Current Pathophysiology, Classification, Diagnosis, and Treatment Options of Dyslipidemia
Peggy K. Han, PharmD, William C. Gong, PharmD, and Mark A. Gill, PharmD
Dr. Han is a Resident in Primary Care Pharmacy at the University of Southern California, School of Pharmacy. Dr. Gong is Director of Residency and Fellowship Training and Associate Professor at the University of Southern California, School of Pharmacy, and Dr. Gill is Professor of Clinical Pharmacy at the University of Southern California, School of
Pharmacy
Coronary heart disease (CHD) is one of the primary causes of morbidity and mortality in Western
countries.1 Every year, 7.2 million people die from CHD worldwide, more than from cancer or infectious causes. In the United States alone, 640,000 deaths can be attributed to
CHD.2 Three of the treatable and preventable risk factors for CHD are hypertension, dyslipidemia, and cigarette
smoking.3 In recent years, more emphasis has been focused on the management of cholesterol primarily through lifestyle modifications and drug therapy. Drug therapy offers numerous options, with each drug class attacking the disease state through its own unique pharmacologic mechanism. The HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, often referred to as the “statins,” continue to be a mainstay in the management of dyslipidemia. With six statins currently available in the United States, more emphasis should be focused on selecting the best statin for each individual patient.
Cholesterol is a lipid that serves primarily as a precursor to steroid hormones and bile acids, and as the main component of cell membranes. Sources of cholesterol needed to carry out normal life functions are manufactured by the body and ingested from exogenous dietary sources. Cholesterol levels in the blood reflect approximately 40% to 60% endogenous cholesterol, with the balance coming from dietary sources. Triglycerides, which are composed of fatty acids esterified to glycerol and used as energy substrates, are supplied by fats in the diet and through the conversion of carbohydrates by the
liver.1
Cholesterol, triglycerides, and other lipids in the body are transported through the bloodstream in spherical particles called lipoproteins. Lipoproteins can be divided
into five major categories depending on their composition (Table
1).1 The classes from largest and least dense to smallest and most dense are chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The larger, more buoyant particles primarily have a triglyceride-rich core, while the smaller, more dense particles have a cholesterol ester
core.4 LDL accounts for approximately 60% to 70% of total serum cholesterol and is the primary atherogenic class of lipoproteins. HDL constitutes approximately 20% to 30% of total serum cholesterol with VLDL comprising about 10% to
15%.5,6
Cholesterol is derived from two sources: exogenously from the systemic circulation and endogenously via intracellular synthesis
(Figure 1).7,8 The exogenous lipoprotein system is responsible for the synthesis, transportation, and catabolism of chylomicron particles and
remnants.7 Saturated, monounsaturated, and polyunsaturated fats and cholesterol esters digested and absorbed in the proximal small bowel are reformulated and packaged into chylomicrons by cells in the intestinal
endothelium.4 Thus, chylomicrons are primarily composed of fatty acids, cholesterol, and apolipoproteins that are obtained from the diet. These chylomicrons then enter the lymphatic system and travel through the body until they are broken down by the enzyme lipoprotein lipase in the capillary beds to chylomicron remnants, which are smaller, contain less fatty acids, but have retained apolipoproteins B-48 and E. These remnants are then cleared from the circulation by the LDL-related receptor protein found in the
liver.7
In addition to replenishing their cholesterol pools by taking up circulating lipoproteins from exogenous sources, cells can also synthesize their own cholesterol through the endogenous pathway. The intracellular synthesis of cholesterol involves a series of biochemical reactions starting with acetyl-CoA
(Figure 2).9 The rate-limiting enzymes involved in this process are HMG-CoA synthetase, which catalyzes the conversion of acetyl- CoA to HMG-CoA, and HMG-CoA reductase, which catalyzes the conversion of hepatic HMG-CoA to mevalonic acid, used in a later step in the biosynthesis of cholesterol. The statins, or HMG-CoA reductase inhibitors, competitively inhibit this enzyme, reducing the capacity of the cell to synthesize
cholesterol.9
Fatty acids and cholesterol produced by the body are then transported through the endogenous pathway
