Angiotensin-(1-7) for Metabolic Effects in High Blood Pressure, Insulin Resistance, Metabolic Syndrome, and Obesity

Recruiting at 1 trial location

Overseen By Cynthia Laws, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Vanderbilt University

Must not be taking: SNRIs, NET inhibitors, Anticoagulants, others

Disqualifiers: Diabetes, Cardiovascular disease, Renal impairment, others

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

Compensation: Varies

Number of Visits: 3

Duration: 2 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how a treatment called angiotensin-(1-7) might benefit individuals with obesity and insulin resistance, a condition where the body doesn't use insulin effectively. Researchers aim to determine if this treatment can improve insulin response and affect blood pressure. Participants will receive either the angiotensin-(1-7) treatment or a placebo, a harmless substance with no active ingredients. Suitable candidates for this trial have a body mass index (BMI) between 30 and 40, struggle with insulin resistance, and have high blood pressure. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

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 cannot participate if you are on certain medications like SNRIs, NET inhibitors, phosphodiesterase 5 inhibitors, anticoagulants, or chronic systemic glucocorticoids. It's best to discuss your specific medications with the trial team.

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

Research has shown that angiotensin-(1-7) positively affects metabolism and heart health in animal studies. In these studies, it improved insulin use and lowered blood pressure, suggesting potential as a treatment for conditions like obesity and type II diabetes.

However, evidence from human studies remains limited. This trial is in its early stages, focusing primarily on the treatment's safety and tolerability. Early-stage trials often indicate that safety data in humans is still being collected. Testing angiotensin-(1-7) in humans suggests it demonstrated initial safety in earlier research. ^{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 conditions like high blood pressure, insulin resistance, metabolic syndrome, and obesity. Unlike traditional treatments, which often focus on blocking or hindering certain pathways, Angiotensin-(1-7) works by enhancing the body's natural processes to improve metabolic functions. This peptide is thought to counteract the effects of angiotensin II, providing a potentially more balanced way to manage these complex conditions. Additionally, its unique intravenous delivery method allows for precise control over dosing, which could lead to more effective and rapid results compared to standard oral medications.

What evidence suggests that angiotensin-(1-7) might be an effective treatment for obesity and insulin resistance?

Research has shown that angiotensin-(1-7), which participants in this trial may receive, might improve insulin use and assist with weight control in animals. Animal studies have found it lowers blood pressure and enhances the body's insulin response. This suggests potential benefits for conditions like obesity and type 2 diabetes. Angiotensin-(1-7) affects insulin handling, which might help reduce high blood sugar levels. While most evidence comes from animal studies, these results are promising for its potential use in humans. ^{1 4 6 7 8}

Who Is on the Research Team?

Alfredo Gamboa, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with obesity (BMI of 30-40), high blood pressure, and insulin resistance but not diabetes. Participants should not be pregnant, breastfeeding, or have a history of serious health issues like heart disease or drug abuse. They mustn't be on certain medications like anticoagulants or antidepressants.

Inclusion Criteria

I have high blood pressure or am taking medication for it.

Able and willing to provide informed consent

You are very overweight, with a body mass index between 30 and 40.

Exclusion Criteria

I am unable to understand or decide about participating in this study.

Pregnancy or breast-feeding

You have a history of drinking too much alcohol or using drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin-(1-7) or saline infusion on two separate study days, with each study day lasting approximately four hours

2 weeks

2 visits (in-person)

Washout

A washout period of at least one week between study days

1 week

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 effects of angiotensin-(1-7) on metabolism in obese individuals with insulin resistance. It involves infusing this peptide to see if it improves insulin sensitivity using a special test called hyperinsulinemic-euglycemic clamp and monitors changes in blood pressure and other related body functions.

How Is the Trial Designed?

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

Subjects will receive intravenous infusion of three ascending doses of Angiotensin-(1-7). The doses are 4, 8, and 16 ng/kg/min. Each dose will be maintained for 10 minutes. The highest dose of Angiotensin-(1-7) will be maintained for an additional 120 minutes during the hyperinsulinemic-euglycemic clamp, for a total of 150 minutes of infusion.

