Targeting Triglycerides

Commentary by Josh Remick MD, PGY-3

Hypertriglyceridemia is defined by the NCEP guidelines for treatment as a fasting triglyceride level greater than 200 mg/dL after the target LDL-C level has been achieved (1). When triglyceride levels are greater than 1000 mg/dL, the risk of pancreatitis increases and treatment with fibrates should be started immediately. Many physicians would also argue for treatment of a triglyceride level greater than 500mg/dL. However, it is the triglyceride level between 200 and 500 mg/dL that is a bit more difficult to interpret. It may be because there is considerable controversy over whether an elevated triglyceride level increases one’s cardiovascular risk or is simply a marker of other lipoprotein abnormalities (specifically small, dense LDL particles) that cause premature cardiovascular disease.

As outlined in the recent Brunzell review in the New England Journal of Medicine (2), the key to assessing triglyceridemia is first to evaluate for reversible causes. These include alcohol use, medications, uncontrolled or untreated diabetes and obesity, particularly central obesity. If the hypertriglyceridemia cannot be attributed to a secondary cause, then an evaluation for a genetic predisposition should be undertaken.

There are essentially 3 inherited lipid disorders that can cause elevated triglyceride levels, but only 2 of them are associated with premature coronary disease. The two genetic variants that are associated with increased cardiovascular risk are familial combined hyperlipidemia and familial hypoalphalipoproteinemia. Both conditions are associated with low HDL levels and increased numbers of small, dense LDL particles. Familial hypertriglyceridemia, the third variant, is not associated with increased coronary disease. Thus, patients with elevated triglyceride levels and a family history of premature coronary disease likely have familial combined hyperlipidemia or familial hypoalphalipoproteinemia. These patients should be treated with lifestyle modifications and medical therapy.

In patients with elevated triglyceride levels and no known family history of premature coronary disease, a useful test is the apolipoprotein B (apo B) level. ApoB is present in each triglyceride-containing particle (LDL, IDL and VLDL) and carries its own risk of coronary disease (3). Measurement of the apoB level can help distinguish familial hypertriglyceridemia from the other genetic variants that confer an increased cardiovascular risk. The apoB level in patients with familial hypertriglyceridemia is lower than that of patients with familial combined hyperlipidemia. Therefore, patients with hypertrigylceridemia and a low apoB level can usually be managed with lifestyle modifications, whereas those with high apoB levels require more aggressive treatment.

Instead of using apoB levels to determine the need for treatment of triglycerides, The National Cholesterol Education Program (NCEP) recommends using non-HDL cholesterol. The non-HDL cholesterol is calculated simply by subtracting the HDL cholesterol from the total cholesterol. The difference between these two measured values includes triglyceride rich lipoproteins. A patient’s non-HDL cholesterol goal is usually 30mg/dL higer than his/her LDL cholesterol goal. According to the NCEP, once LDL goals are achieved, triglycerides that are greater than 200mg/dL may be treated (1).
Weight loss, reduction in dietary fat and an increase in aerobic exercise should be considered first line treatment of hypertriglyceridemia. These interventions alone may lower triglyceride levels approximately 20%. In patients who require medical therapy, statins should already be part of the medication regimen to achieve the patient’s LDL-cholesterol goal. In addition, statins can lower triglyceride levels up to 45% in patients with triglyceride levels > 250 mg/dL(4). If triglyceride levels remain >200 mg/dL despite statin therapy and lifestyle modifications, additional medications should be started. These agents include fribrates, nicotinic acid or omega-3-fatty-acids.

Fibrates produce the greatest decrease in triglyceride levels, ranging from 20-55% (5) regardless of the baseline level of triglycerides. Several large prospective trials have evaluated the role of fibrates in the prevention of coronary disease (6-8). The results are mixed and fail to show an overall mortality benefit, but both gemfibrozil and fenofibrate appear to prevent non-fatal myocardial infarctions. While both medications reduce fibrate levels equally (www.pdr.net, keyword search: fibrate), they have different side effect profiles. Fenofibrate can cause a reversible rise in creatinine, whereas gemfibrozil is associated with an increase in the incidence of myopathy and rhabdomyolysis when used in combination with a statin.

Nicotinic acid is another medication that may be used to lower triglyceride levels. as both the immediate and sustained-released formulations lower triglyceride levels by approximately 20-40%. Side effects include flushing and GI disturbances, which can be mitigated with the administration of Aspirin approximately 30 minutes prior to taking the nicotinic acid. Combination therapy with nicotinic acid and statins has been shown to be safe, but no clinical trials with mortality as an endpoint have been done; rather, the only clinical trials of statin-nicotinic acid therapy with any type of clinical endpoints have shown regression of atherosclerosis on angiogram (9)or via measurement of carotid intima-media thickness. (10)

Lastly, omega-3 fatty acids can also lower triglyceride levels by approximately 30%. A large study in Italy (11)showed that omega-3 fatty acids in addition to the Mediterranean diet reduced mortality by 20% in survivors of myocardial infarction. This data has not been reproduced and there is little known about the combination of omega-3 fatty acids with statins. However, there are few side effects associated with omega-3 fatty acids and therefore little reason not to start patients on this medication, particularly those who have survived a myocardial infarction.

In conclusion, tryiglycerides have not been shown to confer the risk of coronary disease that elevated LDL-cholesterol has. That said, there are patients in whom triglyceride lowering should be attempted in order to prevent morbidity and mortality. Aggressive weight loss, increased aerobic exercise and statin therapy should be initiated first. If these measures do not bring triglyceride levels to an acceptable level, combination therapy with fibrates, nicotinic acid or omega-3 fatty acids should be used.

References:

1. Grundy SM, Cleeman JI, Mertz CNB, et al. Implication of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:763.
2. Brunzell J. Hypertriglyceridemia. N Engl J Med. 2007 September 6;357(10):1009-17.
3. Lamarche B, Moorjani S, Lupien P, Cantin B, Bernard P, Dagenais G, et al. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the quebec cardiovascular study. Circulation. 1996 August 1;94(3):273-8.
4. Stein E, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. The American Journal of Cardiology. 1998 2/26;81(4, Supplement 1):66B-9B.
5. Miller M. Current perspectives on the management of hypertriglyceridemia. American Heart Journal. 2000 8;140(2):232-40.
6. Rubins H, Robins S, Collins D, Fye C, Anderson J, Elam M, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999 August 5;341(6):410-8.
7. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease : The bezafibrate infarction prevention (BIP) study. Circulation. 2000 July 4;102(1):21-7.
8. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.
9. Brown BG, Zhao X, Chait A, Fisher L, Cheung M, Morse J, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 November 29;345(22):1583-92.
10. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Current Medical Research & Opinion. 2006 Nov;22(11):2243-50.
11. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-prevenzione trial. gruppo italiano per lo studio della sopravvivenza nell’infarto miocardico. Lancet. 1999 Aug 7;354(9177):447-55.

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