Continuing Education Activity

Hypertriglyceridemia in many cases is multifactorial, resulting from the combination of genetic factors and other causes of increased production and or impaired clearance of triglyceride-rich lipoproteins (TRLP)s. A severe elevation of triglycerides (TG) increases a person's risk for pancreatitis and requires lowering by lifestyle change and pharmacotherapy in addition to evaluation of underlying etiology. Although statin therapy has improved atherosclerotic cardiovascular disease (ASCVD) outcomes, residual risk remains. In this setting of residual atherosclerotic cardiovascular disease risk, mild to moderate hypertriglyceridemia (HTG) has been shown in many studies to be an independent risk factor for cardiovascular disease (CVD), but data does not show definite evidence that cardiovascular disease risk diminishes with the treatment of hypertriglyceridemia. This activity reviews the evaluation and management of hypertriglyceridemia and highlights the role of the interprofessional team in the recognition and management of this condition.

Objectives:

• Describe the recommended management of hypertriglyceridemia.
• Outline the typical presentation for a patient with hypertriglyceridemia.
• Review the pathophysiology of hypertriglyceridemia.
• Explain the interprofessional team strategies for improving care coordination and communication regarding the management of patients with hypertriglyceridemia.

Introduction

Hypertriglyceridemia (HTG) is increasingly becoming common in the medical world. Hypertriglyceridemia has been associated with an increased risk of cardiovascular disease and pancreatitis. [1] A severe elevation of triglycerides (TG) increases the risk for pancreatitis and requires lowering by lifestyle change and pharmacotherapy. Also, etiology needs to be addressed. Although statin therapy targeting low-density cholesterol (LDL-C) has improved atherosclerotic cardiovascular disease (ASCVD) outcomes, residual risk remains. In the setting of residual atherosclerotic cardiovascular disease risk, multiple studies have shown that mild to moderate hypertriglyceridemia (HTG) is an independent risk factor for cardiovascular disease (CVD), but data does not show definite evidence that cardiovascular disease risk diminishes with the treatment of hypertriglyceridemia. [2] [3] [4]

Etiology

Hypertriglyceridemia is usually multifactorial. A combination of genetic factors, increased production, and or impaired clearance of triglyceride-rich lipoproteins (TRLP) are known to play a role in hypertriglyceridemia. [5]

Genetic causes include syndromes that present primarily with HTG (common) or chylomicronemia (rare). Familial hypertriglyceridemia (excess Very Low-Density Lipoprotein but normal cholesterol) and Familial combined hyperlipidemia (polymorphisms of apolipoprotein C-II (apoC-II), apolipoprotein C-III (apoC-III), etc.) present predominantly with HTG. [6] Lipoprotein lipase deficiency, Apolipoprotein C-II deficiency, Apolipoprotein AV deficiency, and dysbetalipoproteinemia are examples of genetic syndromes that present with chylomicronemia. [6]

Secondary causes of HTG include certain medical conditions, drugs, and dietary causes. Obesity, metabolic syndrome, Diabetes mellitus type 2, hypothyroidism, Cushing's syndrome, chronic kidney disease, Human Immunodeficiency virus, pregnancy, and some autoimmune conditions such as systemic lupus erythematosus have been associated with HTG. [6] Medications that cause HTG include thiazides, beta-blockers, oral estrogens, tamoxifen, OCPs, anti-retroviral protease inhibitors, atypical antipsychotics, isotretinoin, corticosteroids, bile acid-binding resins, and immunosuppressive agents such as sirolimus. [6] Dietary causes of HTG include excessive alcohol intake and foods rich in saturated fat or with a high glycemic index. [6]

Epidemiology

According to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, HTG is classified into mild: TG level 150-199 mg/dL, high: TG 200-499 mg/dL and very high: TG > 500 mg/dL. [6] As per the current guidelines, a triglyceride level of less than 150 mg/dL is desirable from a management perspective. 

