Tadalafil for Obesity

Overseen By Evan Brittain, MD, MSci

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt University Medical Center

Must not be taking: Antihypertensives, Nitrates, PDE-5 inhibitors, others

Disqualifiers: Age, Hypertension, Cardiac history, Diabetes, others

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

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

Compensation: Varies

Number of Visits: 11

Duration: 12 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, double-blinded, placebo-controlled study of the effects of PDE5 inhibition with tadalafil on adipose tissue in obese individuals. Adipose metabolism will be measured using magnetic resonance imaging (MRI) scans and by aspirating a small amount of adipose to measure gene expression.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including anti-hypertensive medications, organic nitrates, PDE-5 inhibitors, and medications that strongly alter CYP3A4 activity. If you are on any of these, you would need to stop them to participate.

What data supports the effectiveness of the drug Tadalafil for obesity?

Research shows that Tadalafil can improve vascular health in obese individuals and reduce visceral fat in animal studies, suggesting potential benefits for obesity management. ^{1 2 3 4 5}

Is tadalafil safe for humans?

Tadalafil is generally safe for humans, with most side effects being mild or moderate and temporary. It is well tolerated even in people with heart-related conditions and can be safely used with certain blood pressure medications. ^{1 4 6 7 8}

How does the drug Tadalafil differ from other obesity treatments?

Tadalafil, commonly used for erectile dysfunction, is being explored for obesity due to its unique mechanism of action that may influence blood flow and metabolism, unlike traditional obesity drugs like orlistat and sibutramine, which focus on fat absorption and appetite suppression. ^{9 10 11 12 13}

Research Team

Evan Brittain, MD, MSci

Principal Investigator

VUMC

Eligibility Criteria

This trial is for adults with obesity (BMI ≥ 30 kg/m2) who are not pregnant, breastfeeding, or planning to become pregnant. Participants should not have a history of significant heart conditions, seizures, diabetes, anemia, or use medications affecting CYP3A4 enzymes. They must weigh less than 300 pounds and not be using PDE5 inhibitors or certain blood pressure medicines.

Inclusion Criteria

My BMI is 30 or higher.

I am 18 years old or older.

Exclusion Criteria

You have a history of priapism (painful and prolonged erection).

You have trouble with your sleep-wake cycle, work night shifts, or travel to different time zones frequently.

I am not pregnant, breastfeeding, and willing to prevent pregnancy during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either tadalafil or placebo for 12 weeks, with monitoring of adipose metabolism using MRI and adipose aspiration

12 weeks

Baseline visit, interim visit (10 weeks post-baseline), and 12-week visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo
• Tadalafil

Trial Overview The study tests the effect of Tadalafil (a drug commonly used for erectile dysfunction), on fat metabolism in obese individuals compared to a placebo. It's randomized and double-blinded meaning neither participants nor researchers know who gets the real drug. Fat metabolism is checked by MRI scans and fat tissue sampling.

Participant Groups

Group I: Tadalafil Active Control 1 Intervention

Subjects will be randomized to one of two arms. 50 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: screening visit, baseline visit, an interim visit (10 weeks post-baseline), and a 12-week visit.

Group II: Placebo Placebo Group 1 Intervention

Subjects will be randomized to one of two arms. 50 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: screening visit, baseline, an interim visit (10 weeks post-baseline), and a 12-week visit.

Tadalafil is already approved in United States, European Union for the following indications:

Approved in United States as Cialis for:

• Erectile dysfunction
• Pulmonary hypertension

Approved in European Union as Tadalafil for:

• Erectile dysfunction
• Pulmonary hypertension

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

In a study involving 80 participants with grade 1 obesity, a single 20 mg dose of tadalafil significantly reduced systolic and diastolic blood pressure, as well as central systolic blood pressure and arterial stiffness markers, indicating potential cardiovascular benefits.

However, tadalafil did not have an effect on flow-mediated dilation, suggesting that while it may improve certain vascular parameters, it does not enhance endothelial function in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tadalafil Improves Haemodynamics and Arterial Stiffness but Not Flow- Mediated Dilation in Grade 1 Obesity. A Single-dose, Placebo-controlled Clinical Trial. Larios-Cárdenas, M., González-Radillo, OI., Trujillo-Quirós, J., et al.[2023]

A patient with obesity hypoventilation syndrome (OHS) and pulmonary hypertension (PH) showed improvement when treated with tadalafil alongside weight loss and bi-level positive airway pressure therapy.

This case suggests that tadalafil may be an effective adjunctive therapy for managing pulmonary arterial pressure in patients with OHS who do not respond adequately to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive tadalafil therapy for managing pulmonary hypertension in a patient with obesity hypoventilation syndrome. Katsuragi, S., Hara, M., Mizote, I., et al.[2020]

In a study involving 18 obese men aged 30 to 50, tadalafil administration for 28 days did not significantly affect total insulin secretion or insulin sensitivity, indicating it may not be effective for improving these metabolic parameters in this population.