(Figure 1).7 Three major lipoproteins are involved in this pathway: VLDL, LDL,
HDL.7 Triglycerides can be synthesized by the liver, especially in the presence of excess carbohydrates, and later secreted into the bloodstream as VLDL. These VLDL particles contain approximately five times more triglycerides than cholesterol, and also contain apolipoproteins B-100, E, and C-II. The B and E proteins link with B-E or LDL cell surface receptors, while apolipoprotein C-II functions as a cofactor for the enzyme lipoprotein lipase. Once secreted into the bloodstream, triglyceride molecules are hydrolyzed from the VLDL particles by lipoprotein lipase, located in the capillary
beds.7 On release, these free fatty acids are used for energy production primarily by heart and skeletal muscle, or stored in fat
cells.4 Nonetheless, this process of lipolysis decreases the triglyceride content and size of the VLDL particles, preparing them for either of their two known metabolic fates: clearance via the hepatic remnant receptor, or further release of triglycerides resulting in the formation of IDL
particles.7
IDL particles are high in triglyceride content, and contain almost all of the cholesterol initially contained in the VLDL particles. Lipolysis continues through the actions of lipoprotein lipase and hepatic lipase, leading to much smaller, cholesterol-rich LDL particles. By this time, apolipoproteins E and C have been removed, leaving only apolipoprotein B-100 on the LDL particles. IDL particles are intermediate products between VLDL and LDL particles and therefore have a short life span. Their cholesterol and triglyceride contents do not significantly impact cholesterol
measurements.7 Except for rare dyslipidemias, less than 5% of cholesterol circulates in IDL
particles.4 Half of these IDL particles are cleared from the circulation by the LDL receptor while the other half is converted to LDL
particles.7
LDL is the primary atherogenic lipoprotein, and the smaller the size of the LDL particle, the more it is able to penetrate into subendothelial tissue, where it contributes to the development of
atherosclerosis.7 Excessive circulating LDL cholesterol will cause cholesterol deposition outside of the cell, causing atherogenic plaque formation in the vascular endothelium, potentially leading to coronary artery disease
(CAD).5,6 Two specific types of LDL particles have recently been identified to be highly associated with CHD risk. The first, a lipoprotein(a) [Lp(a)] particle, is a very small LDL particle surrounded by a plasminogen-like protein. The other subclass of small, dense LDL particles is referred to as atherogenic lipoprotein phenotype B. This subclass is found in approximately 30% of the population and is associated with a high risk of
CHD.7
The third major lipoprotein involved in the endogenous pathway is HDL. Similar to LDL particles, HDL particles are rich in cholesterol and very small. However, HDL particles appear to be involved in reverse cholesterol transport, resulting in an antiatherogenic effect. Specifically, HDL may prevent or remove cholesterol deposits within the arterial wall. Other possible explanations for the beneficial role of HDL cholesterol include the following: (1) prevents LDL oxidation by working as an antioxidant; (2) reduces platelet aggregability by increasing prostacyclin production; (3) stabilizes serum prostacyclin and promotes fibrinolysis; (4) competitively inhibits the uptake of LDL by endothelial cells; (5) prevents LDL aggregation and uptake by macrophages; (6) decreases cholesterol and foam cell formation; and (7) inhibits platelet activation by LDL through the phosphatidylinositol cycle. An important function of HDL is that it can serve as a marker for abnormal metabolism of chylomicrons and VLDL particles, because as triglycerides increase, HDL
decreases.7
Two key enzymes are involved in the transport of cholesterol from the periphery to the liver, where it can be eliminated by HDL particles. Lecithin-cholesterol acyltransferase is responsible for converting the cholesterol in HDL particles into insoluble cholesterol esters, causing them to partition in the core of these lipoproteins. The other enzyme, cholesterol ester transfer protein, is involved in the transfer of cholesterol esters from HDL particles to triglyceride-rich particles in exchange for triglyceride molecules. Once in VLDL and IDL particles, cholesterol is transported to the liver for elimination
(Figure 1).7
