Angiotensin-(1-7) for Obesity and High Blood Pressure

Overseen By Amy Arnold, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Milton S. Hershey Medical Center

Must be taking: Antihypertensives

Must not be taking: SNRIs, Stimulants, Anticoagulants, others

Disqualifiers: Diabetes, Cardiovascular disease, Drug abuse, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 visits, each separated by at least 1 week

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the investigational drug angiotensin-(1-7) can improve heart health in individuals with both obesity and high blood pressure. Participants will receive either angiotensin-(1-7) or a saline placebo through an IV to observe their body's response. Those with a history of high blood pressure and a BMI over 30 may qualify for this study. As an Early Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot be on more than two antihypertensive medications or certain other treatments like SNRIs, anticoagulants, or investigational drugs. Check with the trial team for details.

Is there any evidence suggesting that angiotensin-(1-7) is likely to be safe for humans?

Research has shown that angiotensin-(1-7) might help lower blood pressure and improve heart health. In animal studies, this treatment reduced blood pressure and boosted heart health. Although direct results from human trials are not yet available, these animal studies offer hope for similar benefits in people.

Since angiotensin-(1-7) is being tested in an early phase trial, detailed safety information for humans is not yet available. This phase primarily focuses on determining the treatment's safety and optimal dosage. Participants should understand that early trials help researchers identify possible side effects. As more people join these studies, researchers will gather more safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Angiotensin-(1-7) because it offers a novel approach to treating obesity and high blood pressure. Unlike most current treatments that often target the symptoms, Angiotensin-(1-7) works by influencing the renin-angiotensin system, potentially providing a more direct effect on blood pressure regulation and metabolic processes. This treatment is administered intravenously, allowing precise control over dosage and immediate absorption, which might lead to faster and more controlled outcomes. This unique mechanism and delivery method could represent a significant advancement over existing options like ACE inhibitors or beta-blockers.

What evidence suggests that angiotensin-(1-7) might be an effective treatment for obesity and high blood pressure?

This trial will compare the effects of angiotensin-(1-7) with a saline placebo. Studies have shown that angiotensin-(1-7) can improve heart health, particularly in individuals with obesity and high blood pressure. Research suggests that this treatment might help lower blood pressure and enhance heart function. Angiotensin-(1-7) influences certain bodily processes that regulate blood pressure and energy use. In previous studies, patients who received angiotensin-(1-7) demonstrated better heart health outcomes, indicating its potential benefits. These findings are promising for those dealing with both obesity and high blood pressure. ^{1 4 5 6 7}

Who Is on the Research Team?

Amy Arnold, PhD

Principal Investigator

Pennsylvania State University College of Medicine

Are You a Good Fit for This Trial?

This trial is for individuals who are dealing with obesity and high blood pressure, aiming to explore if angiotensin-(1-7) can enhance heart health. Specific eligibility details are not provided.

Inclusion Criteria

I understand the study and can agree to participate.

Body mass index (BMI) between 30-40 kg/m2

Fluent in written and spoken English

Exclusion Criteria

I do not have a specific condition causing high blood pressure.

Prisoners

Highly trained athletes

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin-(1-7) or saline infusion in a crossover design

2 visits, each separated by at least 1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin-(1-7)

Trial Overview The study investigates the cardiovascular effects of angiotensin-(1-7) compared to saline (a placebo), in people with obesity-related hypertension.

How Is the Trial Designed?

Group I: Angiotensin-(1-7) Experimental Treatment 1 Intervention

Participants will receive intravenous angiotensin-(1-7) at one study visit for a total of 120 minutes. Angiotensin-(1-7) will be given in escalating doses of 2 ng/kg/min, 4 ng/kg/min, and 8 ng/kg/min. Each of these doses will be infused for 10 minutes. Following this 30 minute dose escalation period, angiotensin-(1-7) will be given at 8 ng/kg/min for an additional 90 minutes. Infusion rates will be calculated for each patient based on body mass.

Group II: Saline Placebo Group 1 Intervention

Participants receive intravenous saline at one study visit for a total of 120 minutes. The volume of saline will match the volume of angiotensin-(1-7) infused. Infusion rates will be calculated for each patient based on body mass.

Angiotensin-(1-7) is already approved in United States, European Union for the following indications:

Approved in United States as TXA127 for:

• Duchenne muscular dystrophy (DMD)
• Limb-girdle muscular dystrophy (LGMD)
• Congenital muscular dystrophy MDC1A
• Marfan syndrome
• Dystrophic Epidermolysis Bullosa (DEB)
• Pulmonary arterial hypertension
• Myelodysplastic Syndrome (MDS)

Approved in European Union as TXA127 for:

• Duchenne muscular dystrophy (DMD)

Who Is Running the Clinical Trial?

Milton S. Hershey Medical Center

Lead Sponsor

Trials

515

Recruited

2,873,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 175 adolescents born prematurely, those with overweight or obesity showed significantly higher levels of angiotensin II (Ang II) and lower levels of angiotensin-(1-7), indicating an imbalance in the renin-angiotensin system that could contribute to health issues.

This imbalance was associated with higher blood pressure, suggesting that obesity may increase the risk of hypertension and cardiovascular disease in preterm-born individuals by exacerbating existing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. South, AM., Nixon, PA., Chappell, MC., et al.[2020]

Mas receptor (MasR) deficiency in female mice removes their protection against obesity-induced hypertension, while in male mice, it leads to lower blood pressure despite obesity-related cardiac dysfunction.

