History
The US Preventive Services Task Force (USPSTF) includes the following as risk factors for a 10-year risk of cardiovascular events in patients with dyslipidemias, including hypertriglyceridemia and hyperlipoproteinemia [38] :
-
Diabetes
-
History of coronary heart disease (CHD) or noncoronary atherosclerosis (eg, abdominal aortic aneurysm, peripheral artery disease, carotid artery stenosis)
-
Family history of cardiovascular disease before age 50 years in male relatives or age 60 years in female relatives
-
Tobacco use
-
Hypertension
-
Obesity (body mass index [BMI] >30 kg/m2)
In addition to the risk factors above, the American Association of Clinical Endocrinologists (AACE) includes the following as major risk factors for dyslipidemia and atherosclerosis [39] :
-
Elevated serum total cholesterol levels
-
Elevated levels of non–high-density lipoprotein (non–HDL) levels
-
Elevated low-density lipoprotein (LDL) levels
Gastrointestinal symptoms
Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL. Patients may report pain, which is commonly mid epigastric but may occur in other regions, including the chest or back.
A history of recurrent episodes of acute pancreatitis is common in patients with severe and uncontrolled hypertriglyceridemia. [40] Triglyceride levels often exceed 5000 mg/dL at the onset of pancreatitis.
A study by Vipperla et al indicated that in patients with hypertriglyceridemia-related acute pancreatitis, secondary risk factors, including diabetes, high-risk drinking, obesity, and specific medications, are highly prevalent, with at least one secondary risk factor occurring in 78% of the study’s patients. [41]
Patients with recurrent episodes of abdominal pain that is less severe than acute pancreatitis may experience the chylomicronemia syndrome. [42] Affected patients usually have triglyceride elevations greater than 2000 mg/dL at the onset of symptoms and provide a history of recurrent episodes of abdominal pain, sometimes with nausea, vomiting, or dyspnea. Pancreatitis is not necessarily present. The presentation of hyperchylomicronemia may be confused with conditions such as acute myocardial syndromes or biliary colic.
Dermatologic symptoms
Severe hypertriglyceridemia may cause skin lesions called xanthomas. Patients may report the appearance of any of the following types of xanthomas:
-
Xanthoma striata palmaris: Orange-yellow discolorations of the palmar creases, which in some cases are raised; considered pathognomonic for dysbetalipoproteinemia
-
Tuberoeruptive xanthomas: Nonpainful, raised, erythematous, nodular lesions approximately 0.5 cm in diameter; may be present on the elbows and knees
-
Tuberous xanthomas: Larger, coalesced tuberoeruptive xanthomas; raised, moderately firm, nontender lesions predominantly on the elbows and knees
-
Tendon xanthomas: Occur infrequently; more common in familial hypercholesterolemia
-
Eruptive xanthomas: Small nodular papules commonly seen over the trunk, buttocks, and thighs; associated with chylomicronemia syndrome
Ophthalmologic symptoms
Uncommonly, patients may also note the presence of a corneal arcus, which is a grayish white opacification at the periphery of the cornea and/or xanthelasmas, which are pale yellow, raised lesions around the eyelids.
Physical Examination
When triglycerides are less than 1000 mg/dL, the physical findings are normal unless the underlying condition is dysbetalipoproteinemia, type III hyperlipoproteinemia. In this condition, palmar xanthomas may be discerned infrequently.
When triglycerides are acutely and massively elevated, physical findings may be absent except on funduscopic examination. Therefore, physical findings in patients with severe hypertriglyceridemia are variable, ranging from normal to one or more of the findings discussed below.
In patients with peripheral vascular disease, the pedal pulses or ankle/brachial index may be decreased.
Gastrointestinal
If pancreatitis or the chylomicronemia syndrome is present, the mid epigastric area or upper right or left quadrants are tender to palpitation. Hepatomegaly and, less commonly, splenomegaly may be appreciated.
Dermatologic
Eruptive xanthomas (see the images below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base that are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.
Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
Patients with dysbetalipoproteinemia (type III) may have palmar xanthomas (yellowish creases of the palms). This type of xanthoma is considered pathognomonic for this disorder. Tuberous or tuberoeruptive xanthomas, which also may occur in other hyperlipidemias, may arise on the elbows, knees, or buttocks.
Ophthalmologic
Corneal arcus, lipemia retinalis, and xanthelasma are the most common ocular abnormalities. [2] Triglyceride levels of 4000 mg/dL or higher may cause lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.
The ocular changes are usually not seen until the triglyceride level reaches at least 2000 mg/dL in the early stages; they are best observed in the peripheral fundus. The vessels initially appear salmon-pink, but when the triglyceride level rises further, they become whitish. These changes, which begin in the periphery, progress toward the posterior pole as the triglyceride level rises. In severe cases, the vessels are creamy white, and differentiating the arteries from the veins is difficult. The findings can fluctuate widely from day to day, depending on the triglyceride level.
