Hypertriglyceridemia, or high triglyceride levels, can pose serious health risks, but thanks to ongoing clinical trials, we’re learning more than ever about how to manage this condition. These studies are helping us better understand the role triglycerides play in heart and metabolic health while driving the development of new and innovative treatments. From well-known options like omega-3 fatty acids to cutting-edge therapies like gene editing, there’s a lot of progress being made. Let’s dive into the basics of understanding triglycerides and hypertriglyceridemia, what these trials teach us, and explore how they’re shaping the future of triglyceride management.
What are Triglycerides?
Triglycerides are a type of fat in the blood. They are made from the food we eat, particularly fats and carbs, and are used as energy. Excess calories are converted to triglycerides and stored in fat cells for later use. Unlike cholesterol, which plays a structural role in cell membranes and is a precursor to certain hormones, triglycerides are just energy.
How Does Hypertriglyceridemia Develop?
Hypertriglyceridemia occurs when triglyceride levels are above normal, typically above 150 mg/dL. This can be due to a combination of genetic predisposition and secondary factors such as obesity, a high-carb diet, excessive alcohol consumption, and a sedentary lifestyle. Certain medical conditions like diabetes and hypothyroidism and medications like steroids and beta-blockers can also contribute.
Why is it Dangerous?
High triglycerides are linked to serious health risks, including cardiovascular disease (CVD), such as atherosclerosis, where arteries become clogged and lead to heart attacks and strokes. Severe cases can trigger acute pancreatitis, a life-threatening condition. Hypertriglyceridemia often coexists with other metabolic disorders like insulin resistance and forms a vicious cycle that amplifies the health risks.
Pharmacological Treatments
Managing hypertriglyceridemia often requires a combination of therapies based on the patient’s risk profile and triglyceride levels. Below, we will look at the pharmacological options, their mechanism of action, efficacy and clinical considerations.
Niacin
How it works:
Niacin (vitamin B3) was the first drug approved to treat hyperlipidemia and has been on the market for this condition since around 1955. Niacin controls hypertriglyceridemia by inhibiting the liver’s ability to produce VLDL (very low-density lipoproteins), a precursor to LDL (low-density lipoprotein or “bad” cholesterol). It also increases HDL (high-density lipoprotein or “good” cholesterol).
Efficacy:
Clinical trials for hypertriglyceridemia have shown that niacin can reduce triglycerides by around 20%, depending on the dose—with side effects including flushing, itching and liver toxicity.
A study found that extended-release niacin reduced LDL cholesterol (LDL-C) more in women than men at all doses and triglycerides (TG) at 1,500 mg. This may be due to women’s lower body mass and higher circulating niacin levels. Effects on HDL cholesterol (HDL-C) and lipoprotein(a) [Lp(a)] were similar for both sexes, and niacin’s lipid-lowering effects were dose-dependent. However, its use has declined due to a lack of evidence linking it to reducing cardiovascular events.
Clinical Considerations:
- Niacin is best for patients who can’t tolerate other therapies or need additional lipid profile improvement.
- Extended-release formulations reduce flushing but need to be monitored closely for liver safety.
Omega-3 Fatty Acids (Fish Oil)
How it works:
Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce hepatic triglyceride production and increase their clearance from the bloodstream.
Efficacy:
Prescription-strength omega-3 products (e.g. icosapent ethyl) can lower triglycerides by 25-30%. There have been several hypertriglyceridemia clinical trials that have focused on how Omega-3 fatty acids work on TG levels.
The REDUCE-IT trial showed cardiovascular benefits, including a 25% reduction in major adverse cardiovascular events. The OMEMI trial, which tested omega-3 fatty acids (930 mg EPA and 660 mg DHA) in elderly post-myocardial infarction patients, found no cardiovascular benefits after 2 years. Triglycerides decreased by 8.1% in the omega-3 group, but primary endpoint rates were similar between omega-3 and placebo, which was consistent with the STRENGTH trial.
Clinical Considerations:
- Standard omega-3 supplements may not be potent enough, so prescription versions are preferred for therapeutic use.
- Side effects are minimal, but gastrointestinal discomfort and fishy aftertaste are common.
Fibrates
Fibrates are a class of medications that includes clofibrate, gemfibrozil, fenofibrate, bezafibrate and ciprofibrate. Clofibrate was the first fibrate developed in the 1960s but is no longer available due to its side effects. Gemfibrozil and fenofibrate are available in the US, while other fibrates like bezafibrate and ciprofibrate are available in Europe.
How it works:
These drugs work by activating a nuclear hormone receptor called PPAR alpha. Fibrates (e.g. fenofibrate, gemfibrozil) activate PPAR-alpha, a protein that regulates lipid metabolism. This increases triglyceride breakdown and HDL cholesterol.
Efficacy:
Triglyceride reductions of 30-50% are typical, with the most benefit seen in patients with severe hypertriglyceridemia. Fibrates also reduce pancreatitis risk in patients with very high triglycerides (>500 mg/dL).