The National Health and Nutrition Examination Survey (NHANES) monitored risk factors for cardiovascular disease for more than three decades and as a part of the study looked at the prevalence of triglyceride levels among the US population. Based on the findings from this study, serum triglycerides are usually higher in men than in women, especially until 70 years of age. [7] The levels increase with age in both genders. The prevalence of hypertriglyceridemia is increasing among youth and adolescents due to increasing rates of obesity and Diabetes mellitus. About a third of participants from 1999 through 2008 had serum triglycerides above 150 mg/dL. [7] The prevalence of hypertriglyceridemia was about 42% in people aged 60 years or older. The triglyceride levels were very high (>500 mg/dL) in about 2% of the subjects. [7] The incidence of hypertriglyceridemia is higher among Mexican-Americans as compared to white Americans and lowest in African-Americans. [7]

The significance of HTG as an independent risk factor for cardiovascular disease still remains debatable. However, high levels of triglyceride levels at baseline have been associated with low HDL-C and high LDL-C, and the combination is well known for increased risk for atherogenesis. [7] The lowering of the triglyceride levels from baseline in these patients has shown to reduce cardiovascular risk irrespective of drug class or lipid fraction. [7]

Pathophysiology

Triglycerides are carried in the circulation by triglyceride-rich lipoproteins (VLDL and chylomicrons). [7] Chylomicrons are released from the small intestines and carry a significantly high percentage of TGL. The TGL rich chylomicrons undergo hydrolysis in peripheral tissues. Due to the lipolysis, free fatty acids (FFA) are released. [7] The FFA is taken by muscle cells, where they are a source of energy. In adipose tissue, the FFA is stored as an inactive fuel. [7]

When compared to very large triglyceride-rich lipoproteins, the remnant triglyceride-rich lipoproteins can be atherogenic. [8] Even though triglyceride particles are not found in atherosclerotic plaques, the cholesterol content (especially the LDL particles) of triglyceride-rich lipoproteins plays a role in plaque formation. [9] In addition, the lipolysis of triglyceride-rich lipoproteins produces free fatty acids, lysolecithin, and other reactive lipids that may have pro-inflammatory and pro-coagulant effects. [10]

The release of excess free fatty acids and lysolecithin from chylomicrons in pancreatic capillaries is linked to the causation of pancreatitis. Hyperviscosity from increased chylomicrons leads to acidosis and ischemia in the capillary beds. This leads to the activation of pancreatic lipases, lipolysis, and release of toxic FFA, which cause inflammation, cytotoxic injury, and pancreatitis. [10] The risk of pancreatitis correlates with the level of triglycerides and markedly increases with levels above 500 mg/dL. [10] In most instances, pancreatitis can be prevented by keeping triglyceride levels below 250 mg/dL to 500 mg/dL. 

History and Physical

Practitioners should evaluate for secondary causes of hypertriglyceridemia, including alcohol use, metabolic syndrome, endocrine disorders, and medications. Patients with primary hypertriglyceridemia should be assessed for other cardiovascular risk factors, such as obesity, diabetes, hypertension, and tobacco use. The family history of lipid disorders such as dyslipidemia and cardiovascular disease should be sought. In patients with familial dysbetalipoproteinemia, pathognomonic palmar xanthomas (orange, yellow deposits along the palmar creases), and eruptive xanthomas at pressure sites on the elbows, buttocks, and knees are seen. Chylomicronemia syndrome can present with epigastric abdominal pain, cutaneous eruptive xanthomas on the buttocks, and the extensor surfaces of the upper limb, hepatosplenomegaly, acute pancreatitis, transient memory loss, lipemia retinalis, and rarely, focal neurologic deficits.

Evaluation

Hypertriglyceridemia is diagnosed by a fasting lipid panel. According to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, HTG is classified into mild: TG level 150-199 mg/dL, high: TG 200-499 mg/dL and very high: TG > 500 mg/dL. [7]  When triglycerides are above 400 mg/dL, LDL-C levels are calculated using the Friedewald equation. [11] Since the calculation can underestimate LDL-C, the alternative is to calculate non-HDL-C levels (total cholesterol minus HDL cholesterol) or obtain direct LDL-C levels if possible. [7]

The measurement of LDL size or density is not useful in the management of cardiovascular events. Apo B and Lp(a) may be useful in assessing cardiovascular risk in hypertriglyceridemia. [7] There are some effective therapies for lowering Apo B. Although niacin and estrogen lower Lp(a) levels, there is no evidence behind the lowering of Lp(a) and prevention of atherosclerotic cardiovascular disease events. [7]  High levels of Lp(a) is associated with premature cardiovascular disease. Hence, aggressive management of LDL is recommended in the setting of a high Lp(a). [7]

Hepatic steatosis or non-alcoholic steato-hepatosis (NASH) is associated with hypertriglyceridemia secondary to insulin resistance. It is usually suspected with elevated aminotransferases on the hepatic function panel. Further testing with an ultrasound of the liver is recommended.