Xanthelasma is a deposition of lipid in the eyelid, usually the upper medial lid. The lesions may be excised, but recurrences are common. Current treatments include serial excisions, the use of carbon dioxide and erbium lasers, and trichloroacetic acid peels. With primary excisions, recurrences of up to 40% have been reported, and secondary excision recurrences are even higher. [43] Of the initial failures, 20% are within the first year. [44]
The fundus abnormalities, which improve as the triglyceride levels return to normal, provide a method of following the patient's course and response to therapy.
Neurologic
Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.
-
Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
-
Close-up of eruptive xanthomas.
-
Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.
-
Lipoprotein lipase (LPL) releases free fatty acids (FFAs) from chylomicrons (chylo) and produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chol = cholesterol; TGs, TGS = triglycerides.
-
Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing low-density lipoprotein (LDL), or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E. Chol = cholesterol; TGs = triglycerides.
Tables
Type |
Serum Elevation |
Lipoprotein Elevation |
I |
Cholesterol and triglycerides |
Chylomicrons |
IIa |
Cholesterol |
LDL |
IIb |
Cholesterol and triglycerides |
LDL, VLDL |
III |
Cholesterol and triglycerides |
IDL |
IV |
Triglycerides |
VLDL |
V |
Cholesterol and triglycerides |
VLDL, chylomicrons |
IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein. Source: Fredrickson DS, Lees RS. A system for phenotyping hyperlipidaemia. Circulation. Mar 1965;31:321-7. [3] |
||
Classification |
TG level, mg/dL |
Normal triglyceride level |
< 150 |
Borderline-high triglyceride level |
150-199 |
High triglyceride level |
200-499 |
Very high triglyceride level |
>500 |
Source: National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97. [14] |
|
Classification |
LDL Goal, mg/dL |
Non-HDL Goal, mg/dL |
|
CHD and CHD risk equivalent, diabetes mellitus, and the following: |
10-year risk for CHD >20% |
< 100 |
< 130 |
Two or more risk factors and the following: |
10-year risk < 20% |
< 130 |
< 160 |
0-1 risk factor |
< 160 |
< 190 |
|
CHD = coronary heart disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein. Source: National Cholesterol Education Program. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. May 16 2001;285(19):2486-97. [14] |
|||
Drug |
Lipid Effects |
Lipid Effects in Combination with Statin |
Outcomes Data |
Comments |
Bezafibrate |
LDL decrease: 9.6-25% (400 mg) HDL increase: 15-24% (400 mg) Triglyceride decrease: 25-43% (400 mg) |
Further LDL decrease: 1.1% (400 mg) Further HDL increase: 22% (400 mg) Further triglyceride decrease: 31.7% (400 mg) |
Secondary prevention: Prevents composite endpoint of MI and sudden death in a subgroup with triglycerides of 200 mg/dL or higher. No increase in non-CV death |
First-line option for triglyceride >10 mmol/L Option for triglyceride 5-10 mmol/L Option for low HDL Reversible increase in serum creatinine Requires renal dose adjustment Limited data with statins |
Ezetimibe |
LDL decrease: 18% (10 mg/day) HDL increase: 1% (10 mg/day) Triglyceride decrease: 8% |
Further LDL decrease: 25%, as add-on Further HDL increase: 3%, as add-on Further triglyceride decrease: 14%, as add-on |
Prevention of CV events in post-acute coronary syndrome patient when added to statin showed a benefit of reducing the primary endpoint (composite of CV death, MI, unstable angina requiring rehospitalization, coronary revascularization or stroke) by 6.4% vs statin alone In intermediate outcomes studies, ezetimibe did not reduce regression of carotid intima-media thickness (surrogate marker) when added to a statin |
Efficacy studied in combination with atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin Role as statin add-on to reduce LDL if HDL and triglyceride satisfactory |
Fenofibrate |
LDL decrease: 20.6% (145 mg) HDL increase: 11% (145 mg) Triglyceride decrease: 23.5-50.6% (greatest drop in patients with highest triglycerides) (145 mg) |
Further LDL decrease: 0-6% (200 mg) Further HDL increase: 13-17% (200 mg) Further triglyceride decrease: 20-32% (200 mg) |
Prevention of CV events in type 2 diabetes: Did not reduce primary composite outcome (nonfatal MI or CV death). Improved outcomes included nonfatal MI (24% decrease), coronary revascularization (21% decrease), progression to albuminuria, and reduced laser treatments for retinopathy. Nonsignificant increase in risk of CV death. |