Clinical Considerations:
- Combining fibrates with statins may increase muscle toxicity risk and need to be monitored closely.
- Fenofibrate is preferred due to its lower drug interaction risk.
Volanesorsen
How it works:
Volanesorsen is an antisense oligonucleotide that targets the APOC3 gene which encodes a protein that inhibits triglyceride metabolism. By suppressing APOC3, volanesorsen lowers plasma triglycerides.
Efficacy:
Approved for familial chylomicronemia syndrome (FCS), volanesorsen has shown 70-80% triglyceride reduction. However, its use is limited to rare genetic conditions due to high cost and specific indications.
Clinical Considerations:
- Common side effects are injection site reactions and platelet count reductions, which need to be monitored regularly.
- Reserved for severe, genetically driven hypertriglyceridemia.
Alipogene Tiparvovec (Glybera)
How it works:
As the first gene therapy approved for lipid disorders, Glybera targets lipoprotein lipase deficiency (LPLD), a rare genetic condition that causes severe hypertriglyceridemia. It delivers a functional copy of the LPL gene using a viral vector.
Efficacy:
Glybera showed triglyceride reduction and pancreatitis prevention in clinical trials, but its market presence was short-lived due to high cost and low demand.
Clinical Considerations:
- Glybera shows the potential of gene therapy in lipid disorders but is a niche treatment.
- Gene editing technologies like CRISPR may expand this approach in the future.
Evinacumab (Evkeeza)
How it works:
Evinacumab is a monoclonal antibody that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of triglyceride metabolism. By inhibiting ANGPTL3, evinacumab increases triglyceride and LDL cholesterol breakdown.
Efficacy:
Primarily approved for homozygous familial hypercholesterolemia (HoFH), evinacumab also lowers triglycerides. Clinical trials have shown a 40-50% reduction in severely affected patients.
Clinical Considerations:
- Evinacumab’s role in hypertriglyceridemia is emerging but promising, especially for patients with genetic lipid disorders.
- High cost and intravenous administration are the current barriers to use.
Emerging Therapies: The Future of Treatment
New therapies have introduced triglyceride-lowering drugs that target genetic pathways:
- Antisense Oligonucleotides: Targeting genes like APOC3, these drugs can lower triglycerides in patients with familial chylomicronemia syndrome (FCS).
- ANGPTL3 Inhibitors: These monoclonal antibodies block angiopoietin-like protein 3, a regulator of triglyceride metabolism, another potential treatment option.
- Gene Therapy: Early research suggests that addressing genetic mutations may be the long-term solution for hypertriglyceridemia.
Integrating Lifestyle Modifications
Dietary Changes
Diet is key to triglycerides:
- Low-Carb Diets: Reducing refined carbohydrates and sugars has a direct effect on triglycerides as excess sugars are converted to fat.
- Healthy Fats: Adding unsaturated fats from avocados, nuts and olive oil will improve lipid profiles.
- Marine-Based Omega-3s: Fatty fish like salmon and mackerel are natural triglyceride-lowering compounds.
Exercise
Exercise improves triglycerides by helping the body process and use fat. Aerobic exercises like walking, cycling and swimming are the most effective. American Heart Association recommends at least 150 minutes of moderate exercise per week for cardiovascular health.
Other Lifestyle Changes
- Moderate Drinking: Even small amounts of alcohol can raise triglycerides in some people. Limit intake.
- Weight Loss: Losing 5-10% of body weight can lower triglycerides significantly, especially in obese individuals.
Treatment Strategies Through Risk Profiles
Personalized Treatment
- Genetic Disorders: For familial hypertriglyceridemia, antisense oligonucleotides may be needed.
- High-Risk Cardiovascular Patients: Statins, omega-3 and lifestyle changes work best.
- Mild Cases: Lifestyle changes alone may be enough for borderline triglycerides.
Combination Therapy
Combining pharmacological treatment with lifestyle interventions often yields the best results. For example, omega-3 supplements with statins can provide extra cardiovascular protection with minimal side effects.
Future of Hypertriglyceridemia Management
The field of triglyceride management is evolving. Genetic screening may soon allow us to identify at-risk individuals and intervene before problems arise. Precision medicine will allow us to treat based on genetic profiles and get better results with fewer side effects. New therapies like RNA-based drugs and targeted inhibitors will change the game.
Help Advance Treatment Options By Joining Hypertriglyceridemia Clinical Trials
Managing hypertriglyceridemia is key to preventing serious conditions like cardiovascular disease and pancreatitis. From traditional therapies like niacin and omega-3 to new ones like volanesorsen and evinacumab, there are many ways to manage triglycerides. However, the search for even more effective treatments continues.
Join a hypertriglyceridemia clinical trial to get access to the latest treatments and help develop new ones. If you or someone you know has high triglycerides, consider enrolling in a clinical trial to shape the future of treatment and get access to the latest care. Contact your healthcare provider or visit a clinical trial registry to learn about available opportunities today!
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