Orlistat for High Cholesterol

Overseen By Abhimanyu G [agarg]

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must not be taking: Estrogens, Steroids, Cyclosporine, others

Disqualifiers: Diabetes, Renal disease, Alcoholism, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot participate if you are on certain drugs like lomitapide, anti-coagulants, digoxin, or anti-arrhythmics. You also need to be off orlistat for 2 months before joining.

What evidence supports the effectiveness of the drug Orlistat for high cholesterol?

Research indicates that Orlistat, primarily an anti-obesity drug, can positively affect blood lipid profiles by reducing small, dense LDL cholesterol levels and increasing LDL particle size, which may be beneficial for patients with high cholesterol. ^{1 2 3 4 5}

How does the drug Orlistat differ from other treatments for high cholesterol?

Orlistat is unique because it works by blocking the absorption of dietary fat in the intestines, which not only helps with weight loss but also reduces cholesterol levels. Unlike other cholesterol-lowering drugs that work directly in the bloodstream, Orlistat acts in the digestive system and is taken with meals. ^{2 6 7 8 9}

What is the purpose of this trial?

Type I hyperlipoproteinemia (T1HLP, also known as familial chylomicronemia syndrome or FCS) is a rare diseasewhere the blood triglycerides (fats) are very high. It is caused by lack of certain enzymes and proteins in the bodythat are important in disposing circulating fats from blood. Treatment of T1HLP patients who have very high levels of blood fats (≥ 1,000 mg/dL) is challenging as conventional triglyceride-lowering medications, such as fibrates and fishoil, are ineffective. The purpose of this trial is to study the long-term efficacy and safety of orlistat for reducing blood triglyceride levels in patients with T1HLP.

Research Team

Chandna Vasandani, Ph.D

Principal Investigator

UT Southwestern Medical Center

Abhimanyu Garg

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for people aged 8-70 with a rare condition called Type I hyperlipoproteinemia, confirmed by specific genetic variants. They must have very high blood fat levels (≥1000 mg/dL) and not have taken orlistat recently. Both men and women of childbearing age should use effective contraception.

Inclusion Criteria

Fasting serum triglyceride levels of greater than 1000 mg/dL.

Effective contraception for males and females of childbearing age.

I have not taken orlistat for at least 2 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

8 weeks

Outpatient visits

Baseline

Participants consume an extremely low fat diet (≤15% of total energy from fat) and undergo baseline assessments

8 weeks

Outpatient visits

Treatment

Participants are randomly assigned to receive either Orlistat or placebo for 24 weeks

24 weeks

Outpatient visits with blood lipids and chemistry panel analysis

Open-label Extension

All participants receive Orlistat for an additional 24 weeks

24 weeks

Outpatient visits with blood lipids and chemistry panel analysis

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Orlistat
• Placebo

Trial Overview The trial is testing the long-term effectiveness and safety of a drug called orlistat in reducing extremely high triglyceride (blood fat) levels in patients with Type I hyperlipoproteinemia, compared to a placebo.

Participant Groups

Group I: Orlistat Drug Active Control 1 Intervention

Drug will be given orally.

Group II: Placebo Placebo Group 1 Intervention

Placebo will be given orally.

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

Approved in European Union as Xenical for:

• Obesity management

Approved in United States as Xenical for:

• Obesity management in patients with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with other risk factors

Approved in United States as Alli for:

• Weight loss in overweight adults 18 years and older when used along with a reduced-calorie and low-fat diet

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

Current lipid-lowering therapies are effective and well-tolerated, but research is ongoing to find even better treatments, including new inhibitors and combination therapies.

Orlistat, a new antiobesity drug, has been shown to positively impact blood lipid profiles, and there is growing interest in improving HDL cholesterol levels through niacin and other enzyme inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid-altering drugs in development. Bays, HE., Dujovne, CA.[2018]

Fibrates and niacin are effective in reducing small, dense low density lipoprotein (sdLDL) particles and shifting LDL size towards larger, healthier particles in obese patients with mixed dyslipidaemia.

Ezetimibe primarily decreases larger LDL subclasses and has a modest effect on sdLDL, while orlistat and rimonabant can reduce sdLDL-C levels and increase LDL particle size, suggesting a combination of these treatments may enhance LDL profile in overweight/obese patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of non-statin lipid lowering and anti-obesity drugs on LDL subfractions in patients with mixed dyslipidaemia. Florentin, M., Tselepis, AD., Elisaf, MS., et al.[2019]

Severe hypertriglyceridemia is linked to a higher risk of cardiovascular disease and pancreatitis, necessitating prompt hospitalization and treatment with hypolipidemic drugs, insulin/dextrose infusion, or therapeutic apheresis for affected patients.