First-line option for triglyceride >10 mmol/L (about 1000 mg/dL) Option for triglyceride >500 mg/dL or 5-10 mmol/L Option for low HDL Requires renal dose adjustment Associated with reversible increase in serum creatinine |
Gemfibrozil |
LDL: No effect HDL increase: 6% (1200 mg/day) Triglyceride decrease: 33-50% (greatest drop in patients with highest triglycerides) (1200 mg/day) |
Further triglyceride decrease: 41% Further HDL increase: 9% |
Primary prevention of coronary heart disease Secondary prevention of cardiac events in men with low HDL |
First-line option for triglyceride >10 mmol/L (about 1000 mg/dL) Option for triglyceride >500 mg/dL or 5-10 mmol/L Option for low HDL Requires renal dose adjustment Avoid with statin |
Icosapent ethyl |
LDL decrease: 5% HDL decrease: 4% Triglyceride decrease: 27% |
Further triglyceride decrease: 21.5% (4 g/day), 10.1% (2 g/day) Further LDL decrease: 6.2% (4 g/day) |
Secondary CV risk prevention; REDUCE-IT trial showed primary endpoint (major CV events) occurred in 24.7% of placebo compared with 18.2% of icosapent ethyl treated patients (p = 0.000001) [80] |
Option for triglyceride >500 mg/dL Safe for use with statins Use caution with fish or shellfish allergy |
Niacin |
LDL decrease: 14-17% (Niaspan 2 g/day); 12% (niacin immediate-release 1.5 g/day and Niaspan 1.5 g/day) HDL increase: 22-26% (2 g/day Niaspan); 17% (niacin immediate release 1.5 g/day); 20-22% (Niaspan 1.5 g/day) Triglyceride decrease: 20-50% |
Further LDL decrease: 1-5% (Niaspan 1 g/day); 10% (Niaspan 2 g/day) Further HDL increase: 24% (Niaspan 2 g/day); 15-17% (Niaspan 1 g/day) Further triglyceride decrease: 24% (Niaspan 2 g/day); 12-22% (Niaspan 1 g/day) |
Secondary MI prevention; in combination with a resin, slows progression or promotes regression of atherosclerosis; reduces mortality |
Option for triglyceride >500 mg/dL (about 5 mmol/L) Raises HDL more than any other agent Dose-dependent risk of hyperglycemia (especially in patients with type 2 diabetes) and liver toxicity May increase risk of statin myopathy |
Omega-3 ethyl esters |
LDL increase: 44.5% (4 g/day) HDL increase: 9.1% (4 g/day) Triglyceride decrease: 45% (4 g/day) |
LDL increase: 0.7% (4 g/day) Further HDL increase: 3.4% (4 g/day) Further triglyceride decrease: 29.5% (4 g/day) |
Secondary prevention: Reduces cardiovascular death; sudden death; and combined endpoint of death, nonfatal MI, and nonfatal stroke Secondary prevention in patients with, or at risk for, type 2 diabetes: did not reduce CV events |
Option for triglyceride >500 mg/dL (about 5 mmol/L) Safe for use with statins Associated with an increase in risk for recurrence of symptomatic atrial fibrillation or flutter within first 3 months of therapy Use with caution with fish or shellfish allergy |
Drug |
Potency (average LDL decrease) |
Renal Considerations |
Liver Function Monitoring |
Atorvastatin |
10 mg: 35-39% 20 mg: 43% 40 mg: 50% 80 mg: 55-60% |
No dose adjustment necessary for reduced renal function |
Check liver function tests at baseline and when clinically indicated |
Fluvastatin |
20 mg: 22% 40 mg: 25% 80 mg: 35% (as XL product) |
In severe renal impairment, use daily doses >40 mg with caution |
Check liver function tests at baseline and when clinically indicated |
Lovastatin |
10 mg: 21% 20 mg: 24-27% 40 mg: 30-31% 80 mg: 40-42% (as 40 mg BID) |
If CrCl < 30 mL/min, use daily doses over 20 mg with caution |
Check liver function tests at baseline and when clinically indicated |
Pitavastatin |
1 mg: 31-32% 2 mg: 36-39% 4 mg: 41-45% |
For glomerular filtration rate 15-59 mL/min/1.73 m2, including hemodialysis, initial daily dose is 1 mg, not to exceed 2 mg/day |
Check liver function tests at baseline and when clinically indicated |
Pravastatin |
10 mg: 22% 20 mg: 32% 40 mg: 34% 80 mg: 37% |
In significant renal impairment, start with 10 mg/day |
Check liver function tests at baseline and when clinically indicated |
Rosuvastatin |
5 mg: 45% 10 mg: 46-52% 20 mg: 47-55% 40 mg: 55-63% |
If CrCl < 30 mL/min/1.73 m2 (but not on hemodialysis), starting dose is 5 mg/day, not exceed 10 mg/day Rosuvastatin levels in hemodialysis patients are about 50% higher than levels in normal renal function |
Check liver function tests at baseline and when clinically indicated |
Simvastatin |
5 mg: 26% 10 mg: 30% 20 mg: 38% 40 mg: 29-41% 80 mg: 36-47% |
In severe renal impairment, starting dose is 5 mg daily with close monitoring |
Check liver function tests at baseline and when clinically indicated |