Group II: Saline Placebo Group 1 Intervention

Subjects will receive an intravenous infusion of saline that is matched in volume to the Angiotensin-(1-7) study day. The saline infusion will also be maintained for a total of 150 minutes.

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?

Vanderbilt University

Lead Sponsor

Trials

714

Recruited

6,143,000+

Published Research Related to This Trial

Angiotensin (1-7) can counteract the negative effects of angiotensin II on insulin signaling in human umbilical vein endothelial cells, restoring insulin-induced activation of key enzymes like eNOS and promoting nitric oxide production.

The beneficial effects of angiotensin (1-7) are mediated through the Mas receptor, suggesting that the balance between angiotensin II and angiotensin (1-7) is crucial in preventing endothelial dysfunction and insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin (1-7) counteracts the negative effect of angiotensin II on insulin signalling in HUVECs. Tassone, EJ., Sciacqua, A., Andreozzi, F., et al.[2021]

Chronic treatment with Angiotensin (Ang)-(1-7) significantly lowered blood pressure in aged mice, indicating its potential as a therapeutic option for managing age-related hypertension.

Ang-(1-7) improved insulin sensitivity in aged mice to levels comparable to young mice, suggesting it may help mitigate metabolic issues associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. Miller, AJ., Bingaman, SS., Mehay, D., 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]

In a study involving 34 male Wistar rats with diabetes induced by streptozotocin, treatment with angiotensin-(1-7) (Ang-(1-7)) significantly improved glucose metabolism and insulin resistance, reversing many of the negative effects of diabetes.

Ang-(1-7) treatment enhanced the expression of key proteins involved in insulin secretion and glucose transport, such as Pdx1, Glut2, and glucokinase, indicating its potential as a protective agent against diabetes-related pancreatic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Islet Function in a Rat Model of Streptozotocin- Induced Diabetes Mellitus by Up-Regulating the Expression of Pdx1/Glut2. Li, J., Zhu, R., Liu, Y., et al.[2021]

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]

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) (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]

Oral Angiotensin (Ang)-(1-7) treatment significantly improved metabolic syndrome (MetS) in rats by reducing mean arterial pressure (MAP), insulin resistance, and inflammation in white adipose tissue (WAT) after 6 weeks of treatment following a 13-week high-fat diet.

The treatment led to a decrease in body mass and adiposity, normalization of fasting plasma glucose and insulin levels, and improved expression of uncoupling proteins in muscle and brown adipose tissue, indicating a restoration of metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome. Barbosa, MA., de Sousa, GG., de Castro, UGM., et al.[2021]

Insulin resistance is a key factor in the development of Type 2 diabetes and is linked to metabolic syndrome, which includes obesity and hypertension, highlighting the need for effective treatments.

Angiotensin-(1-7) has been shown to improve insulin action and counteract the negative effects of angiotensin II, suggesting that targeting the ACE2/Ang-(1-7)/Mas receptor pathway could be a promising therapeutic strategy for managing diabetes and metabolic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of the action of insulin by angiotensin-(1-7). Dominici, FP., Burghi, V., Muñoz, MC., et al.[2021]

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]

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/PMC6336955/

Angiotensin-(1–7) contributes to insulin-sensitizing effects ... Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of ...

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

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 rodent models of ...

4. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.115.06935?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub

Chronic Angiotensin-(1–7) Improves Insulin Sensitivity in High- ... Our data suggest that Ang-(1–7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new ...

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/PMC4833535/

CHRONIC ANGIOTENSIN-(1–7) IMPROVES INSULIN ... Our data suggest that angiotensin-(1–7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure.

7. 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.

8. diabetesjournals.org diabetesjournals.org/diabetes/article/62/4/1121/18225/Angiotensin-1-7-as-Means-to-Prevent-the-Metabolic

Angiotensin 1-7 as Means to Prevent the Metabolic Syndrome Our data show an improvement in insulin resistance upon Ang 1-7 treatment, suggesting that Ang 1-7 could have a potential role in the treatment of the MetSyn.