eMedicine Specialties > Endocrinology > Metabolic Disorders

Hypercholesterolemia, Polygenic: Treatment & Medication

Author: Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Coauthor(s): William L Isley, MD, Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester
Contributor Information and Disclosures

Updated: Nov 17, 2009

Treatment

Medical Care

During the 1990s, the cholesterol revolution occurred. Numerous studies documented the efficacy of low-density lipoprotein cholesterol (LDL-C) reduction in the reduction of coronary heart disease (CHD) events and, in some situations, the reduction of CHD and total mortality rates.

• Medical therapy involves lifestyle modification and pharmacologic therapy.
  • For patients with known atherosclerosis (clinical CHD, symptomatic carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm), the LDL-C goal is less than 100 mg/dL, although an LDL-C goal of less than 70 mg/dL is now considered a therapeutic option in patients considered to be at very high risk (acute coronary syndrome patients, diabetes mellitus, multiple risk factors with uncorrected risk factors such as continued smoking).
  • For patients with 2 or more risk factors, the LDL-C goal is less than 130 mg/dL, with recommendations for drug therapy that depend on the estimated 10-year risk of a CHD event based on the modified Framingham equation (see below).
  • For patients at low risk (0-1 risk factors), the LDL-C goal is less than 160 mg/dL.
  • The LDL-C goal for patients with CHD equivalent risk, including patients with diabetes mellitus, should also be less than 100 mg/dL. In patients considered to be very high risk, a goal of less than 70 mg/dL is an acceptable option
• The evaluation generally begins with a risk-factor analysis. Patients are then categorized according to CHD or CHD risk equivalent (particularly diabetes), ie, those with multiple risk factors and those at low risk (<2 risk factors). Patients with CHD or CHD equivalent risk have a greater than 20% 10-year risk for CHD events. Low-risk patients generally have a 10-year CHD risk of less than 10%. Patients with multiple risk factors may or may not be at high risk.
• The new National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend calculating a Framingham risk score in patients with multiple risk factors to quantify risk and set LDL-C goals. The Framingham score calculator is available through the NCEP and the US National Heart, Lung, and Blood Institute (see Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD).
  • Patients with CHD or CHD equivalent are prescribed drug therapy simultaneously with therapeutic lifestyle changes if their LDL-C concentration is greater than or equal to 130 mg/dL. Drug therapy is optional for patients whose LDL-C value is 100-129 mg/dL.
  • For patients with multiple risk factors, the LDL-C level at which drug treatment is recommended depends on the Framingham score. The LDL-C goal is less than 130 mg/dL. For patients with multiple risk factors and a 10-year risk of greater than 20%, the treatment is similar to that of patients with CHD. For patients with a 10-year risk of 10-20%, drug treatment is considered if their LDL-C level is greater than or equal to 130 mg/dL. For patients with multiple risk factors and a 10-year risk of less than 10%, drug therapy is considered if their LDL-C levels are greater than or equal to 160 mg/dL.
  • For patients at low risk, the LDL-C goal is less than 160 mg/dL, with therapeutic lifestyle changes for patients with higher values and drug therapy considered at LDL-C levels of greater than or equal to 190 mg/dL.
