2013 mar 04 (1411): drugs for hypertriglyceridemia

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Drugs for Hypertriglyceridemia . p 17
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March 4, 2013
Drugs for Hypertriglyceridemia
27.3/1000 with gemfibrozil and 41.4/1000 withplacebo (p<0.02).4 Controlled trials with other fibrateshave not shown a significant reduction in cardiovas- Fibrates, niacin and fish oil are promoted for treatment cular outcomes.5,6 In the ACCORD trial, fenofibrate of hypertriglyceridemia. HMG-CoA reductase inhibitors failed to reduce cardiovascular events in a large (statins) can lower elevated serum concentrations of cohort of diabetic patients, despite raising HDL and triglycerides, but less so than fibrates, niacins or fish oil.
Lifestyle changes such as weight reduction, exerciseand decreasing alcohol intake can also lower serum Adverse Effects – Fibrates are generally well toler-
triglyceride levels and should be tried first.1-3 ated. Gastrointestinal problems are the most commoncomplaint. Cholelithiasis, hepatitis and myositis can TRIGLYCERIDE LEVELS AND RISK — Mildly (150-
occur. Fibrates are contraindicated in patients with liver 200 mg/dL) and moderately (200-500 mg/dL) and gall bladder disease. A paradoxical severe increased levels of plasma triglycerides are associ- decrease in HDL-C has been reported; if this occurs, ated with increased cardiovascular risk. This risk may not be due to triglycerides themselves, but rather tothe cholesterol component of triglyceride-rich lipopro- Drug Interactions – Fibrates may potentiate the effects
teins. Whether lowering triglyceride levels decreases of oral anticoagulants and oral hypoglycemic drugs.
the risk of cardiovascular disease is unclear.
Gemfibrozil can inhibit the metabolism of statins and Triglyceride concentrations >1000 mg/dL are associ- increase the risk of rhabdomyolysis. Fenofibrate does ated with lipemic plasma, eruptive xanthomas, not inhibit statin metabolism and is much less likely to hepatomegaly and a risk of pancreatitis; at these lev- increase the risk of rhabdomyolysis; it is the preferred els, it is standard practice to treat hypertriglyc- fibrate for use in combination with a statin. Fenofibrate is eridemia, but no controlled trials are available to eliminated in urine and should be used with caution in demonstrate that lowering very high triglyceride con- patients taking cyclosporine (Neoral, and generics) or centrations decreases the risk of pancreatitis.
FIBRIC ACID DERIVATIVES — Fibrates usually
NIACIN (NICOTINIC ACID) — Niacin decreases
lower triglycerides by 30-50% and may increase triglycerides by 10-50%, decreases LDL-C and total HDL-C. When elevated triglycerides are decreased, plasma cholesterol, and increases HDL-C. A meta- LDL-C may be lowered as well. Gemfibrozil is the analysis of 11 randomized controlled trials in a total of only fibrate with demonstrated beneficial effects on 6616 patients with hyperlipidemia found that niacin cardiovascular outcomes. In the Helsinki Heart Study, alone or in combination with a statin decreased the a randomized double-blind 5-year trial in 4081 incidence of coronary events and stroke.8 The random- asymptomatic middle-aged men with primary dyslipi- ized, placebo-controlled AIM-HIGH trial, however, demia, gemfibrozil caused a marked increase in HDL showed no beneficial cardiovascular effects from addi- cholesterol and persistent reductions in LDL choles- tion of niacin to simvastatin (Zocor, and others) in terol, non-HDL cholesterol and triglycerides. The patients with mild hypertriglyceridemia, low HDL and cumulative rate of cardiac events at 5 years was FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS
Table 1. Drugs for Hypertriglyceridemia
Formulations
Usual Dosage Cost1
Fibrates
sustained-release – Slo-Niacin (Upsher-Smith) Niacin Combinations
extended-release niacin and lovastatin – extended-release niacin and simvastatin – 1. Wholesale acquisition cost (WAC) of 30 days’ treatment with the highest recommended usual adult dosage. Source: $ource® Monthly (Selected from FDB MedKnowledge™) February 6, 2013. Reprinted with permission by FDB, Inc. All rights reserved. 2013. www.fdbhealth.com/policies/drug-pricing-policy. Actualretail prices may be higher.
2. Should be taken with food.
3. Niacin is available OTC in multiple immediate- and extended-release formulations. The dose should be slowly titrated over a few weeks.
4. Only available by prescription.
5. Each 1-g capsule contains about 465 mg EPA and 375 mg DHA (total 900 mg polyunsaturated fatty acids [PUFAs]).
6. Each 1-g capsule contains 1000 mg of EPA.
7. USP-verified fish oil products are manufactured by Berkley & Jensen, Kirkland and Nature Made.
8. Most 1- or 1.2-g capsules contain 300 mg PUFAs (180 mg EPA and 120 mg DHA). Three capsules are approximately equal to one Lovaza capsule.
9. Cost of 2 bottles containing 400 Nature Made capsules (enough for 30 days’ treatment) based on retail price at Costco.com. Accessed February 25, 2013.
