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Mechanisms of action of triglyceride-lowering drugs
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The two main triglyceride-containing lipoproteins are very-low density lipoprotein (VLDL) and chylomicrons.
VLDL is secreted from the liver and is metabolized by lipoprotein lipase, a capillary-bound enzyme that removes the triglyceride from the particle. The VLDL particle shrinks as the core components are removed. As it shrinks, VLDL becomes an intermediate-density lipoprotein and a low-density lipoprotein (LDL).
Chylomicrons are produced in the gut from dietary fat. As with VLDL, lipoprotein lipase clears the triglyceride from the chylomicron particle, producing a remnant particle that is picked up by the liver.
Drug mechanisms to lower triglycerides
Niacin, fibrates and prescription omega-3 fatty acids are approved for the treatment of patients with hypertriglyceridemia.
Adipose tissue releases free fatty acids that drive the production of triglycerides in the liver. Niacin has two mechanisms by which it reduces triglyceride levels. It blocks the release of free fatty acids from adipose tissue, which also results in a reduced rate of secretion of VLDL particles.
Fibrates have no effect on free fatty acid kinetics. Instead, fibrates inhibit the secretion of triglycerides from the liver, which reduces levels of blood triglycerides and stimulates the clearance of triglycerides by activating lipoprotein lipase.
Omega-3 fatty acids act similarly to fibrates to reduce triglyceride levels. Although they operate differently in the liver, prescription omega-3 fatty acids inhibit the release of triglycerides from the liver, reducing the number of VLDL particles. They also stimulate lipoprotein lipase, which increases the rate of clearance of triglycerides from the plasma.
Enhanced triacylglycerol (triglyceride) clearance may contribute to the hypotriacylglycerolemic effect of omega-3 fatty acids in humans. Healthy patients and hypertriacylglycerolemic patients were given a placebo (olive oil) or a fish-oil concentrate (41% eicosapentaenoic acid and 23% docosahexaenoic acid) in two independent, randomized, blind trials.1
In the healthy patients, the fish oil concentrate decreased plasma triacylglycerol concentrations by 18%, whereas in the hypertriacylglycerolemic patients, concentrations were reduced by 35%. LDL cholesterol concentrations increased by 25% in the latter group. Fish oil concentrate increased the endogenous activities of lipoprotein lipase by 62% and hepatic lipase by 68% in the healthy patients, but only lipoprotein lipase by 65% in the patients with hypertriacylglycerolemia.
These data suggest that endogenous lipase activities may be altered by nutritional interventions and that accelerated lipolysis may contribute, at least in part, to the observed effects of omega-3 fatty acids on human lipoprotein metabolism.
Evidence also indicates that omega-3 increases plasma lipoprotein lipase and lipoprotein lipase gene expression in adipose tissue. In a randomized, double-blind, placebo-controlled, crossover study, 51 men who expressed an atherogenic lipoprotein phenotype had their diets supplemented with fish oil for 6 weeks, producing a 35% decrease in fasting plasma triglyceride, attenuation of the postprandial triglyceride response, and a decrease in small, dense LDL.2 These changes were accompanied by a marked increase in the concentration of lipoprotein lipase mRNA in adipose tissue and post-hepatic lipoprotein lipase. Also, evidence showed an association between lipoprotein lipase gene expression and polymorphism in the apolipoprotein E gene.
The atherogenic lipoprotein phenotype originates from defects in triglyceride metabolism that include the impaired clearance of triglyceride-rich lipoproteins in the postprandial period, coupled with an oversupply of lipid substrates for the production of triglyceride and secretion of apolipoprotien B as triglyceride-rich VLDL in the liver (Figure).