Fibrates are the first-line treatment for severe hypertriglyceridemia, but often a combination of medications, including omega-3 fatty acids, niacin, and high-dose statins, is required to effectively manage triglyceride levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recommendations for severe hypertriglyceridemia treatment, are there new strategies? Filippatos, TD., Elisaf, MS.[2019]

A case study of a nonobese Asian Indian man with severe hypertriglyceridemia showed that the combination of gemfibrozil and orlistat significantly reduced triglyceride levels from 766 mg/dL to as low as 224 mg/dL, demonstrating the efficacy of this combination therapy.

Monotherapy with either gemfibrozil or orlistat alone was ineffective, highlighting the need for further research into the mechanisms behind their synergistic effect in treating combined hyperlipidemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia. Tolentino, MC., Ferenczi, A., Ronen, L., et al.[2021]

Raising high-density lipoprotein cholesterol (HDLC) in patients with low levels is considered in high-risk individuals, such as those with established heart disease or diabetes, but there is still uncertainty about the benefits of HDL-raising therapies due to a lack of event-based trials.

In high-risk patients, statins are typically used to lower low-density lipoprotein cholesterol (LDLC), and additional medications like niacin or fibrates may be added to effectively raise HDLC levels, although specific HDLC targets are not formally established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Drug Options for Raising HDL Cholesterol. Dunbar, RL., Rader, DJ.[2020]

Orlistat, a lipase inhibitor, effectively reduces dietary fat absorption by about 30%, and when combined with a low-calorie, low-fat diet, it nearly doubles the success rate of obese individuals losing at least 10% of their initial body weight over two years.

In addition to weight loss, Orlistat also helps lower serum cholesterol levels by 6-10%, although it may cause intestinal side effects that typically lessen over time and with reduced fat intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacy-clinics medication of the month. Orlistate (xenical)]. Scheen, AJ., Ernest, P., Letiexhe, MR.[2018]

Orlistat, a pancreatic lipase inhibitor, significantly aids in weight loss for obese patients on a hypocaloric diet, with participants losing an average of 5% of their body weight compared to 3.5% for those on placebo over 12 weeks.

In long-term studies of up to 2 years, orlistat continued to show greater weight loss compared to placebo, with more patients achieving over 5% or 10% weight loss, indicating its sustained efficacy in managing obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orlistat. McNeely, W., Benfield, P.[2018]

In a study of 28 participants (13 obese and 15 non-obese), treatment with orlistat for 16 weeks led to significant reductions in BMI, blood pressure, insulin levels, and cholesterol levels in obese subjects, indicating its efficacy in promoting weight loss and improving metabolic health.

Orlistat treatment also resulted in increased levels of folic acid and vitamin B12, suggesting potential nutritional implications, while the relationship between leptin and NPY levels in obese patients remained unclear despite significant changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects]. Czerwieńska, B., Kokot, F., Franek, E., et al.[2018]

Orlistat is effective for weight reduction and maintenance, and it positively impacts cardiovascular risk factors associated with obesity, including lowering serum insulin levels and reducing the incidence of type 2 diabetes in at-risk patients.

In addition to weight loss, orlistat helps lower total and LDL cholesterol levels, improves triglyceride levels after meals, and has beneficial effects on inflammatory markers, indicating its multifaceted role in managing obesity-related health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of orlistat on metabolic parameters and other cardiovascular risk factors. Kiortsis, DN., Filippatos, TD., Elisaf, MS.[2020]

References

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

Lipid-altering drugs in development. [2018]

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

Effect of non-statin lipid lowering and anti-obesity drugs on LDL subfractions in patients with mixed dyslipidaemia. [2019]

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

Recommendations for severe hypertriglyceridemia treatment, are there new strategies? [2019]

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

Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia. [2021]

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

Current Drug Options for Raising HDL Cholesterol. [2020]

6. Belgium pubmed.ncbi.nlm.nih.gov

[Pharmacy-clinics medication of the month. Orlistate (xenical)]. [2018]

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

Orlistat. [2018]

8. Poland pubmed.ncbi.nlm.nih.gov

[Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects]. [2018]

9. France pubmed.ncbi.nlm.nih.gov

The effects of orlistat on metabolic parameters and other cardiovascular risk factors. [2020]