Approach Considerations
Rule out secondary causes of hypertriglyceridemia, including diabetes mellitus (fasting or random glucose levels), hypothyroidism (thyroid-stimulating hormone [TSH] levels), chronic renal failure (urinalysis, creatinine, and microalbumin), alcohol abuse, hormone replacement therapy, and/or oral contraceptives. [45, 46]
Measure plasma lipid and lipoprotein levels while the patient is on a regular diet after an overnight fast. The Endocrine Society also recommends using fasting triglyceride levels over nonfasting triglyceride levels for the diagnosis of hypertriglyceridemia. [46]
Abnormal lipoprotein patterns can often be identified after determining serum cholesterol and triglyceride levels and visual inspection of the plasma sample (stored at 4°C). In some cases, performing electrophoresis and ultracentrifugation of whole plasma specimens may be necessary to help establish a diagnosis.
If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol). A biopsy of cutaneous lesions suspected to be either planar or tuberous xanthomas will reveal cholesterol deposition.
Although some studies have shown that tests such as C-reactive protein (CRP) and total homocysteine levels have some predictive value in screening for vascular disease, and thus are emerging as nontraditional risk factors for coronary heart disease, further investigation is needed to determine their value. [45] Nonfasting triglyceride levels may reflect the level of atherogenic remnant lipoproteins and may even be stronger predictors of cardiovascular events than traditional fasting lipids. [47]
Lipid Analysis
Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.
Moderately elevated total cholesterol and triglyceride levels accompanied by the presence of palmar crease xanthomas confirm the diagnosis dysbetalipoproteinemia. Further laboratory workup may not be necessary.
Very low-density lipoproteins (VLDLs) are increased and chylomicrons are absent when triglyceride levels are elevated but below 1000 mg/dL. If triglyceride levels are above 1000 mg/dL, both VLDL and chylomicrons are usually present.
A standard lipid profile using the Friedewald equation to calculate the LDL cholesterol is not useful if the triglyceride level is more than 400-500 mg/dL. The excess cholesterol present in beta-VLDL is included in the LDL cholesterol value. If the triglycerides are elevated but less than 1000 mg/dL and the total cholesterol is elevated, the lipoprotein abnormality may be caused by either: (1) elevations of both low-density lipoprotein (LDL) and VLDL, which is type IIb or mixed hyperlipoproteinemia, or (2) increased remnant VLDL or intermediate-density lipoprotein (IDL), which is type III hyperlipidemia or dysbetahyperlipoproteinemia (total cholesterol levels, about 300-600 mg/dL; triglyceride levels, about 400-800 mg/dL). The 2 disorders may be distinguished by obtaining a direct LDL cholesterol analysis (enzymatic analysis), which is available at most commercial laboratories. If the direct LDL cholesterol is significantly lower than the calculated LDL cholesterol, a diagnosis of type IIIhyperlipoproteinemia is likely. Furthermore, if the cholesterol-to-triglyceride ratio in isolated VLDL is greater than 0.3, dysbetalipoproteinemia is likely (normal ratio, 0.2).
The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL cholesterol and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification (lipoprotein electrophoresis). This expensive analysis involves ultracentrifugation followed by electrophoresis. However, it is not performed by most commercial or hospital laboratories. Studies that can isolate and measure VLDL and IDL include density-gradient ultracentrifugation and nuclear magnetic resonance spectroscopy. These tests are reliable in helping diagnose dysbetalipoproteinemia, but they may be available only at lipid specialty laboratories.
Specialized lipid centers should be contacted if type IIb or III must be confirmed. In most clinical settings, however, distinguishing between these entities is rarely necessary, because the treatment of both conditions is essentially the same. Diet modification, exercise, and appropriate weight loss improve both. Type IIb and III also respond to the same medications—niacin and/or fibric acid derivatives. [48] Therefore, no matter which diagnosis applies to a given patient, the treatment is the same.
The Endocrine Society does not recommend routinely measuring lipoprotein particle heterogeneity in patients with hypertriglyceridemia, suggesting that although apolipoprotein B (apo B) or lipoprotein(a) [Lp(a)] levels may be useful, results of other apolipoproteins are generally not clinically useful. [46] However, apo E genotyping or phenotyping can be used to determine if the patient is homozygous for apo E-2, but this finding is not sufficient for the diagnosis of dysbetalipoproteinemia without clinical or lipid abnormalities consistent with the disorder.
Chylomicron Determination
If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of an upright tube of plasma or serum. If a creamy supernatant is seen the next day, chylomicrons are present. If the infranatant is cloudy, high levels of very low-density lipoprotein (VLDL) are present (type V hyperlipidemia). If the infranatant is clear, the VLDL content is normal and type I hypercholesterolemia (elevated chylomicrons only) should be suspected.
Type I hyperlipoproteinemia (pure hyperchylomicronemia)
To make a definitive diagnosis of type I hyperlipidemia, a deficiency of either lipoprotein lipase or apo C-II must be confirmed. The presence of lipoprotein lipase activity may be measured in plasma following intravenous heparin administration (50 IU of heparin per kg body weight) or by analysis of muscle or adipose tissue biopsy samples.
Defective or absent apo C-II must be determined at a lipid center that performs 1 of the 3 following assays: (1) gel electrophoresis, (2) radioimmunoassay, or (3) confirmation that lipoprotein lipase added to the patient's plasma is not active.
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Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
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Close-up of eruptive xanthomas.
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Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein.
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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.
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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 |
