2023]

In 2018, 1043 patients in Ireland were prescribed Entresto, showing a steady increase in its use since reimbursement approval, with a total expenditure of €1.2 million, which was lower than expected.

Patients in Ireland using Entresto were generally older and more symptomatic than those in the pivotal PARADIGM-HF trial, and starting treatment with Entresto led to a reduction in the use of other heart failure medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan (Entresto) utilisation and prescribing patterns in the context of a reimbursement application system. Kennedy, C., Smith, A., Doran, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9686067/

Cooling down with Entresto. Can sacubitril/valsartan ... A novel combination drug, sacubitril/valsartan, has been shown to be more efficient in reducing cardiovascular events and heart failure readmission compared to ...

2. frontiersin.org frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.940654/full

Effects of sacubitril/valsartan on both metabolic parameters ... Our data seem to indicate that sal/val enhances metabolic control and improves insulin resistance also in prediabetic non-obese patients with HFrEF.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9402256/

Effects of sacubitril/valsartan on both metabolic parameters ... Our data seem to indicate that sal/val enhances metabolic control and improves insulin resistance also in prediabetic non-obese patients with HFrEF.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0753332222007715

Sacubitril/valsartan combination enhanced cardiac ... Sacubitril/valsartan therapy provides a more favorable metabolic and cardioprotective response compared to valsartan alone in a rat model of DCM.

5. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/2785700

Effect of Treatment With Sacubitril/Valsartan in Patients ... The results of the LIFE trial show there was no difference between sacubitril/valsartan and valsartan with respect to lowering NT-proBNP levels ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK507904/

Sacubitril-Valsartan - StatPearls - NCBI Bookshelf The medication is FDA-approved to treat patients with chronic heart failure with reduced ejection fraction (HFrEF) in NYHA class II, III, or IV.

7. dmsjournal.biomedcentral.com dmsjournal.biomedcentral.com/articles/10.1186/s13098-022-00944-4

Cooling down with Entresto. Can sacubitril/valsartan ... A novel combination drug, sacubitril/valsartan, has been shown to be more efficient in reducing cardiovascular events and heart failure readmission compared to ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2021/207620Orig1s018.pdf

207620Orig1s018 - accessdata.fda.gov To reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.

9. ema.europa.eu ema.europa.eu/en/documents/assessment-report/entresto-epar-public-assessment-report_en.pdf

entresto-epar-public-assessment-report_en.pdf - EMA The applicant indicated that sacubitril , as part of the fixed dose combination sacubitril/valsartan, was considered to be a new active.