  • Therapeutic lifestyle treatment (ie, dietary changes and exercise) is recommended for patients whose LDL-C concentrations are greater than their goal LDL-C.
• The new NCEP guidelines also recommend trying to identify patients with what has been called the metabolic syndrome. Such patients in particular should be targeted for therapeutic lifestyle changes. These patients meet at least 3 of the following criteria:
  • Abdominal obesity (waist >40 in for men, >35 in for women)
  • High triglyceride level (>150 mg/dL)
  • Low high-density lipoprotein cholesterol (HDL-C) value (<40 mg/dL for men, <50 mg/dL for women)
  • High blood pressure (>130/85 mm Hg)
  • Impaired fasting glucose (IFG) value (plasma glucose level >110 mg/dL, although the lower limit now generally used in the American Diabetes Association IFG cutpoint of 100 mg/dL or greater)
• If the patient's serum triglyceride level remains greater than or equal to 200 mg/dL after the LDL-C goal is reached, a secondary non–HDL-C goal is set. The non–HDL-C goal is the LDL-C goal plus 30 mg/dL. This goal may be achieved with an increase in the statin dose, a more efficacious statin, or the addition of another agent (eg, fibrate, niacin, fish oil). Fenofibrate has less of a propensity for drug interactions; therefore, it is preferred in most situations. If fish oil is used, the correct dose is at least 2-3 g of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) daily. Because most 1-g fish oil capsules contain only approximately 300 mg of DHA and EPA, a patient must consume 10 1-g fish oil capsules daily to reach the goal. More highly concentrated fish oil capsules or liquids can be used, but the patient usually cannot find these in local pharmacies.
• Screen all patients via a fasting lipid profile every 5 years beginning at age 20 years. Patients with CHD should undergo a lipid profile determination at least yearly. Patients with multiple risk factors should have their lipid profiles determined at least every other year.
• In 3 months, recheck the lipid profiles of patients treated with therapeutic lifestyle intervention. In 6-12 weeks, recheck the lipid profiles of patients treated with drugs.
• Liver function testing is indicated periodically for patients taking statins or fibrates, although the risk for hepatotoxicity is very low. Liver function abnormalities are more common at the highest doses of each of the approved statins. Checking liver test results 6-12 weeks after an increase in the dose is reasonable, particularly in patients on high-dose statins.
• The dosage and approximate LDL-C lowering of various statins is as follows:
  • For atorvastatin at 10-80 mg/d, the LDL-C level is lowered by 39-60%.
  • For fluvastatin at 20-80 mg every bedtime or 40 mg twice daily, the LDL-C level is lowered by 22-36%.
  • For lovastatin at 20-40 mg every evening or 40 mg twice daily, the LDL-C level is lowered by 24-42%.
  • For pravastatin at 10-80 mg every bedtime, the LDL-C level is lowered by 22-34%.
  • For rosuvastatin at 5-40 mg/d, the LDL-C level is lowered by 45-63%.
  • For simvastatin at 20-80 mg every bedtime, the LDL-C level is lowered by 38-47%.¹⁰
• Statin intolerance creates a treatment dilemma for patients and practitioners in terms of selecting therapeutic options to treat hypercholesterolemia. Red yeast rice is an herbal supplement known to decrease LDL-C levels. Becker et al randomly assigned 62 patients (1:1 ratio) who discontinued statin therapy because of myalgias to receive either red yeast rice (1800 mg) or placebo twice daily for 6 months.¹¹ During the study, all patients also took part in a 12-week therapeutic lifestyle change program.
  
