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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1113 CLINICAL STATEMENTS AND GUIDELINES

IIa B-R 2.  In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to reevaluate ASCVD risk after lifestyle and secondary factors are addressed and to consider a persistently elevated triglyceride level as a factor favoring initiation or intensification of statin therapy (see Section 4.4.2.).S4.5.2-2–S4.5.2-6

IIa B-R 3.  In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy.S4.5.2-3–S4.5.2-5,S4.5.2-7,S4.5.2-8

IIa B-NR 4.  In adults with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.7 mmol/L]), and especially fasting triglycerides ≥1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.S4.5.2-7,S4.5.2-9

Synopsis

Two categories of hypertriglyceridemia consist of moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175-499 mg/dL [2.0-5.6 mmol/L]) and severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.6 mmol/L]). In the former, excess triglycerides are carried in VLDL. In the latter, most patients have elevated VLDL plus chylomicrons. VLDL are believed to be atherogenic, similar to LDL. There are many causes of elevated VLDL, and it is reasonable to reduce their levels to reduce risk of ASCVD. With severe hypertriglyceridemia, elevations of VLDL raise risk of ASCVD, but increases in chylomicrons impart risk of acute pancreatitis. Therapies should address excesses in both lipoproteins.

Recommendation-Specific Supportive Text

1.	 In patients with moderate hypertriglyceridemia, it is reasonable to reduce both atherogenic VLDL and associated risk factors by nonpharmacological means where possible. This can best be achieved by identification and treatment of the multiple underlying causes of elevated triglycerides (eg, lifestyle causes, secondary disorders, and triglyceride-raising drugs).S4.5.2-1 Triglycerideraising drugs include oral estrogens, tamoxifen, raloxifene, retinoids, immunosuppressive drugs (cyclosporine, sirolimus, tacrolimus), beta blockers, interferon, atypical antipsychotic drugs, protease inhibitors, thiazide diuretics, glucocorticoids, rosiglitazone, bile acid sequestrants, L-asparaginase, and cyclophosphamide. 2.	 Most patients with severe hypertriglyceridemia have multiple ASCVD risk factors and are at enhanced risk of developing atherosclerotic disease.S4.5.2-3–S4.5.2-5,S4.5.2-9 This risk is conveyed by atherogenic VLDL plus other factors, such as obesity, metabolic syndrome, and hyperglycemia. Although chylomicronemia per se may not be atherogenic, in most patients it associates with other atherogenic factors.S4.5.2-10–S4.5.2-13 For this reason, initiation of statin therapy is reasonable. We stress that statins alone cannot prevent increasing levels of triglycerides in the face of secondary causes (see Recommendation 1) from triggering acute hypertriglyceridemic pancreatitis. Indeed, in the pregnant woman with severe hypertriglyceridemia, statins are not part of the treatment regimen because they are not recommended at the present time in pregnancy. (See Section 5., “Statin Safety and Statin-Associated Side Effects.”) 3.	 Epidemiological studies show that patients with moderate hypertriglyceridemia generally are at increased risk of ASCVD.S4.5.2-2–S4.5.2-4 Few studies that primarily recruited patients with hypertriglyceridemia have been carried out with triglyceride-lowering drugs. Statin therapy reduces VLDL similarly to fibrates,S4.5.2-5 and statin trials include hypertriglyceridemic patients. Indeed, there is evidence to show that VLDL excess increases the patient’s ASCVD risk and hence benefit from statin therapy.S4.5.2-6 Therefore, if an adult patient with moderate hypertriglyceridemia has poorly controlled major risk factors for ASCVD and a 10-year risk of ASCVD ≥7.5% by the PCE, it is reasonable to either initiate or intensify statin therapy. (See Section 4.4.2., “Primary Prevention in Adults 40 to 75 Years of Age.”) 4.	 Most patients with triglycerides ≥500 mg/dL (≥5.6 mmol/L) have elevations of both VLDL and chylomicrons. Elevations of chylomicrons typically are present when triglycerides are ≥500 mg/dL (≥5.6 mmol/L), and chylomicronemia may cause acute pancreatitis. The higher the triglyceride level, the greater is the risk.S4.5.2-7 Patients with triglycerides in the 500- to 999-mg/dL (5.6- to 11.2-mmol/L) range are at risk of developing unrecognized marked increases in triglycerides, leading to pancreatitis. Most cases of severe hypertriglyceridemia have a genetic component, but secondary factors may contribute.S4.5.2-9,S4.5.2-14 To prevent acute pancreatitis, it is reasonable to reduce triglycerides whenever levels exceed 500 mg/dL (5.6 mmol/L). This reduction can be achieved by addressing and eliminating the underlying factors as described in

Recommendations for Hypertriglyceridemia (Continued)

COR LOE Recommendations

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