Sympathetic Blockade for Obesity

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vanderbilt University Medical Center

Must be taking: Antihypertensives

Must not be taking: Glucocorticoids, Investigational drugs

Disqualifiers: Pregnancy, Smoking, Cardiovascular disease, others

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

We will study obese hypertensive subjects in a randomized, crossover study to determine if two weeks sympathetic blockade improves endogenous glucose production. Subjects will be studied on 3 different occasions after two weeks of receiving either placebo, amlodipine (vasodilator arm) or moxonidine (study arm). The order of the studies will be determined using computer-generated randomization. Patients will be blinded as to which treatment they are receiving on each day. An investigator blinded to the treatment assignment will perform the analysis of the data.

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

The trial protocol does not specify if you need to stop taking your current medications. However, since the study involves hypertensive patients, you may need to continue your antihypertensive medication. It's best to discuss this with the trial coordinators.

Is the treatment generally safe for humans?

The safety of the treatment you are considering, which may include drugs like Amlodipine or Moxonidine, is not directly addressed in the provided research articles. However, some related drugs like sibutramine have been associated with cardiovascular safety issues, while others like orlistat have mostly transient tolerability issues. More specific safety data for your treatment would be needed to provide a clear answer. ^{1 2 3 4 5}

How does the drug Amlodipine and Moxonidine differ from other obesity treatments?

Amlodipine and Moxonidine are unique in obesity treatment as they focus on sympathetic blockade, which is different from most current obesity drugs that target appetite suppression or fat absorption. This approach may offer a novel mechanism by potentially reducing the body's stress response, which can contribute to weight gain. ^{4 6 7 8 9}

What data supports the effectiveness of the drug Amlodipine and Moxonidine for obesity?

The research suggests that calcium channel blockers like Amlodipine may be considered for use in obese patients with high blood pressure, as they have minimal effects on insulin sensitivity. Moxonidine, a centrally acting antihypertensive, may also be beneficial as it inhibits the overactive sympathetic nervous system in obese patients. ^{2 4 8 10 11}

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-65 with obesity (BMI ≥ 30 kg/m2) and high blood pressure (>130/85 mmHg or on medication). Participants must be able to consent. Exclusions include immunological/hematological disorders, allergies to study meds, impaired kidney function, Type I diabetes, serious cerebrovascular disease, heavy smoking, substance abuse, certain cardiovascular diseases.

Inclusion Criteria

Able and willing to provide informed consent

Obesity will be defined as having a body mass index (BMI) ≥ 30 kg/m2

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

Exclusion Criteria

Pregnancy or breast feeding

I have not had a heart attack or serious heart issues in the last 6 months.

I have been on long-term steroid treatment for more than a week in the past month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 weeks of treatment with either placebo, amlodipine, or moxonidine in a randomized, crossover design

6 weeks

3 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

• Amlodipine
• Moxonidine
• Placebo

Trial Overview The study tests if sympathetic blockade by moxonidine improves glucose production in obese hypertensive subjects compared to amlodipine and placebo. It's a randomized crossover trial where patients receive each treatment for two weeks with random order and are blinded to the treatments.

How Is the Trial Designed?

Group I: Moxonidine Experimental Treatment 1 Intervention

Subjects will received 2 weeks of capsules containing moxonidine.

Group II: Amlodipine Active Control 1 Intervention

Subjects will received 2 weeks of capsules containing amlodipine.

Group III: Placebo Placebo Group 1 Intervention

Subjects will received 2 weeks of capsules containing placebo.

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

Approved in United States as Norvasc for:

• Hypertension
• Angina
• Variant angina

Approved in European Union as Norvasc for:

• Hypertension
• Coronary artery disease
• Variant angina

Approved in Canada as Norvasc for:

• Hypertension
• Angina

Approved in Japan as Norvasc for:

• Hypertension
• Angina pectoris

Approved in China as Norvasc for:

• Hypertension

Approved in Switzerland as Norvasc for:

• Hypertension
• Coronary artery disease

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

Two new medications, phentermine/topiramate ER (Qsymia™) and lorcaserin (Belviq®), have been approved by the FDA for long-term weight management in individuals with obesity or overweight with related health issues, marking a significant advancement in obesity treatment.

The review highlights that these new drugs are either reformulations of existing medications or new approaches targeting previously established mechanisms, indicating a trend of revisiting and optimizing older treatments for obesity management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic treatment options for obesity: what is old is new again. Ryan, DH., Bray, GA.[2021]

Orlistat is preferred for treating obesity-related hypertension as it can lead to a small decrease in blood pressure, while sibutramine may actually increase blood pressure, making it less suitable for these patients.

ACE inhibitors and AT(1) receptor antagonists are recommended for obese hypertensive patients because they lower blood pressure without negatively affecting insulin sensitivity, and they also provide kidney protection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evidence for drug treatments in obesity-associated hypertensive patients--a discussion paper. Doggrell, SA.[2018]

Lorcaserin and the combination of Phentermine-topiramate (phen-top) are two FDA-approved drugs for obesity, with lorcaserin showing moderate efficacy and an acceptable safety profile, while phen-top has shown reasonable efficacy but carries risks like teratogenicity and psychiatric issues.