  LDL-C levels were significantly lower in the red yeast rice group compared with the placebo group at 12 weeks and 24 weeks (P <0.001 and P=0.011, respectively). Compared with the placebo group, the red yeast rice group also had a significant decrease in total cholesterol levels at 12 weeks and 24 weeks (P <0.001 and P=0.016, respectively). The study was small, but the results indicated that red yeast rice, along with a therapeutic lifestyle change, lowers LDL-C and total cholesterol levels. (It should be noted that red yeast rice contains a small amount of lovastatin.) Additional study is warranted to examine treatment alternatives for statin intolerance.

Diet

The NCEP has created dietary guidelines for all people older than 2 years. The reduction of saturated fat intake is vitally related to reduced low-density lipoprotein cholesterol (LDL-C) levels. In general, replacing fat with complex carbohydrates is helpful. Because carbohydrates are less calorically dense than fat, this substitution may also help prevent obesity. Adopting an appropriate diet may help patients reduce their LDL-C value by approximately 10-15%.⁶ However, in real-world studies, a 5% reduction is more likely. Reduction in trans fat intake also helps to reduce LDL-C levels and may help to raise high-density lipoprotein cholesterol (HDL-C) levels.

• NCEP dietary guidelines are as follows:
  • Total fat - Less than 30% of energy intake (calories)
  • Saturated fat - Less than 7% of energy intake
  • Polyunsaturated fat - Less than or equal to 10% of energy intake
  • Monounsaturated fat - From 10-15% of energy intake
  • Cholesterol - Less than 200 mg/dL
  • Carbohydrates - From 50-60% of energy intake
• Extreme fat and cholesterol restriction has been achieved with vegetarian diets, as demonstrated by the 1990 studies performed by Ornish and colleagues. This type of dietary restriction has resulted in a marked reduction in LDL-C levels and improvement in CHD symptoms. Whether these dietary restrictions are realistic for most Americans is debatable. Moreover, such a diet also reduces HDL-C levels and raises triglyceride levels.
• Plant sterols and plant stanol esters can be included in the diet and may reduce LDL-C values by approximately 10-15%. Commercial preparations are available as margarine substitutes (eg, Benecol, Take Control).⁷
• After years of lay promotion, small, short-term (6 mo) studies have suggested that high-fat, low-carbohydrate diets (eg, the Atkins diet) may facilitate weight loss without adversely affected serum lipid concentrations. However, the long-term effects of such diets remain to be determined.

Activity

Although exercise has little effect on low-density lipoprotein cholesterol (LDL-C) concentrations, aerobic exercise may improve insulin sensitivity, high-density lipoprotein cholesterol (HDL-C) concentrations, and triglyceride levels and, thus, may help reduce CHD risk. Patients who exercise and adhere to an appropriate diet appear to be more successful in long-term lifestyle modifications that improve their CHD risk profile.

Medication

The statin (HMG-CoA reductase inhibitor) class of drugs has revolutionized the treatment of hypercholesterolemia. Statins are highly efficacious and very well tolerated.⁵ Thus, other drugs are often not needed for low-density lipoprotein cholesterol (LDL-C) reduction.

Statins

Studies have shown the efficacy of statin drugs in reducing coronary heart disease (CHD) events, CHD death, and total mortality rates (see images below and Images 4-5). Efficacy for LDL-C lowering at approved doses of statins is listed in Medical Care under Dosage and approximate LDL-C lowering of various statins. Primary prevention implies the use of statins in an asymptomatic population, which may include some people with clinically occult disease. Secondary prevention implies the use of statins in patients with clinically apparent disease.^5,10

The West of Scotland Coronary Prevention Study (WOSCOPS) studied high-risk male subjects who had no history of CHD events (primary prevention).¹⁴ Pravastatin was administered at a dose of 40 mg/d for 4.9 years. Cardiovascular events were reduced by 31%, and the treatment caused a borderline statistically significant reduction of 31% in the total mortality rate compared with placebo.

The Cholesterol and Recurrent Events (CARE) study of subjects with CHD and cholesterol concentrations within the reference range (mean LDL-C level of 138 mg/dL) examined the effects of pravastatin at a dose of 40 mg/d. Compared with placebo, the CHD events were reduced by 24% at 5 years, with no significant change in total mortality.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) enrolled more than 6000 subjects with average LDL-C concentrations and below-average high-density lipoprotein cholesterol (HDL-C) values. Lovastatin was administered at a dose of 20-40 mg/d for approximately 5 years, resulting in a 37% reduction in first major acute coronary events compared with placebo therapy.¹⁵

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study used pravastatin at a dose of 40 mg/d for an average of 6.2 years in subjects with CHD; the CHD mortality rate decreased by 24%, and the total mortality rate decreased by 22% compared with placebo treatment.¹⁶

The Atorvastatin versus Revascularization Treatment (AVERT) study compared 80 mg atorvastatin daily with standard therapy and angioplasty in subjects with CHD. Although event rates at 18 months were the same between both groups, the time until the first CHD event was longer, with aggressive LDL-C lowering. Angioplasty alone has not been proven to prevent events, so this is not necessarily tantamount to a no-therapy comparison trial.¹⁷

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial showed borderline significant reduction in coronary events in subjects treated with atorvastatin (80 mg/d) who presented with an acute coronary syndrome, although significant abnormalities revealed via liver function test were common. The major positive finding from this study was a 61% reduction in stroke in the atorvastatin-treated group.