The study used rigorous methods, including a randomized, double-blind, placebo-controlled design, but ultimately found no beneficial effects of tadalafil on insulin-related measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men. González-Ortiz, M., Martínez-Abundis, E., Hernández-Corona, DM., et al.[2018]

In a study involving 2102 men with erectile dysfunction, tadalafil significantly improved erectile function compared to placebo, with mean improvements in the International Index of Erectile Function (IIEF) scores of 6.5 and 8.6 for the 10 mg and 20 mg doses, respectively.

Tadalafil was effective for up to 36 hours after dosing and showed consistent efficacy across different severities and causes of erectile dysfunction, with common side effects including headache and back pain, indicating it is a well-tolerated treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of tadalafil: an update. Carson, CC., Rajfer, J., Eardley, I., et al.[2023]

In an animal model of metabolic syndrome induced by a high-fat diet, tadalafil treatment reduced visceral adipose tissue accumulation and improved hypertriglyceridemia, indicating its potential efficacy in combating metabolic syndrome.

Tadalafil promoted the differentiation of preadipocytes into metabolically healthy adipocytes, enhancing insulin sensitivity and increasing the expression of brown fat-specific markers, which suggests a mechanism for its beneficial effects on fat metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits. Maneschi, E., Cellai, I., Aversa, A., et al.[2017]

Tadalafil is generally safe and well-tolerated for chronic treatment of erectile dysfunction, even in high-risk populations, with most side effects being mild or moderate and reversible without stopping the medication.

It does not increase the risk of cardiovascular issues and can be safely used alongside antihypertensive medications and selective alpha-receptor blockers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and tolerance of tadalafil in the treatment of erectile dysfunction]. He, XY.[2015]

Tadalafil, a new oral treatment for erectile dysfunction, is highly effective with a duration of action lasting up to 36 hours, making it a convenient option for patients.

The medication has a strong safety profile, with only a few mild to moderate side effects reported, which is particularly important for patients who may have other medical conditions or take multiple medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tadalafil for erectile dysfunction: excellent safety and tolerance]. Bai, WJ.[2015]

Tadalafil, a PDE-5 inhibitor, is effective for treating erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia, showing good tolerance in patients.

The drug is considered safe for patients with cardiovascular comorbidities and may even provide beneficial effects on cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of tadalafil in patients with cardiovascular comorbidities]. Nikitina, IL., Gaysina, GG., Galimov, SN., et al.[2019]

Sibutramine and orlistat are two FDA-approved medications for long-term obesity treatment, with distinct mechanisms of action: sibutramine acts as a reuptake inhibitor of monoamines, while orlistat inhibits pancreatic lipase to reduce fat absorption.

Dexfenfluramine has been withdrawn from the market due to its association with serious heart valve issues, highlighting the importance of safety monitoring in obesity pharmacotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in obesity pharmacotherapy. Ryan, DH.[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 a significant health risk, and various pharmacologic treatments are available, including recently approved agents like dexfenfluramine and sibutramine, which primarily work by inhibiting serotonin reuptake and may also affect thermogenesis.

Current research is exploring new drug targets, such as beta 3-adrenergic receptor agonists and agents that influence leptin and other biologic substances related to satiety, aiming to not only treat obesity but also prevent related conditions like diabetes and cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacologic approach to the treatment of obesity. Weiser, M., Frishman, WH., Michaelson, MD., et al.[2019]

Sibutramine and orlistat are the only two anti-obesity medications approved for long-term use, with sibutramine reducing food intake and orlistat inhibiting fat absorption, though orlistat can cause gastrointestinal side effects like flatulence and diarrhea.

Rimonabant, an endocannabinoid receptor antagonist approved in 2006, was suspended in 2008 due to psychiatric side effects, highlighting the need for further studies on the long-term safety and efficacy of anti-obesity medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for obesity. Li, M., Cheung, BM.[2021]

Obesity rates have more than doubled globally since 1980, leading to increased prevalence of related diseases such as diabetes and heart disease, highlighting the urgent need for effective obesity treatments.

Currently, orlistat is the only anti-obesity drug approved in Europe, while other previously used medications like sibutramine have been removed from the market due to safety concerns, emphasizing the challenges in developing safe and effective obesity therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targets for medical therapy in obesity. Baretić, M.[2012]

References

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

Tadalafil Improves Haemodynamics and Arterial Stiffness but Not Flow- Mediated Dilation in Grade 1 Obesity. A Single-dose, Placebo-controlled Clinical Trial. [2023]

2. Japan pubmed.ncbi.nlm.nih.gov

Adjunctive tadalafil therapy for managing pulmonary hypertension in a patient with obesity hypoventilation syndrome. [2020]

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

Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men. [2018]

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

The efficacy and safety of tadalafil: an update. [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits. [2017]

6. China pubmed.ncbi.nlm.nih.gov

[Safety and tolerance of tadalafil in the treatment of erectile dysfunction]. [2015]

7. China pubmed.ncbi.nlm.nih.gov

[Tadalafil for erectile dysfunction: excellent safety and tolerance]. [2015]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Safety of tadalafil in patients with cardiovascular comorbidities]. [2019]

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

Recent progress in obesity pharmacotherapy. [2019]

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

[Pharmacological therapy of obesity]. [2018]

11. England pubmed.ncbi.nlm.nih.gov

The pharmacologic approach to the treatment of obesity. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for obesity. [2021]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Targets for medical therapy in obesity. [2012]