Hypertriglyceridemia Medication

Updated: Mar 30, 2017
  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
  • Print
Medication

Medication Summary

Three classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids. High doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) also lower triglycerides, by as much as approximately 50%.

Fibrates raise HDL, and they may increase LDL, particularly if the triglyceride level is greater than 400 mg/dL. Because LDL particles change from being small and dense to being large and buoyant, they may be less atherogenic. Fibrates activate peroxisome proliferator activated receptor (PPAR) alpha, increasing the activity of lipoprotein lipase, which causes a decrease in triglyceride levels. LDL changes from small, dense morphology to large, buoyant particles that are more rapidly cleared by liver. PPARalpha activation also increases HDL production.

Four fibrates are used clinically: 2 are available in the United States, both in generic formulations: gemfibrozil (Lopid) and fenofibrate (multiple brand names); the other 2 agents, bezafibrate and ciprofibrate, are available in Europe and elsewhere but have not been approved by the US Food and Drug Administration (FDA). Fenofibrate is available in micronized and nonmicronized formulations; no convincing data suggest that one has greater efficacy than the other. Some formulations are better absorbed with food. Relatively recently, the FDA approved a new fenofibrate formulation known as fenofibric acid (Trilipix) with a specific indication for use with a statin in patients with mixed dyslipidemia. [55, 56, 57, 58, 59]

High-dose niacin (vitamin B-3) 1500 or more mg/d) decreases triglyceride levels by at least 40% and can raise HDL cholesterol levels by 40% or more. [54] Niacin also reliably and significantly lowers LDL cholesterol levels, which the other major triglyceride-lowering medications do not. In the Coronary Drug Project, niacin, in comparison with placebo, reduced coronary events. [60]

Niacin has multiple adverse effects, the worst of which is chemical hepatitis. However, at doses of 1.5-2 g/d, complications are unusual. Sustained-release niacin is more hepatotoxic than immediate-release niacin but is better tolerated. [61] Flushing, itching, and rash are expected adverse effects that are less common with long-acting formulations. These symptoms are an annoyance but are not life threatening and may be minimized by starting at low doses and increasing slowly. Switching from immediate-release niacin to an equal dose of time-release preparation has been reported to cause severe hepatotoxicity. Niacinamide, also called vitamin B-3, has no lipid-lowering effects; nor does inositol hexanicotinate.

If niacin is prescribed for patients with type 2 diabetes, glucose control should be carefully monitored, modest increases in insulin resistance can occur. [62] In addition, because uncontrolled diabetes can cause hypertriglyceridemia, patients with diabetes mellitus should be treated aggressively to reduce the HbA1c level to less than 7%. Niacin is the best available agent to increase HDL cholesterol. It also lowers lipoprotein (a).

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At very high doses (≥4 g/d), triglycerides are reduced. The triglyceride-lowering impact of fish oils is entirely dependent on the omega-3 content, and, therefore, the number of capsules required for a total dose of 4 g/d requires determining the content of eicosapentaenoic (EPA) and docosahexaenoic (DHA) per capsule. Nonprescription fish oil supplements vary in concentration from approximately 0.4 g to 1 g of EPA and DHA per capsule, and there have not been clinical trials to determine the optimal dose and efficacy. The EPA and DHA contained in the supplement fish oil versions vary widely between products. Therefore, a minimum dose of 4 g of omega-3 fatty acids per day may require at least 8-12 capsules/day. [63]

Several prescription fish oil products have been approved by the FDA for triglyceride levels exceeding 500 mg/dL. One example is Lovaza. One 1-g capsule contains approximately 465 mg of EPA and 375 mg of DHA. Like the fibrates, high-dose Lovaza and other DHA-containing prescription omega-3 products increase LDL-C levels, particularly when triglyceride levels are greater than 400 mg/dL. The impact on HDL-C levels varies; levels may modestly increase or remain unchanged.

Another prescription fish oil is an ultra-pure omega fatty acid that contains an ethyl ester of EPA, icosapent ethyl (Vascepa). Each 1-g icosapent capsule contains at least 96% EPA and no DHA. Past studies suggest that highly purified EPA may lower TG levels without increasing LDL cholesterol levels. [66, 67] TG-lowering therapies (eg, fibrates, fish oils containing both EPA and DHA) can substantially increase LDL cholesterol levels in patients with severe hypertriglyceridemia (≥500 mg/dL).

The Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial randomized 229 diet-stable patients with fasting TG levels from 500-2000 mg/dL (with or without background statin therapy) to icosapent 4 g/day, icosapent 2 g/day, or placebo. Results showed that icosapent significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. Icosapent 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76; P < 0.0001) and icosapent 2 g/day by 19.7% (n = 73; P = 0.0051). For a baseline TG level >750 mg/dL, icosapent 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28; P = 0.0001) and icosapent 2 g/day by 32.9% (n = 28; P = 0.0016). [68]

Vascazen, a medical food derived from fish oil, is also available. Each 1-g Vascazen capsule contains at least 900 mg of ethyl esters of omega-3 fatty acids sourced from fish oils and includes approximately 680 mg of EPA and approximately 110 mg of DHA.

Note that although fatty fish (eg, salmon, tuna, trout, mackerel, sardines) are good sources of omega-3 fatty acids, they also usually contain high concentrations of mercury and polychlorinated biphenyls (PCBs). Fish oil supplements that can be obtained without a prescription have negligible amounts of mercury. [75] The advantage of prescription fish oil is that fewer capsules are necessary to achieve a therapeutic dose, facilitating adherence. Additionally, the prescription products have been thoroughly tested in phase 3 trials to show safety and efficacy (particularly for lowering very high TGs). [68, 69] Consistency of potency is ensured with the prescription fish oil products.

Low doses of EPA and DHA (750-1000 mg/d) do not affect lipid levels, but they have been demonstrated to lower the incidence of fatal coronary events probably due primarily to its antiarrhythmic properties. [64]

Bile acid sequestrants are usually avoided, because these agents increase triglycerides. Ezetimibe should be considered only for lowering LDL-C levels.

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) are not the drugs of choice to treat dysbetalipoproteinemia, but their use may be necessary if the response to a fibrate and or niacin is inadequate. For patients with mixed hyperlipidemias (elevations of both LDL-c and triglycerides), a moderate dose of a HMG CoA reductase inhibitor may be appropriate if the amount of triglyceride lowering necessary is only about 20%. If a patient is taking gemfibrozil, the addition of a statin should prompt switching to fenofibrate, which has a lower risk of causing severe myopathy.

Maximum doses of the strongest statins, atorvastatin, simvastatin, or rosuvastatin (cerivastatin was recalled from US market on 8/8/01), lower triglycerides approximately 40%, but such doses are not appropriate unless the LDL-c is at least 30% above the desired level.

Bile acid sequestrants (cholestyramine or colestipol) raise triglyceride levels and are not appropriate therapy for hypertriglyceridemia. However, in patients with a mixed hyperlipidemia, resins may be combined with niacin or a fibrate.

Patients with the metabolic syndrome are often treated with metformin, which improves impaired fasting glucose levels, frequently causes modest weight loss, and can lower triglyceride levels.

Table 4. Fibric Acid Agents, Omega Acid Ethyl Esters, and Niacin Drug Characteristics [76] (Open Table in a new window)

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.



As statin add-on, did not lower risk of non-fatal MI, nonfatal stroke, or CV death more than statin alone in patients with type 2 diabetes at high risk for CV disease



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



Preferred over gemfibrozil for use with statins



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)



A study, REDUCE IT, is underway to look at reduction in CV events with icosapent ethyl 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



As statin add-on, reduces carotid intima-media thickness (surrogate marker) compared with ezetimibe as statin add-on in patients with lower HDL



No CV event benefit from niacin plus statin versus statin alone in patients with well-controlled LDL, low HDL, and high triglycerides



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



 

Table 5. Statin Drug Characteristics [77] (Open Table in a new window)

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

 

Next:

Fibric Acid Agents

Class Summary

Fenofibrate is reported to lower LDL levels more reliably than either clofibrate or gemfibrozil, but none of the drugs in this class should be used for isolated LDL elevations. The fibrates are commonly used to treat hyperlipidemias types IV (high VLDL) and V (high VLDL and chylomicrons), as well as type III dysbetalipoproteinemia (IDL or VLDL remnant disease).