In the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study that compared pravastatin 40 mg/d versus placebo in subjects aged 70-82 years with a history of CHD or risk factors for CHD, active therapy reduced cardiovascular events by 15%.¹⁸

The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) assessed the effects of simvastatin (40 mg/d) versus placebo in approximately 20,000 subjects with vascular disease or at high risk for CHD with total cholesterol levels greater than 135 mg/dL, including approximately 6000 subjects with diabetes mellitus. CHD endpoints were reduced by approximately 24% and were effective in multiple subgroups, including subjects with diabetes. The mortality rate was reduced by approximately 15%.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) used 10 mg of atorvastatin versus placebo in approximately 10,000 subjects with hypertension. CHD event rates were reduced approximately 36%. However, most subgroups, including subjects with diabetes mellitus or metabolic syndrome, did not return positive results, perhaps because of the short duration (3.3 y) of the study.¹⁹

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared treatment with atorvastatin (80 mg) with treatment with pravastatin (40 mg) in subjects with CHD. After 18 months, the atorvastatin treatment group had a slight decrease in atheroma volume based on intravascular ultrasonography evaluations, and the pravastatin group had a slightly increased atheroma volume.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study also compared atorvastatin therapy (80 mg/d) with pravastatin therapy (40 mg/d) in subjects who had been hospitalized for acute coronary syndromes. The baseline LDL-C level was approximately 106 mg/dL. After a mean follow-up of 2 years, the intensively treated group had LDL-C levels of approximately 62 mg/dL, compared with approximately 95 mg/dL in the pravastatin group. Cardiovascular events were reduced by 16%.

Unfortunately, the study had a dropout rate of approximately one third. The number of patients needed to treat was 26, but the number needed to cause transaminase values to exceed 3 times the upper limit of normal was only 46 patients. In this scenario, 26 patients would have to be treated to prevent one clinical event, and 46 patients would have to be treated to see one case of transaminases >3 X ULN (and possibly end up stopping therapy). Interestingly, subjects pretreated with statins or those with baseline LDL-C levels of less than 125 mg/dL did not show a benefit from high-dose atorvastatin therapy compared with pravastatin therapy (40 mg).

The Treating to New Targets (TNT) study assessed the effect of therapy with atorvastatin 80 mg/d versus atorvastatin 10 mg/d in patients with stable CHD for a period of 4.9 years. The mean on-treatment LDL-C level was 77 mg/dL in the former group and 101 mg/dL in the latter group. The relative risk of cardiovascular events was reduced by 22%. Mortality was higher but not significantly statistically different in the high-dose atorvastatin group, although persistent transaminase elevations were 6 times higher in this group.

The statins lower LDL-C by inhibiting HMG-CoA reductase, the enzyme that regulates the rate-limiting step in cholesterol synthesis. The amount of the intermediate (ie, mevalonate) is lowered, and, subsequently, cholesterol levels are reduced in hepatic cells. This, in turn, results in up-regulation of LDL receptors and increased hepatic uptake of LDL from the circulation.

Atorvastatin (Lipitor)

Highly efficacious at high doses, resulting in as much as a 60% reduction in LDL-C. Inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism. Half-lives of atorvastatin and its active metabolites are longer than those of all other statins (ie, approximately 17 h for native drug, approximately 48 h for active metabolites, compared with 3-4 h for other drugs).
Used for primary prevention (10-mg dose) in the ASCOT trial of subjects with hypertension and at the 80-mg dose in the AVERT, MIRACL, REVERSAL, PROVE-IT, and TNT trials.

Fluvastatin (Lescol)

Least potent of statin drugs. The Lescol Intervention Prevention Study showed that in subjects with CHD monitored after a first percutaneous intervention, fluvastatin at 80 mg/d reduced CHD events compared with placebo. Synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, structurally distinct and has different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration). Fluvastatin has been shown to reduce CHD events after revascularization.

Lovastatin (Mevacor, Altocor)

First statin approved by the FDA. Has been shown to retard atherosclerosis in angiographic and carotid ultrasound trials and to reduce clinical events in primary prevention (AFCAPS/TexCAPS). Prodrug hydrolyzed in vivo to mevinolinic acid, one of several active metabolites. Once hydrolyzed, it competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, thus reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol can also be taken up by the liver from LDL by endocytosis. The diminishing de novo synthesis of cholesterol leads to increased clearance of circulating LDL. In the AFCAPS/TexCAPS study, 20-40 mg lovastatin daily reduced the incidence of CHD events in a relatively low-risk primary prevention population. Available as IR (Mevacor and generic) and SR (Altocor) dosage forms.