A physiologic increase in LDL cholesterol occurs in patients receiving fibrates or omega-3 fatty acids by stimulating lipoprotein lipase activity. A blockade of lipoprotein lipase, the enzyme that removes the triglyceride from the VLDL particle, is responsible for elevated triglyceride levels in patients with hypertriglyceridemia. Removing this blockade by stimulating lipoprotein lipase activity with a fibrate or omega-3 fatty acids decreases the number of VLDL particles and results in a small increase in LDL.
| Triglyceride Metabolism
Dunbar RL, Rader DJ. Demystifying triglycerides: A practical approach for the clinician. Cleve Clin J Med. 2005;72(8):661-680. Reprinted with permission. Copyright © 2005 Cleveland Clinic. All rights reserved. |
Effects of fibrates and omega-3 fatty acids on lipid profiles
The effects of fenofibrate and prescription omega-3 fatty acids on lipid profiles have been assessed in patients with hypertriglyceridemia. The pattern of response was similar with each agent.
In a double-blind prospective trial, 42 patients with triglyceride levels of 500 mg/dL to 2,000 mg/dL were randomized to placebo or omega-3 acid ethyl esters, 4 g/day, for 4 months.3 Compared with baseline values, omega-3 acid ethyl esters significantly reduced mean triglyceride concentrations by 45% (P<.00001), total cholesterol by 15% (P<.001), VLDL cholesterol by 32% (P<.0001) and the total cholesterol:high-density lipoprotein (HDL) cholesterol ratio by 20% (P =.0013), and increased HDL cholesterol by 13% (P = .014) and LDL cholesterol by 31% (P =.0014). Placebo had no effect on these parameters.
In a randomized double-blind, placebo-controlled, multicenter trial of fenofibrate, 147 adults with a history of type IV or V hyperlipoproteinemia were recruited.4 Type IV is isolated hyperlipoproteinemia, with triglycerides between 200 and 1,000 mg/dL, whereas type V is severe hyperlipoproteinemia, with triglycerides >1,000 mg/dL. After a 6-week to 12-week dietary stabilization period and a 4-week placebo period, patients whose 12-hour fasting total plasma triglyceride levels ranged from 350 mg/dL to 1,500 mg/dL were continued in the study. Patients were stratified into two groups based on their triglyceride levels at entry—group A (350 mg/dL to 499 mg/dL) and group B (500 mg/dL to 1,500 mg/dL). Patients in each group were randomly assigned to receive 100 mg of fenofibrate or placebo three times daily for 8 weeks.
In groups A and B, patients who received fenofibrates had statistically significant reductions in levels of total cholesterol, VLDL cholesterol, total triglycerides, and VLDL triglycerides, and significant increases in HDL cholesterol. Patients in group B also experienced a significant increase in LDL cholesterol levels. Sixteen of the 75 patients who received fenofibrates and 11 of the 72 patients who received placebo reported adverse events that were potentially drug related. Most of these were gastrointestinal; a few reported musculoskeletal and skin reactions.
Safety profiles
Contraindications, precautions, and the potential for drug interactions differentiate fenofibrate from prescription omega-3 fatty acids. According to the package insert for fenofibrate, it is contraindicated in patients with hepatic, renal, or gall bladder disease, and cautious use is warranted in patients with elevated liver function tests or cholelithiasis. Fenofibrate interacts with coumadin, resins, statins, and cyclosporine, and its use with statins is not recommended unless the physician believes that the benefits outweigh the risks of myopathy and rhabdomyolysis.
In contrast, prescription omega-3 fatty acids have no contraindications, and no precautions for its use appear in the package insert. Recipients of prescription omega-3 fatty acids who are also taking anticoagulants should be monitored periodically for a prolongation in bleeding time. They can be used safely with statins; in patients taking simvastatin, an additional 23% lowering in triglycerides is observed with the use of prescription omega-3 fatty acids.
Conclusion
Niacin, fibrates, and prescription omega-3 fatty acids reduce triglyceride secretion from the liver by different mechanisms. Only fibrates and prescription omega-3 fatty acids also enhance triglyceride clearance. Fibrates and prescription omega-3 fatty acids have similar effects on lipid profiles in patients with high triglycerides.
References
- Harris WS, Lu G, Rambor GS, et al. Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases. Am J Clin Nutr. 1997;66:254-260.
- Khan S, Minihane AM, Talmud PJ, et al. Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. J Lipid Res. 2002;43:979-985.
- Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4:385-391.
- Goldberg AC, Schonfeld G, Feldman EB, et al. Fenofibrate for the treatment of type IV and V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study. Cin Ther. 1989;11:69-83.