These agents can also be used to treat type IIb mixed hyperlipidemia if used in conjunction with an LDL-lowering medication such as a resin.

Gemfibrozil (Lopid)

Gemfibrozil lowers triglycerides, VLDL, and IDL, but raises HDL. LDL is usually is unaffected but may increase if it is initially low or decrease if it is initially high. This agent increases the activity of lipoprotein lipase, which hydrolyzes triglycerides in triglyceride-rich lipoproteins. Gemfibrozil reduces synthesis of VLDL in the liver and increases the clearance of remnant lipoproteins from blood.

Gemfibrozil is available in generic formulation, most cost-effective fibrate at this time. Its FDA-approved indications are for type IV and V hyperlipidemia (ie, elevations in VLDL only or both VLDL and chylomicrons).

Fenofibrate (Tricor, Lofibra, TriCor, Antara, Triglide)

Fenofibrate is similar to other fibric acid derivatives in triglyceride-lowering and HDL-raising effects. However, this agent differs in that modest LDL-lowering can be expected with greater frequency than with gemfibrozil.

The FDA-approved indications for fenofibrate are for hypertriglyceridemia and hypercholesterolemia, but this difference does not qualify fenofibrate for treatment of isolated LDL elevations. Fenofibrate is taken once a day, which may increase patient compliance. Patients with mild-to-moderate renal disease should receive a reduced dose (about one third of the usual dose), and it is contraindicated in severe renal impairment.

Previous
Next:

Omega-3 Acids

Class Summary

Prescription omega-3 acids (fish oil) are available and have shown to be effective in lowering very high serum triglycerides (≥ 500 mg/dL).

Icosapent ethyl (Vascepa)

Ethyl ester of eicosapentaenoic acid indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (> 500 mg/dL). Reduces hepatic VLDL-TG synthesis and/or secretion; enhances TG clearance from circulating VLDL particle; may also increase beta-oxidation, inhibits acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT), decreases lipogenesis in liver, and increases plasma lipoprotein lipase activity. Icosapent does not increase LDL-cholesterol.

Omega-3-acid ethyl esters (Lovaza)

Omega-3-acid ethyl esters were the first prescription omega-3-acid. These are purified fish oil, without heavy metals and polychlorinated biphenyl (PCBs). Each 1-g cap contains at least 900 mg of omega-3-acid ethyl esters, predominantly a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as vitamin E to protect the long chain fatty acids (EPA and DHA) from oxidation.

This agent is theorized to reduce triglyceride synthesis in the liver. EPA and DHA are poor enzyme substrates for triglyceride synthesis in the liver, and they inhibit esterification of other fatty acids. Potential mechanisms of action include acyl CoA:1,2-diacylglycerol acyltransferase inhibition, increased hepatic mitochondrial and peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.

Omega-3-acid ethyl esters are indicated as adjunctive treatment to dietary changes to reduce very high triglyceride levels (ie, >500 mg/dL).

Clinical trials show significant reduction in non–HDL, triglyceride, total cholesterol, VLDL, and apo B levels from baseline when combined with simvastatin compared with simvastatin and placebo. Monotherapy with omega-3-acid ethyl esters reduces median triglyceride, VLDL, and non–HDL levels from baseline.

Omega 3 carboxylic acids (Epanova)

Omega 3 acids are thought to inhibit acyl CoA:1,2-diacylglycerol acyltransferase. Increased mitochondrial and peroxisomal beta-oxidation in liver , decreased hepatic lipogenesis, and increased activity of plasma lipoprotein lipase activity may also be possible mechanisms. Omega 3 carboxylic acids is the first prescription omega-3 product in free fatty acid form approved in the United States. It is indicated as an adjunct to diet in patients with severe hypertriglyceridemia (ie, TG ≥ 500 mg/dL).