Pravastatin (Pravachol)

Reduces CHD events when used in primary prevention in patients with marked LDL-C elevations (WOSCOPS). Also reduces CHD events and mortality rates in patients with CHD and moderate increases in LDL-C (LIPID study). Reduces CHD events in patients with cholesterol levels within reference range and known CHD (CARE study). Reduces cardiovascular events in elderly persons (PROSPER).

Simvastatin (Zocor)

First drug shown to reduce total mortality rate by reducing LDL-C concentrations in patients with CHD with marked LDL-C elevations at baseline (4S). Markedly affects mortality rates and CHD events in patients with CHD and marked hypercholesterolemia (4S). Also reduces CHD events by >40% in similar patients with type 2 diabetes mellitus. Has also been shown to reduce CHD events in patients with a wide variety of cholesterol concentrations (>135 mg/dL) at baseline, ie, in the HPS. Adverse effects, including LFT abnormalities and myalgia, were minimal at this dose.

Rosuvastatin (Crestor)

HMG-CoA reductase inhibitor that decreases cholesterol synthesis and increases cholesterol metabolism. Reduces total cholesterol, LDL-C, and triglyceride levels and increases HDL-C level. Used adjunctively with diet and exercise to treat hypercholesterolemia. Most efficacious of the statins. May raise HDL-C at higher doses than equally effective doses of atorvastatin. Not metabolized by cytochrome P450 system. Dose of 40 mg associated with hematuria and proteinuria, which is of unknown clinical significance. No clinical outcome studies completed as yet.

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.

Cholesterol absorption inhibitors

These drugs inhibit dietary cholesterol absorption. Ezetimibe (Zetia) is the only medication in this class with FDA approval. It selectively inhibits cholesterol absorption in the intestine by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein. Alone or with a statin, ezetimibe lowers LDL-C levels by 12-19%.¹⁰ In individuals who hyperabsorb cholesterol, LDL-C reduction of as much as 40% has been documented.

Two studies have brought national media attention to ezetimibe. The first study, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial,²⁰ was undertaken to demonstrate that progression of atherosclerosis reflected by changes in carotid intima-media thickness (CIMT) would be reduced if ezetimibe was added to 80 mg of simvastatin in patients with heterozygous familial hypercholesterolemia. At the end of the 24-month study, however, no significant difference in CIMT was found between patients using ezetimibe in combination with simvastatin and those using simvastatin alone, despite greater reductions in LDL-C and C-reactive protein levels in the ezetimibe/simvastatin combination group.

Prominent investigators weighed in, stating that if ezetimibe could not improve CIMT, then it had no role in cholesterol management. It should be noted, however, that the cholesterol levels in the study subjects had been aggressively managed for many years, and they did not have increased CIMT at baseline. The study sought to show increased regression and decreased progression in subjects receiving both simvastatin and ezetimibe, compared with simvastatin alone. But regression cannot occur in subjects whose CIMT is normal, and therefore no difference in regression between the 2 treatment groups would have been possible at the end of the study. In order to demonstrate reduced progression, the CIMT in the simvastatin-only arm would have had to increase. In fact, no progression occurred in this group. Therefore, the simvastatin-ezetimibe subjects could not have benefited from decreased progression because no progression occurred in thesimvastatin-onlysubjects.

The second trial, SEAS (Simvastatin and Ezetimibe in Aortic Stenosis),²¹ was meant to demonstrate that intensive LDL-C lowering through administration of a daily dose of 40 mg of simvastatin plus 10 mg of ezetimibe would reduce the incidence of major cardiovascular events and also reduce the number of events related to aortic stenosis. As expected, cardiovascular endpoints were clinically and statistically lower in patients using the combination therapy than they were in in placebo-treated patients. However, events related to aortic stenosis were not reduced in the combination group. In addition, the investigators made an unexpected finding, that the incidence of cancer was significantly greater in the ezetimibe/simvastatin group than it was in the patients using placebo (11.1% vs 7.5% [P = 0.01]).

