Original Article: Management of Hypertriglyceridemia: Common Questions and Answers

Issue Date: September 15, 2020

See additional reader comments at: https://www.aafp.org/afp/2020/0915/p347.html

To the Editor: We commend Drs. Oh, Trivette, and Westerfield for providing an updated guide on the management of hypertriglyceridemia—an underappreciated risk factor that is often overshadowed by low-density lipoprotein cholesterol and other chronic conditions family physicians see every day. We would like to offer additional comments to help family physicians with this important update.

Pitavastatin (Livalo, Zypitamag) is a currently available therapy and a good choice as a last resort for patients who are otherwise intolerant of statins because it uses a less common clearance pathway, rendering it less susceptible to pharmacokinetic interactions. We discourage clinicians from prescribing the 80-mg dose of simvastatin (Zocor) because it has been shown to significantly increase muscle-related adverse events without benefit (the U.S. Food and Drug Administration rescinded its approval for initiating this dose).¹

A low-carbohydrate diet is also a good strategy for managing hypertriglyceridemia. However, it should not be a universal recommendation in patients with triglyceride levels greater than 500 mg per dL (5.65 mmol per L) because some of these patients may have familial chylomicronemia syndrome, a rare genetic disorder where loss-of-function mutations limit the ability to effectively break down triglycerides. Instead of a low-carbohydrate diet, patients with familial chylomicronemia syndrome should be placed on a very low-fat diet. This diagnosis should be considered in patients with triglyceride levels greater than 1,000 mg per dL (11.30 mmol per L) without an obvious secondary cause; occurrence at a young age; and debilitating physical, emotional, and cognitive symptoms.²

Intensive therapies such as insulin infusions, plasmapheresis, or parenteral heparin are not standard care or sufficiently supported by the literature to recommend their use; these therapies also carry substantial risks and expense. As mentioned by Dr. Oh and colleagues, expert consultation is required in these cases.

The statement that icosapent (purified eicosapentaenoic acid; Vascepa) may not be cost-effective should be updated because a recent cost-effectiveness analysis from the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) U.S. cohort demonstrated that icosapent was dominant (lower cost with a better outcome) for secondary prevention and cost-effective (incremental cost-effective ratio less than $50,000 per quality-adjusted life-year) for primary prevention.³

Additionally, we disagree that there are no data demonstrating cardiovascular risk reduction with hypertriglyceridemia treatment. Although no individual trial has met this primary end point, meta-analyses have consistently demonstrated a reduction in cardiovascular risk from triglyceride-lowering therapies.^4–6

In Reply: We appreciate the letter from Drs. Elkhal and Warden. We agree that caution is warranted before prescribing simvastatin, 80 mg, because of the no generic equivalents in the United States. It costs approximately $300 per month compared with generic statins, which range from $10 to $15 per month.¹ For patients with significant hypertriglyceridemia leading to acute pancreatitis, we suggest that other medications be considered to reduce pancreatitis-associated morbidity and mortality. Insulin has been successfully used in the hospital setting and is supported in the literature.^2,3 Physicians without experience using insulin and other intensive therapies for this indication should consult an expert.

Familial chylomicronemia syndrome is a rare genetic condition that should be considered if hypertriglyceridemia is refractory to traditional management, including nutrition, exercise, and medication. Lowering fat intake is important to consider in the management of familial chylomicronemia syndrome because of the inability of lipoprotein lipase to metabolize triglycerides and fat. Reduction of refined carbohydrates, including sucrose and fructose, is critical in the management of familial chylomicronemia syndrome because of their conversion in the liver to triglycerides. A diet lower in refined carbohydrates, higher in lean protein, and lower in fat can be an option for patients with familial chylomicronemia syndrome.⁴ Essential carbohydrates, although important, are a nonessential dietary macronutrient. However, even patients with familial chylomicronemia syndrome require dietary intake of essential proteins and fatty acids.

Studies of hypertriglyceridemia as an independent risk factor for cardiovascular disease are difficult to interpret because of the complex relationship between triglycerides and other cardiovascular risk factors. Recent guidelines identify hypertriglyceridemia as a risk enhancer and not an independent risk factor.⁵ REDUCE-IT is the first study of its kind, demonstrating a reduction of mortality in high-risk patients who have elevated triglycerides despite statin therapy. However, another similarly designed study did not show benefit.⁶ Additionally, drug therapy should always be the last resort. The most cost-effective therapy is a healthy diet, physical activity, and nonpharmaceutical interventions to lower cardiovascular risk. This approach is especially important for patients who may have difficulty with payment or insurance coverage for expensive medications. We implore family physicians to double down on nonpharmaceutical interventions while we wait for more data and experience with icosapent to determine its appropriate role in primary or secondary prevention.