Adverse Effects – Niacin can cause skin flushing and
mg vitamin E, both, or neither for 3.5 years. The pri- pruritus, gastrointestinal distress, blurred vision, mary endpoint (death, non-fatal myocardial infarction fatigue, glucose intolerance, hyperuricemia, hepatic or stroke) was significantly decreased with n-3 PUFAs toxicity, exacerbation of peptic ulcer and, rarely, dry alone and with the combined treatment, while vitamin eyes and hyperpigmentation. Flushing has been less frequent and hepatotoxicity has seldom been reported A randomized, placebo-controlled, 5-year trial in with the extended-release preparation in daily doses 18,645 statin-treated hypercholesterolemic Japanese up to 2 grams. The cutaneous reactions can be dimin- patients found that daily intake of 1.8 g of eicosapen- ished by starting with a low dose, by taking niacin after taenoic acid (EPA) added to statin therapy signifi- meals, and by taking aspirin (325 mg) or ibuprofen cantly reduced major coronary events (262 vs. 324).11 However, a trial in 4837 patients who had previously FISH OIL — Long-chain, highly unsaturated omega-3
had an MI and were receiving antihypertensive, fatty acids, which are present in cold water fish such antithrombotic and lipid-modifying therapy (mainly as herring or salmon and commercially available in statins) found that addition of omega-3 fatty acids in capsules, can decrease fasting triglyceride concentra- margarine had no demonstrable cardiovascular tions by 20-50% by reducing hepatic triglyceride pro- duction and increasing triglyceride clearance. In anItalian study of secondary prevention, 11,324 patients A recent meta-analysis of 14 randomized, double- with a recent MI were randomly assigned to receive blind trials in a total of more than 20,000 patients with 1 g of n-3 polyunsaturated fatty acids (PUFAs), 300 a history of cardiovascular disease found that supple- The Medical Letter • Volume 55 • Issue 1411 • March 4, 2013 mentation with omega-3 fatty acids did not reduce the 10. GISSI-Prevenzione Investigators. Dietary supplementation with n- 3 polyunsaturated fatty acids and vitamin E after myocardialinfarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447.
Two Prescription Products – The FDA has approved
11. M Yokoyama et al. Effects of eicosapentaenoic acid on major 2 fish-oil products for treatment of triglyceride levels coronary events in hypercholesterolaemic patients (JELIS): a >500 mg/dL. In recommended doses, Lovaza (for- randomised open-label, blinded endpoint analysis. Lancet merly Omacor), a combination of EPA and docosa- 12. D Kromhout et al. n-3 fatty acids and cardiovascular events hexaenoic acid (DHA), lowers triglycerides by 20-50%.
after myocardial infarction. N Engl J Med 2010; 363:2015.
It does not interact with statins and does not increase 13. SM Kwak et al. Efficacy of omega-3 fatty acid supplements the risk of rhabdomyolysis.14 Vascepa, which was (eicosapentaenoic acid and docosahexaenoic acid) in the sec-ondary prevention of cardiovascular disease: a meta-analysis launched in January 2013, is an ethyl ester of EPA; it of randomized, double-blind, placebo-controlled trials. Arch Int will be reviewed in a future issue. Neither Lovaza nor Vascepa has been shown to reduce cardiovascular 14. Fish oil supplements. Med Lett Drugs Ther 2012; 54:83.
Adverse Effects – Fish oil supplements are generally
well tolerated. Adverse effects have included eructation,
dyspepsia and an unpleasant aftertaste. Worsening
glycemic control has been reported in diabetic patients
taking large doses. Large doses of fish oil can inhibit
platelet aggregation and increase bleeding time;
whether they could cause clinically significant bleeding
has not been established.
STATINS — Statins typically lower triglyceride levels by
10-30%. Their beneficial effect on cardiovascular risk is
well established.
CONCLUSION — The evidence that treating hyper-
triglyceridemia with a fibrate, niacin or fish oil can
reduce cardiovascular risk is weak, especially in
patients already taking a statin. Most patients with
hypertriglyceridemia might be better served by
lifestyle changes, taking a statin and, perhaps for
some, fewer measurements of their serum triglyc-
eride concentrations. 
M Miller et al. Triglycerides and cardiovascular disease. A sci-entific statement from the American Heart Association.
Circulation 2011; 123:2292.
Drugs for lipids. Treat Guidel Med Lett 2011; 9:13.
L Berglund et al. Evaluation and treatment of hypertriglyc-eridemia: an Endocrine Society clinical practice guideline. JClin Endocrinol Metab 2012; 97: 2969.
MH Frick et al. Helsinki Heart Study: primary-prevention trialwith gemfibrozil in middle-aged men with dyslipidemia. Safetyof treatment, changes in risk factors, and incidence of coro-nary heart disease. N Engl J Med 1987; 317:1237.
BIP Study Group. Secondary prevention by raising HDL cho-lesterol and reducing triglycerides in patients with coronaryartery disease: the Bezafibrate Infarction Prevention (BIP)study. Circulation 2000; 102:21.
Fenofibric acid (Trilipix). Med Lett Drugs Ther 2009; 51:33.
ACCORD Study Group. Effects of combination lipid therapy intype 2 diabetes mellitus. N Engl J Med 2010; 362:1563.
E Bruckert et al. Meta-analysis of the effect of nicotinic acidalone or in combination on cardiovascular events and athero-sclerosis. Atherosclerosis 2010; 210:353.
AIM-HIGH Investigators. Niacin in patients with low HDL cho-lesterol levels receiving intensive statin therapy. N Engl J Med2011; 365:2255.
The Medical Letter • Volume 55 • Issue 1411 • March 4, 2013 EDITOR IN CHIEF: Mark Abramowicz, M.D.
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