Treatment / Management

Pancreatitis associated with hypertriglyceridemia is treated with intravenous (IV) fluids and bowel rest. Also, IV insulin infusion (as low as 1 unit/hour) is an effective management strategy as it suppresses lipolysis and decreases triglyceride assembly in the liver. Plasmapheresis is an effective option when the triglyceride levels are extremely high. Upon recovery from an acute episode of pancreatitis, attention must be paid to reduce triglyceride levels below 500 mg/dL, although less than 150 mg/dL is considered ideal. [12]

Fibrates are the first-line drugs for lowering triglycerides and can achieve a 30% to 50% reduction with a concomitant increase in HDL-C. [13] The mechanisms of action of fibrates include a decrease in VLDL production, an increase in fatty acid oxidation, an increase in triglyceride catabolism, increase in LpL synthesis, and reduction in apoC-III. The effect of fibrates on LDL-C can be variable: when the triglyceride levels are high, LDL-C can increase, but when the triglyceride levels are only mildly elevated, LDL-C levels can actually decrease. [13] Since fibrates are largely excreted through kidneys, so, dose adjustment is necessary for patients with decreased renal function. Fibrates are contraindicated in patients with the hepato-biliary disease. Fenofibrate is associated with a lower risk of myositis as compared to gemfibrozil and is the preferred agent among the two in patients already on statins. [13] Due to its protein binding nature, fenofibrate has interactions with other medications. Patients on fibrates and warfarin require close monitoring due to potential interactions. The goals of fibrate therapy are to reduce the triglyceride levels to less than 200 mg/dL to decrease cardiovascular disease risk, as has been demonstrated in studies and trials. Also, a reduction of triglyceride levels less than 500 mg/dL is associated with a decrease in risk for pancreatitis. Other benefits include the reduction of diabetic microvascular complications such as retinopathy and albuminuria. [14]

Omega-3 fatty acids (OM3FA) are FDA approved for the treatment of severe and very severe hypertriglyceridemia (greater than 1000 mg/dL). OMF3FA reduces triglycerides by 20% - 50% at a dosage of 3 g to 4 g/day. [13] Most OM3FA contain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Studies have shown that the treatment of higher baseline triglycerides with OM3FA is associated with greater triglyceride lowering. The effects of OM3FA on triglyceride lowering is dose-related, and the fact that various nonprescription OM3FA medications contain variable amounts of EPA and DHA, attention must be paid to the constituents in the selection of omega-3 fatty acids. Gastrointestinal discomfort and fish-like taste are the limiting factors with high doses of nonprescription OM3FA. In such cases, switching to FDA-approved prescription OM3FA may be helpful. OM3FA has been shown to be associated with increased conversion of VLDL to LDL, thereby increasing levels of low-density lipoprotein cholesterol (LDL-C), but this effect has not been shown with the EPA-only prescription products. [10] However, so far, no studies have demonstrated cardiovascular disease benefit in hypertriglyceridemia with high dose OM3FA. In recent trials that lowering concomitant use of OM3FA with statins has failed to demonstrate a reduction in cardiovascular disease risk in spite of TGL lowering effects. [13] 

Niacin has two formulations - immediate release and extended-release. Niacin reduces triglycerides by about 10% - 30%, while it increases HDL-C by 10-40% and lowers LDL-C by 5-20%. [13] Niacin decreases triglyceride synthesis and lipolysis. Clinical trials have not demonstrated any cardiovascular disease benefit of niacin in combination with statins, thereby resulting in decreased use of niacin. Among the side effects of niacin, flushing is common and can be reduced by concomitant administration of uncoated aspirin. [13] Complications of niacin use include impaired glucose tolerance, hepatotoxicity, and hyperuricemia. [6] A notable contraindication to niacin use is active peptic ulcer disease. [6]