An expert statistician, Richard Peto, with special expertise in analyzing cancer data was invited to analyze the SEAS findings.^22,23 He was also given access to data from 2 much larger, ongoing clinical trials—SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)—with a total of 20,617 randomized patients. SHARP was designed to compare results from the use of simvastatin 20 mg plus ezetimibe to those from placebo, and IMPROVE-IT was designed to compare the results from the administration of simvastatin 40 mg plus ezetimibe to simvastatin 80 mg.

In the combined data from the SHARP and IMPROVE-IT trials, more cancer deaths and fewer cases of cancer were found in the patients assigned to ezetimibe; neither difference was statistically significant. Several features of the data suggested lack of credibility: cancer incidence and death were not prespecified endpoints in SEAS; no excess of cancers at any particular site (more that 15 different sites were involved) were observed; and longer duration of follow-up did not result in an increased trend in cancer incidence or death. The final conclusion by Peto et al was that the available data from the SHARP, IMPROVE-IT, and SEAS trials did not "provide credible evidence of any adverse effect of ezetimibe on rates of cancer." A more definitive answer will be possible when the SHARP and IMPROVE-IT trials are analyzed after a longer follow-up period.

Ezetimibe (Zetia); Ezetimibe and simvastatin (Vytorin)

First in a new class of cholesterol-lowering agents that inhibits cholesterol intestinal absorption. Approved as monotherapy or in addition to HMG-CoA reductase inhibitors. Reduces LDL-C by approximately 18-20% as monotherapy, and lowers approximately 15% more when added to statin. No clinical endpoint trials completed yet.
Combination product lowers LDL-C levels 45-60%. Effect on CHD events compared with statin alone is unknown.

Nicotinic Acid

Nicotinic acid/niacin is the most effective agent for raising HDL-C levels. It lowers triglycerides as effectively as fibrates do and is more reliable for lowering LDL-C. It is an effective add-on to statin therapy and is available in a single tablet (Advicor), in combination with simvastatin (Zocor), and as extended-release niacin (Niaspan).

Niacin has several features that make it the most difficult lipid agent to prescribe:

• Niacin at doses greater than 2 grams or in time-release formulations can cause significant hepatotoxicity. Immediate-release niacin is the least likely to cause hepatic injury, and time-release niacin is the most likely to cause it. Extended-release niacin has an intermediate risk, and if the FDA maximum approved dose for Niaspan, 2000 mg/day, is not exceeded, the risk of serious hepatic injury is minimal.
• Niacin inhibits urate metabolism and can precipitate an acute gouty attack. Patients with a history of gout whose uric acid levels have been normalized with allopurinol have minimal, if any, risk.
• Niacin may increase insulin resistance but is not contraindicated in the treatment of patients with diabetes.²⁴
• Patient tolerability limits niacin's use, the most common side effect being flushing, sometimes accompanied by pruritus and/or rash. Several techniques can lessen or, in some cases, prevent these symptoms, which are prostaglandin-mediated. Time itself will usually decrease symptoms; therefore, to enhance tachyphylaxis and, more importantly, to decrease the risk of hepatotoxicity, niacin should always be started at a low dose and gradually increased ("start low, go slow").
  
  Many patients who will be treated with niacin are already on prophylactic aspirin, 81 mg/day. Aspirin taken 30-60 minutes before niacin may lessen symptoms, but 325 mg is often necessary. Taking niacin with a small, low-fat snack slows absorption and thereby decreases symptoms. Activities that might cause vasodilation (hot food or beverages, spicy food, hot showers) should be avoided. Benadryl is sometimes effective in decreasing a severe reaction.

Niacin is used primarily to treat hypertriglyceridemia, but it also has a beneficial impact on HDL-C and LDL-C levels, and it is the only lipid medication that lowers lipoprotein (a). Niacin has been shown to retard progression of atherosclerosis and reduce CHD events when used in conjunction with a bile acid sequestrant or lovastatin.