Cetilistat, currently in phase 3 trials, is a lipase inhibitor that may offer a better safety profile than orlistat, and other promising anti-obesity drugs targeting the gut, such as exenatide and liraglutide, are also under investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging drug molecules against obesity. George, M., Rajaram, M., Shanmugam, E.[2014]

Recent advances in medical weight management have led to the approval of several medications for treating obesity, including orlistat, phentermine/topiramate, and the newer tirzepatide, which primarily work by reducing appetite and increasing feelings of fullness.

While current anti-obesity medications improve weight and metabolic health, there is still no evidence supporting a reduction in serious cardiovascular outcomes, although such data is expected soon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. Chakhtoura, M., Haber, R., Ghezzawi, M., et al.[2023]

Pharmacotherapy for obesity can be considered for individuals with a BMI of 30 or greater, or 27 or greater with weight-related health issues, highlighting the importance of medication in weight management when lifestyle changes alone are insufficient.

The effectiveness of antiobesity medications, such as phentermine and liraglutide, relies on customizing treatment to individual patient behaviors and health conditions, along with careful monitoring of their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity Pharmacotherapy. Saunders, KH., Umashanker, D., Igel, LI., et al.[2022]

Orlistat and sibutramine were found to be more effective than placebo in promoting weight loss in obese individuals with hypertension, as shown in eight studies included in the Cochrane review.

Orlistat not only aided in weight loss but also significantly reduced both systolic and diastolic blood pressure, while sibutramine was associated with an increase in blood pressure, highlighting potential safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Long-term effects of weight-reducing drugs in hypertensive patients--a survey of a Cochrane review]. Madsbad, S.[2018]

New generation anti-obesity medications, such as orlistat, phentermine/topiramate, and liraglutide 3.0 mg, have varying safety profiles, with some presenting significant risks like fetal toxicity and gallstone disease, while others mainly cause transient tolerability issues.

Despite their effectiveness in weight loss, the prescription rates for these medications are low, partly due to safety concerns and the need for more long-term data to better understand their risk-benefit profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of new-generation anti-obesity medications: a narrative review. Patel, DK., Stanford, FC.[2023]

Sibutramine, an anorectic banned since 2010 due to cardiovascular safety concerns, was found to significantly inhibit hERG channel currents and increase heart rate and blood pressure in beagle dogs, indicating serious cardiovascular risks.

The study demonstrated that sibutramine shortens action potential duration in rabbit Purkinje fibers, further highlighting its potential to cause adverse cardiovascular effects, which is crucial for drug safety regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety Pharmacology of Sibutramine. Yun, J., Chung, E., Choi, KH., et al.[2020]

Several anti-obesity drugs have been withdrawn from the market due to serious cardiovascular risks, such as fenfluramine and sibutramine, highlighting the importance of safety in obesity treatments.

Current treatments like GLP-1 analogues and metformin not only aid in weight loss but also have favorable cardiovascular profiles, suggesting they could be effective options for managing obesity alongside type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of current and future anti-obesity drugs. Comerma-Steffensen, S., Grann, M., Andersen, CU., et al.[2019]

Sibutramine, a serotonin/noradrenaline reuptake inhibitor, has been shown to reduce body weight by an average of 4.45 kg compared to placebo, while also improving triglycerides and HDL cholesterol, but it may cause increased heart rate and has contraindications for patients with uncontrolled hypertension or cardiovascular issues.

Orlistat, a pancreatic lipase inhibitor, results in an average weight loss of 2.89 kg and significantly decreases waist circumference and blood pressure, but primarily causes gastrointestinal side effects and should be avoided in patients with chronic malabsorption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological therapy of obesity]. Pagotto, U., Vanuzzo, D., Vicennati, V., et al.[2018]

Obesity is now recognized as a chronic disease, leading to the development of safer long-term pharmacotherapies, such as phentermine/topiramate and bupropion/naltrexone, which target multiple neurotransmitter pathways to help reduce appetite.

New potential treatments like tesofensine and semaglutide are in advanced trials, indicating a shift towards drugs that not only act on the central nervous system but also target peripheral tissues, reflecting a deeper understanding of obesity's complex mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Centrally Acting Agents for Obesity: Past, Present, and Future. Coulter, AA., Rebello, CJ., Greenway, FL.[2019]

Citations

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

Pharmacologic treatment options for obesity: what is old is new again. [2021]

2. Spain pubmed.ncbi.nlm.nih.gov

Clinical evidence for drug treatments in obesity-associated hypertensive patients--a discussion paper. [2018]

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

New and emerging drug molecules against obesity. [2014]

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

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. [2023]

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

Obesity Pharmacotherapy. [2022]

6. Denmark pubmed.ncbi.nlm.nih.gov

[Long-term effects of weight-reducing drugs in hypertensive patients--a survey of a Cochrane review]. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of new-generation anti-obesity medications: a narrative review. [2023]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Cardiovascular Safety Pharmacology of Sibutramine. [2020]

9. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of current and future anti-obesity drugs. [2019]

10. Italy pubmed.ncbi.nlm.nih.gov

[Pharmacological therapy of obesity]. [2018]

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

Centrally Acting Agents for Obesity: Past, Present, and Future. [2019]