Statins lower triglyceride by about 10% - 30% but in a dose-dependent manner. Statins are used as monotherapy in triglyceride levels of more than 500 m/dL when indicated to decrease cardiovascular risk. [7] Recently, a combination of fibrates with statins has been discouraged due to the increased risk of myositis and other side effects. Ezetimibe can reduce TGL by about 5-10%. A couple of trials (IMPROVE-IT and PRECISE IVUS) have shown that a combination of statin and ezetimibe has shown cardiovascular benefits.[7] However, it should be remembered that neither statins nor ezetimibe has significant effects on TGL reduction, especially in high and very severe HTG. [7]

Differential Diagnosis

• Differential diagnoses include disorders that present with chylomicronemia or hypertriglyceridemia.

• Lipoprotein lipase deficiency, Apo C II deficiency, Apo AV homozygosity, and glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) mutations all present with chylomicronemia. [7]

  Syndromes presenting with hypertriglyceridemia: 

  • Familial combined hyperlipidemia is marked by elevated VLDL and or LDL. The phenotype varies from isolated hypertriglyceridemia to isolated hypercholesterolemia. Regardless, increased apo B concentration is seen and is used to distinguish from familial hypertriglyceridemia. It is associated with premature cardiovascular disease. [7]
  • Familial hypertriglyceridemia is more common and is associated with the secretion of large VLDL particles, typically with low LDL and HDL. There is increased VLDL production and decreased VLDL catabolism, resulting in saturation of lipoprotein Lipase. It has an autosomal dominant inheritance. It is usually not associated with the premature cardiovascular disease unless the TGL levels are very high but can present with pancreatitis. [7]
  • Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is due to defective Apo E. It is characterized by the build-up of chylomicrons and VLDL remnants. Elevation in both cholesterol and triglycerides and roughly similar levels should raise suspicion for this syndrome. It is associated with premature cardiovascular disease and peripheral vascular disease. [7]

Pearls and Other Issues

In April 2016, the FDA withdrew approval for the triple therapy of extended-release niacin plus fenofibrate plus a statin, citing the lack of evidence for the reduction in cardiovascular risk in statin-treated patients.

Knowledge Pearls:

• The general population's ideal triglyceride level is less than 150 mg/dL. 
• Non-HDL cholesterol levels should be calculated if triglycerides are more than 200 mg/dL, as hypertriglyceridemia is associated with atherogenic triglyceride-rich particles.
• Initiate therapy if the triglyceride level is greater than 200 mg/dL.
• Pancreatitis risk increases if triglyceride levels are more than 500 mg/dL, then dramatically rises if more than 1500-2000 mg/dL. The first target of therapy is triglycerides less than 500 mg/dL.

Enhancing Healthcare Team Outcomes

The management of hypertriglyceridemia is by an interprofessional team that includes an endocrinologist, gastroenterologist, internist, primary care provider, nurse practitioner, and a cardiologist. Besides pharmacological therapy, the key is to educate the patient on changes in lifestyle and addressing the secondary causes.

Lifestyle changes include dietary changes such as reduction of carbohydrate intake, avoidance of sugar-sweetened beverages, and processed carbohydrates, regular exercise, and weight loss. Weight loss of 5% to 10% is associated with a reduction of triglyceride levels. Similarly, regular aerobic exercise can reduce triglycerides. The amount of decrease in triglycerides due to exercise and dietary modifications is usually variable. [15] Many studies have shown that monounsaturated fatty acid-rich Mediterranean-type diet has reduced postprandial lipemia. When triglyceride levels are in excess of 500 mg/dL, restriction of dietary fat is key to avoid a postprandial rise in chylomicrons and thereby reduce the risk of pancreatitis. 

In addition to pharmacotherapy and lifestyle modification, addressing the secondary contributors is important. Alcohol cessation and tighter glycemic control in diabetes are effective strategies to control secondary contributors. The primary goal of reduction of triglyceride levels in patients (with triglycerides of more than 500 mg/dL) is to decrease the risk of pancreatitis. When the triglycerides are moderately elevated (200 mg/dL to 500 mg/dL), the goal should be to prevent cardiovascular events and disease. Reducing non-HDL cholesterol levels down to 30 mg/dL above the LDL goal helps in cardiovascular risk reduction. [15]