Drug Safety and Efficacy: Treatments for Very High Triglycerides

Patients with "very high triglycerides" (VHTG) whose triglycerides are 500 mg/dL or greater are of particular concern for clinical and public health. These patients now constitute 1.7% of the US adult population. VHTG is disproportionately prevalent among certain demographic groups, such as Mexican-American men and Indian Americans. It is imperative that these patients' triglyceride levels are addressed because they are at increased risk of developing pancreatitis and cardiovascular disease (CVD). This article looks specifically at VHTG and the options for treating this condition.

A number of triglyceride-lowering pharmacotherapies are now available, but before examining these options, it is worth outlining a few caveats. On a positive note, lifestyle modifications (i.e., exercise, weight loss, dietary changes) can produce a ≥ 50% reduction in triglycerides, making them potentially as effective as some higher doses of pharmacotherapies. It is, therefore, important to communicate to patients the extent to which triglyceride reduction is within their control. Patients with VHTG should be counselled to abstain from alcohol; lower their consumption of fructose, added sugars, and simple carbohydrates; and increase their consumption of foods high in mono- and polyunsaturated fats, such as salmon.

Less positively, it has not yet been clearly established that lowering a patient's triglyceride levels decreases pancreatitis and CVD risk. In short, the nature of the relationship between triglyceride levels and disease remains somewhat unclear. Additionally, before prescribing any pharmacotherapy for a patient previously found to have a triglyceride level ≥ 500 mg/dL, physicians should obtain a fasting triglyceride level. Secondary causes of VHTG should be ruled out or, if applicable, treated. These include diseases such as nephrotic syndrome, chronic renal failure, and lipodystrophies; disorders and altered states of metabolism such as poorly controlled diabetes, hypothyroidism, obesity, and pregnancy; and use of certain medications.1

Long-chain omega-3 fatty acids, which are naturally present in oily fish, are perhaps the best known among pharmacotherapies for VHTG. Six prescription formulations have received Food and Drug Administration (FDA) approval for use as an adjunct to diet for the treatment of VHTG. These formulations comprise varying combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or EPA alone. A plethora of dietary supplements is also available, but, for reasons that will be outlined, use of these supplements is problematic.

Over-the-counter drugs require a more rigorous FDA approval process than do dietary supplements, but none is available for the treatment of VHTG at present. Therefore, it is essential that a course of omega-3 fatty acids or any treatment for VHTG is undertaken only under clinician supervision. In "Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease: A Scientific Statement from the AHA," the authors recommend that patients needing to lower their triglyceride levels take 2-4 g of EPA plus DHA under a physician's care – a dose that cannot be derived from diet alone and requires pharmacotherapy.2 The FDA recommendation for the treatment of VHTG of up to 4 g per day of a prescription omega-3 fatty acid is consistent with this.

Well-designed clinical trials are still needed to determine the effect of prescription omega-3 fatty acid formulations on pancreatitis and CVD risk in patients with VHTG specifically. Further investigation of their mechanism of action and long-term bioavailability is also necessary. The prescription omega-3 fatty acid formulations have not been compared in clinical trials. In an exploratory, hypothesis-generating literature review, Jacobson et al. determined that DHA lowered triglycerides and raised LDL-C more than EPA3; however, the clinical significance of these findings is unknown and the increase in LDL-C may be an artifact of Friedewald estimation. The review included non-prescription omega-3 products and patients who did not have VHTG, so the results may have been different if only the prescription omega-3 products were evaluated in patients with VHTG.

The cost of prescription formulations may make dietary supplements a tempting option for many patients with VHTG. But unlike prescription formulations and over-the-counter drugs, dietary supplements do not require adequate, well-controlled trials for market approval. Indeed, omega-3 dietary supplements have not been studied in patients with VHTG. Nor is their manufacturing process regulated as stringently as that for prescription medication. The numerous supplements available, therefore, vary greatly in strength and quality. Their EPA/DHA content has been found to range from 20% to 80%.

The accuracy of dietary supplement labels is also questionable, particularly in terms of the concentrations of ingredients. EPA and DHA may represent only a small component of the fatty acids present, with large quantities of ingredients such as palmitic and myristic acids sometimes included. Additionally, fatty acids are subject to oxidation, which poses problems for maintaining purity and efficacy. For these reasons, dietary supplements should not be used to treat VHTG. Information regarding assistance with covering the cost of omega-3 prescription formulations should, therefore, be provided to patients with VHTG to maximize adherence to a prescription regimen and minimize the chance that a patient will attempt substitution with a dietary supplement.

Like prescription omega-3 fatty acid formulations, niacin (nicotinic acid) is FDA-approved as an adjunct to diet for triglycerides ≥ 500 mg/dL. It works by inhibiting an enzyme needed for triglyceride synthesis.4 Niacin is available in immediate-release and extended-release formulations. Immediate-release niacin is associated with a triglyceride reduction of 20%-50%, compared with 10%-30% for extended-release formulations. Nevertheless, the immediate-release form is used less frequently owing to potential side effects such as flushing and itching, gastrointestinal upset, elevated blood sugar, increased uric acid levels, and increased LFTs. Flushing and itching may be alleviated with nonsteroidal anti-inflammatory drugs, but patient selection remains essential to successful use of niacin for treating VHTG.

Fibrates, the final class of triglyceride-lowering pharmacotherapy, are approved for the same indication as omega-3 fatty acids and niacin, underscoring the importance of lifestyle modifications for all patients with VHTG. They work by inhibiting hepatic triglyceride secretion. Clinical trials have varied in their findings regarding fibrates' efficacy in reducing CVD risk, although they have found a triglyceride-lowering effect.

The 2013 ACC/AHA guideline on the treatment of blood cholesterol recommends that fibrates be used only with low- or moderate-intensity statins because of the increased myalgia risk associated with use with high-intensity statins.1 The exception to this is gemfibrozil, a fibrate formulation, which should not be initiated in patients on any statin therapy because of the increased risk of rhabdomyolysis and muscle symptoms. Fibrate dose should be adjusted for patients with renal dysfunction. Additionally, fibrates are contraindicated in patients with liver and/or gall bladder disease.

Finally, whichever therapies are chosen, it is vital that patients are urged to undertake treatment only under clinician supervision. Patients should also be counseled about the importance of diet and lifestyle modifications in addition to any pharmacotherapy.


  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25_PA):2889-934.
  2. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57.
  3. Jacobson TA, Glickstein SB, Rowe JD, et al. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J of Clin Lipidol 2012:6;5-18.
  4. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008;101:20B-26B.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Diet

Keywords: Blood Glucose, Cardiovascular Diseases, Cholesterol, HDL, Demography, Diabetes Mellitus, Diet, Dietary Supplements, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fasting, Fatty Acids, Fatty Acids, Omega-3, Fibric Acids, Fish Oils, Fructose, Gallbladder Diseases, Gemfibrozil, Hypertriglyceridemia, Hypothyroidism, Kidney Failure, Chronic, Life Style, Lipodystrophy, Lipoproteins, HDL, Lipoproteins, LDL, Liver, Myalgia, Myristic Acids, Nephrotic Syndrome, Niacin, Nonprescription Drugs, Obesity, Pancreatitis, Patient Selection, Pharmaceutical Preparations, Pruritus, Rhabdomyolysis, Triglycerides, Uric Acid, Weight Loss

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