Infusion of angiotensin-(1-7) (ANG-(1-7)) can restore cardiac function in male mice with MasR, but not in those lacking the receptor, suggesting that MasR agonists could be potential therapies for cardiovascular issues related to obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. Wang, Y., Shoemaker, R., Powell, D., et al.[2021]

Angiotensin-(1-7) (Ang-[1-7]) protects heart cells from high glucose-induced damage by inhibiting the reactive oxygen species-leptin-p38 MAPK/ERK1/2 pathways, which are activated during diabetic conditions.

In laboratory tests on H9c2 heart cells, Ang-(1-7) treatment led to increased cell viability, reduced apoptosis, and lower reactive oxygen species production, demonstrating its potential as a therapeutic agent in diabetic cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Lei, Y., Xu, Q., Zeng, B., et al.[2022]

In a study involving 12 non-obese and 11 obese men, the application of Angiotensin II (Ang II) resulted in subtle changes in tissue metabolism and blood flow, but did not show a significant increase in responsiveness to Ang II in obese individuals.

Obese subjects exhibited higher baseline levels of certain metabolites in adipose tissue and muscle, indicating altered metabolic responses, yet the overall effects of Ang II on tissue perfusion and metabolism were minimal across both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic and metabolic responses to interstitial angiotensin II in normal weight and obese men. Boschmann, M., Adams, F., Schaller, K., et al.[2006]

The renin-angiotensin system is linked to obesity and metabolic diseases, influencing appetite, metabolism, and fat tissue growth, as shown by various animal and human studies.

New pharmaceuticals that inhibit the renin-angiotensin system, originally designed for treating hypertension and heart failure, may also be effective in addressing obesity and metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of angiotensin in obesity and metabolic disease. Mathai, ML., Chen, N., Cornall, L., et al.[2019]

Chronic infusion of angiotensin-(1-7) in obese female mice improved glucose tolerance, highlighting a significant sex difference in response to this treatment compared to male mice, who showed similar insulin sensitivity but did not experience the same level of improvement in glucose tolerance.

Both male and female obese mice experienced reduced body mass and adiposity with angiotensin-(1-7) treatment, suggesting its potential as a therapeutic target for obesity-related insulin resistance, particularly in females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice. White, MC., Miller, AJ., Loloi, J., et al.[2020]

Angiotensin-(1-7) has shown potential as a therapeutic agent for treating and preventing metabolic disorders, particularly in the context of rising obesity and metabolic syndrome rates worldwide.

The activation of the ACE2/Ang-(1-7)/Mas pathway may counteract the negative effects of Angiotensin II, which is linked to appetite regulation and fat metabolism, suggesting a promising approach for managing metabolic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. Santos, SH., Andrade, JM.[2020]

Angiotensin 1-7 (ANG 1-7) has been shown to dilate human microvessels, but this effect is significantly reduced in patients with coronary artery disease (CAD).

Treatment with ANG 1-7 can restore the nitric oxide (NO) component of flow-mediated dilation in arterioles from CAD patients, and this effect is dependent on telomerase activity, highlighting its potential as a vasoprotective agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular Actions of Angiotensin 1-7 in the Human Microcirculation: Novel Role for Telomerase. Durand, MJ., Zinkevich, NS., Riedel, M., et al.[2021]

Angiotensin II (Ang II) plays a significant role in metabolism and may contribute to obesity-related conditions like hypertension and type 2 diabetes by acting through its receptors in adipose tissue.

The review discusses how Ang II is produced and its signaling pathways, as well as the potential of pharmaceutical agents targeting the renin-angiotensin system (RAS) to treat obesity-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Goossens, GH., Blaak, EE., van Baak, MA.[2019]

Obesity is a significant risk factor for hypertension and is often accompanied by issues like insulin resistance and dyslipidemia, which can lead to serious health complications such as left ventricular hypertrophy and increased inflammation.

Antihypertensive medications that target the renin-angiotensin system, like ACE inhibitors and angiotensin receptor blockers, may not only lower blood pressure but also improve metabolic health and protect against organ damage in obese patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there a rationale for angiotensin blockade in the management of obesity hypertension? Sharma, AM.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT03604289?term=NCT03604289&draw=2&rank=1

NCT03604289 | Angiotensin 1-7 in Obesity Hypertension The purpose of this study is to find out if the investigational drug angiotensin-(1-7) improves cardiovascular health in patients with obesity and high blood ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11677932/

Angiotensin-(1-7) and Central Control of Cardiometabolic ... Relevant to this review, accumulating evidence shows that systemic Ang-(1-7) treatment improves both cardiovascular and metabolic outcomes in ...

3. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.117.10406

Angiotensin-(1–7) and Vascular Function | Hypertension In obesity, it seems that Ang-(1–7) signals through Mas receptor (MasR)–independent pathways, possibly involving Ang II type 2 receptor (AT2R), ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39769086/

Angiotensin-(1-7) and Central Control of Cardiometabolic ... This review will highlight emerging translational studies exploring the cardiovascular and metabolic regulatory actions of angiotensin-(1-7), with an emphasis ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02245230?term=AREA%5BConditionSearch%5D(%22Hypertension%22)%20AND%20AREA%5BInterventionSearch%5D(%22Angiotensin%20I%20(1-7)%22)&rank=1

Cardiovascular Effects of Angiotensin (1-7) in Essential ... The primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7) infusion, with comparisons made between intact and blocked ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6856625/

Angiotensin-(1-7): Translational Avenues in Cardiovascular ... Ang-(1–7) is a biologically active RAS component, which antagonizes Ang II actions as well as promotes direct blood pressure lowering effects in animal models.

7. mdpi.com mdpi.com/1422-0067/25/24/13320

Angiotensin-(1-7) and Central Control of Cardiometabolic ... In addition to positive cardiovascular effects, systemic Ang-(1-7) infusion improves metabolic outcomes in animal models of hypertension, obesity, diabetes, ...