The ARBITER 6–HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies) trial compared the effects of 2 lipid-lowering combination therapies on CIMT.²⁵ In a prospective, randomized, parallel-group, open-label study, patients received either extended-release niacin (2 g/d target dose) or ezetimibe (10 mg/d) in addition to their long-term statin therapy. All participants (n=363) had been treated with statin monotherapy at a consistent dose. Inclusion required that lipid panels were obtained within 3 months before enrollment showing an LDL cholesterol level of less than 100 mg/dL (2.6 mmol/L), as well as an HDL cholesterol level of less than 50 mg/dL (men) or 55 mg/dL (women) (1.3 or 1.4 mmol/L, respectively). The mean common CIMT change from baseline after 14 months was the study’sprimary end point.

Following a prespecified interim analysis conducted after 208 patients (mean age 65 y, 80% men) had completed the trial, the trial was terminated early on the basis of efficacy. The results are described for these 208 patients. In the niacin group, HDL cholesterol level were increased by 18.4% to 50 mg/dL (P <0.001). Niacin also significantly reduced LDL cholesterol and triglyceride levels. The ezetimibe group showed a 19.2% decrease in LDL cholesterol, 66 mg/dL (1.7 mmol/L) (P <0.001). Ezetimibe did not increase HDL cholesterol (HDL levels were actually reduced), but it did reduce triglycerides. Niacin was more effective than ezetimibe in changing mean CIMT over 14 months (P = 0.003), leading to a significant reduction of mean (P = 0.001) and maximal CIMT (P £ 0.001 for all comparisons).

This trial concluded that niacin is superior to ezetimibe for combination therapy in high-risk patients taking statin monotherapy. Two editorials stated that the early termination of and small number of patients in the study, along with the limited duration of follow-up, do not yet merit changes in cholesterol therapy guidelines, but they did support niacin as the preferred agent for statin combination therapy until the completion of clinical trials with clinical end points can be completed.^26,27

Two well-powered studies of clinical end points — AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes; NCT00120289) and HPS2-THRIVE (Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events; NCT00461630) — will, it is hoped, determine if adding niacin to statin therapy leads to a further risk reduction in patients with hypercholesterolemia.²⁷

Niacin and lovastatin (Advicor)

Niacin: Niacin functions in the body after conversion to NAD in the NAD coenzyme system. Niacin in gram doses reduces levels of total cholesterol, LDL-C, and triglycerides and increases HDL-C levels. The severity and type of underlying lipid abnormality may influence the magnitude of individual lipid and lipoprotein responses may be influenced.
Lovastatin: Competitively inhibits HMG-CoA reductase, which catalyzes rate limiting step in cholesterol synthesis.
Formulation contains lovastatin and niacin in pills of 20 mg lovastatin, with 500 mg, 750 mg, or 1000 mg of niacin (Niaspan). Not indicated for initial therapy of dyslipidemia. Combination therapy causes greater increases in HDL-C levels than statins alone.

Niacin (Niaspan, Niacor, Slo-Niacin)

Immediate release dosage form is less hepatotoxic than sustained-release (SR) form but not as well tolerated by patients because of prostaglandin-mediated flushing, itching, or rash. Immediate-release (IR) niacin started at low doses and gradually increased over several weeks allows some patients to accommodate to these adverse effects.
Higher doses (4-6 g/d) can be used more safely than SR niacin.

Niacor and Nicolar are prescription formulations of IR niacin that, while more expensive than over-the-counter brands, may make it less likely that patient will switch brands. Changing formulation of niacin while on high doses may increase risk of hepatotoxicity.

Sustained-release (SR) dosage form is more hepatotoxic than IR niacin; therefore, strongly advise against switching formulations or brands during treatment. Over-the-counter and prescription SR niacin are available. Over-the-counter brands cost less, but if using this option, recommend only reliable manufacturers.

Slo-Niacin is an over-the-counter formulation available in 250-mg, 500-mg, and 750-mg tabs. Sundown also is a manufacturer of over-the-counter SR niacin. Prescription SR niacin, Niaspan, is available in 375-mg, 500-mg, and 1000-mg tabs.

Niaspan with nocturnal dosing may be more tolerable than the other preparations. Niacin has no real utility in treating pure hypercholesterolemia because of the availability of statins. It is questionable whether adding it to statins to increase a low serum HDL-C reduces CHD risk beyond that observed with a statin alone.