Previous
Next:

Lipid-Lowering Agents, Other

Class Summary

Niacin (vitamin B-3) inhibits the hepatic secretion of VLDL cholesterol. This agent is effective in most categories of hyperlipidemia. Niacin has been demonstrated to lower LDL cholesterol by 32% (generally, 15-25% decrease), lower triglycerides by 20-50% (≥1.5 g/d decreases triglycerides by as much as 50%), and raise HDL cholesterol by 43%, particularly at higher doses. Niacin lowers lipoprotein (a) levels, which may be of some clinical importance, because lipoprotein (a) levels have been associated with coronary heart disease in numerous epidemiologic studies. The clinical benefit of lowering lipoprotein (a) levels has not been determined.

Whether purchased by prescription or not, niacin costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, occurring more so with time-release than immediate-release niacin. Insulin resistance may increase; nevertheless, niacin is a useful medication in patients with type 2 diabetes. [62]

Niacin (Slo-Niacin, Niaspan, Niacor)

Niacin, or water-soluble vitamin B-3, functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. In gram doses, niacin reduces levels of total cholesterol, VLDL, IDL, LDL, and triglycerides but increases HDL. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. Thus, although niacin may increase insulin resistance and worsen glucose control, it is useful for the dyslipidemias common in patients with diabetes. This agent should be taken at bedtime after a low-fat snack and individualized according to patient response.

The slow-release formulation is more hepatotoxic than immediate-release niacin; carefully monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels indefinitely in these patients. Patients strongly advised against switching formulations or brands during treatment. Both prescription and nonprescription formulas are available. Nonprescription brands cost less, but only reliable manufacturers should be recommended. Slo-Niacin is a nonprescription formulation that is available in 250-, 500-, and 750-mg tablets. Prescription extended-release (ER) niacin (Niaspan) is available by prescription in 500-, 750-, and 1000-mg tabs.

At high doses (4-6 g/d), the immediate-release formulation of niacin is less hepatotoxic than the sustained-release (SR) formulation, but it is also less well tolerated by patients due to prostaglandin-mediated flushing, itching, and rash. Therapy is best started at a low dose, such as 100 mg tid pc, and increased gradually (titrated) over several weeks, allowing some patients to accommodate adverse effects. Changing formulation at high doses may increase risk of hepatotoxicity.

Niacor and Nicolar are prescription formulations that, although more expensive than nonprescription brands, may have an advantage in making it less likely that the patient switches brands.

Previous
Next:

Lipid-Lowering Agents, Statins

Class Summary

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors are competitive inhibitors of 3-hydroxy-3-methyl Co-A reductase, an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, resulting in upregulation of LDL receptors in response to the decrease in intracellular cholesterol. The HMG-CoA reductase inhibitors are indicated for the secondary prevention of cardiovascular events and for the treatment of hypercholesterolemia and mixed dyslipidemia.

HMG-CoA reductase inhibitors are indicated for patients with primary and familial hypercholesterolemia, as well as combined hyperlipidemia, as an adjunct to other lipid-lowering treatments. Their main differences lie in their metabolism and therapeutic half-life and in their drug interactions.

FDA warnings

On March 1, 2012, the US Food and Drug Administration (FDA) issued updates to the prescribing information concerning interactions between protease inhibitors (such as those used to treat hepatitis C or human immunodeficiency virus infection) and certain statin drugs, notably that the combination of these agents taken together may raise the blood levels of statins and increase the risk for myopathy. [51] The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. [51]

Two days earlier, on February 28, 2012, the FDA approved important safety label changes for statins, including removal of routine monitoring of liver enzymes from drug labels. [52] Information about the potential for generally nonserious and reversible cognitive side effects and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels were added to the statin labels. In addition, the lovastatin label was extensively updated with new contraindications and dose limitations when this agent is taken with certain medicines that can increase the risk for myopathy. [52]

On June 8, 2011, the FDA recommended limiting the use of the highest approved dose of simvastatin (Zocor) (80 mg) due to the increased risk of myopathy. [53] The agency also required changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines. [53]

Atorvastatin (Lipitor)

Fluvastatin

Lovastatin (Mevacor)

Pitavastatin

Pravastatin

Rosuvastatin (Crestor)

Simvastatin (Zocor)

Vytorin

Previous