Antilipemic agent, fibric acid

Older fibrates (eg, clofibrate, gemfibrozil) are used primarily for triglyceride lowering. The Helsinki Heart Study, published in 1987, showed a decrease in CHD events in patients with elevated non–HDL-C concentrations when used in primary prevention. With the advent of statins, fibrates have largely fallen out of favor when pure LDL-C lowering is needed. However, fenofibrate is more efficacious for LDL-C lowering than earlier fibrates. Ongoing studies may help determine if fenofibrate is useful in patients with mixed dyslipidemia, particularly subjects with type 2 diabetes mellitus. The Diabetes Atherosclerosis Intervention Study showed that such subjects with CHD have stabilization of angiographic findings when treated with fenofibrate compared with placebo. This trial was inadequately powered to assess an effect on CHD events. Currently, fenofibrate should probably be relegated to second-line therapy for LDL-C reduction in patients intolerant of statins.

The publication of the Veterans Affairs HDL Intervention Trial is notable. This trial consisted of male subjects with CHD, relatively low LDL-C concentrations (mean of 112 mg/dL), and low HDL-C concentrations (mean of 32 mg/dL). Coronary events were reduced 22% with gemfibrozil treatment compared with placebo treatment. This effect was thought to be due to an increase (6%) in HDL-C levels; however, the almost 30% decrease in triglyceride levels in subjects treated with gemfibrozil may also have played a role in risk reduction.

Fenofibrate (Tricor, Lofibra, generics)

Lowers LDL-C better than older fibrate drugs. Presently used primarily for triglyceride reduction and in mixed dyslipidemias. Induces lipoprotein lipase and decreases hepatic production of apolipoprotein CIII (an inhibitor of LPL) via PPAR alpha activity, which enhances plasma catabolism and clearance of triglyceride-rich particles. Fatty acid oxidation is enhanced by fenofibrate activation of acyl-CoA synthetase and other enzymes. Inhibition of acetyl-CoA carboxylase and fatty acid synthetase activity by fenofibrate further decreases synthesis of triglycerides. Result is a marked reduction in plasma triglyceride and VLDL levels and an increase in HDL-C levels. Diabetes Atherosclerosis Intervention Study associated with decreased progression of coronary atherosclerosis in subjects with type 2 diabetes mellitus.

Gemfibrozil (Lopid)

Used primarily to lower serum triglyceride levels. Statin clinical endpoint trials have largely made use for pure cholesterol lowering obsolete. The Veterans Affairs HDL Intervention Trial suggests that gemfibrozil (and probably other fibrates) may be used in patients with CHD, low LDL-C, and low HDL-C. Mechanism of action is unknown but probably similar to fenofibrate. May inhibit lipolysis and secretion of VLDL and decrease hepatic fatty acid uptake.

Bile acid sequestrants

These agents are also called resins. Bile acid sequestrants are used primarily as additional therapy in patients with familial hypercholesterolemia who experience inadequate LDL-C lowering with statins. These agents are also useful in pediatric hypercholesterolemia. Several studies show that LDL-C lowering with resins retards the progression of atherosclerosis. The Lipid Research Clinics Coronary Primary Prevention Trial showed that cholestyramine therapy could reduce the risk for CHD events.

Interference with anionic drug absorption and patient compliance are major problems with this class of drugs. Resins may be used as an adjunct in primary hypercholesterolemia. These drugs form a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Cholestyramine (Questran, Questran Light)

Flavored to improve palatability. Light version is sweetened with aspartame and is more palatable to some patients.

Colesevelam (WelChol)

New high-capacity bile acid sequestrant. Better tolerated than older agents (eg, cholestyramine and colestipol), and drug interactions are less of a problem. Can lower LDL-C levels by 15-18% as monotherapy. Useful in patients who cannot tolerate statins, have contraindications for statin therapy, or request nonsystemic therapy. Can also be used in combination with a statin for additive LDL-C lowering. Has no effect on serum triglyceride levels and a modest beneficial effect on HDL-C.

Colestipol (Colestid)

Available in tabs, powder form, and flavored and unflavored varieties. Interference with anionic drug absorption and patient compliance are major problems. Forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound LDL-C.

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