All three lipoproteins are highly involved in the transport of triglycerides and cholesterol from the liver to the body where they may be used by cells, and from the body to the liver where they may be eliminated. If the amount of cholesterol is insufficient to meet the requirements of any cell, the cell will up-regulate its synthesis of the LDL receptor. The newly formed LDL receptor will migrate to an area on the surface of the cell called the coated pits. Once in the coated pits, the cell is capable of recognizing circulating lipoproteins that contain either apolipoprotein E or B (VLDL, IDL, and LDL particles). Both the VLDL and IDL particles contain both B and E proteins and therefore may have a higher binding affinity for the LDL receptor than the LDL particles. Once binding occurs, the lipoproteins are internalized by the cell, taken up by liposomes, and broken down into elemental substances to be used by the cell. The LDL receptor protein returns to the cell surface where it can bind with another circulating lipoprotein, repeating the process
again.7
The processes by which lipids and lipoproteins participate in atherosclerotic plaque formation and CHD events continue to be an area of controversy and research. One of the initiating events of atherosclerotic plaque formation appears to be the entrance of lipoproteins LDL and Lp(a) into the subendothelial space with their oxidatively modified free radicals produced by smooth muscle cells, activated macrophages, and endothelial cells. These oxidatively modified lipoproteins enter macrophages through a scavenger receptor pathway, ultimately yielding lipid-rich foam cells. Circulating monocytes are also attracted to smooth muscle and endothelial cells by chemoattractant that is augmented by the oxidatively modified
lipoproteins.7
As the macrophage scavenger receptor continues to uptake oxidatively modified lipoproteins, foam cells continue to form and progress to the next level of atherogenesis, which is the formation of the fatty streak. At the same time, smooth muscle cells migrate into the subendothelial space and begin proliferating within the intima, contributing to the overall atherogenic process. As the process continues, lesions continue to grow by increased smooth muscle cell proliferation and collagen synthesis. At this point, necrosis of the foam cell and formation of an extracellular lipid core occurs, as long as plasma LDL levels are elevated. The final phase appears to involve an autoimmune inflammatory response that causes T lymphocyte infiltration of the adventitia (the outermost connective tissue covering of a vessel). This inflammatory response appears to complete the process of plaque formation that is the underlying culprit in
CHD.7
Dyslipidemia can be the result of a genetic predisposition, secondary causes, or a combination of
both.1 Cholesterol and triglycerides can produce three forms of dyslipidemia: hypercholesterolemia, hypertriglyceridemia, and a combination of both. In each case, the dyslipidemia is the result of an elevation in either the number or composition of specific lipoproteins, which is an important determinant when selecting the appropriate drug therapy
(Table
2 9,10 and Figures 37 and
41,7).
Hypercholesterolemia is associated with an increased concentration of one or more of the cholesterol-carrying lipoproteins (LDL, VLDL, HDL), which may occur because of a higher concentration of cholesterol in each particle, an increased number of particles, or a combination of both. Both VLDL and LDL particles contain one apolipoprotein B-100 molecule and, therefore, an elevation of the apolipoprotein B concentration reflects an increased number of cholesterol-containing particles, which is associated with hypercholesterolemia. Conversely, the cholesterol content of chylomicron particles is minimal; therefore, an elevation in chylomicron concentrations rarely causes hypercholesterolemia. Under normal situations, approximately 70% to 80% of total cholesterol can be found in LDL particles. The most common cause of hypercholesterolemia is an elevation in LDL cholesterol. Yet, total cholesterol is the arithmetic sum of the cholesterol found in LDL, HDL, and VLDL particles. Therefore, any one or a combination of these particles may be
responsible for the elevation. For example, hypercholesterolemia can occur because of a high HDL cholesterol although LDL and VLDL concentrations are within acceptable
concentrations.7
One of the most studied forms of dyslipidemia is familial hypercholesterolemia. These patients have a defective gene from one or both parents for the B-E/LDL receptor, significantly reducing their ability to clear LDL from the blood. Homozygous familial hypercholesterolemia can result in four to six times the normal concentrations of cholesterol and significant atherosclerotic disease, detected during the teenage years. Heterozygous familial hypercholesterolemia can cause two to four times the normal concentrations of cholesterol with premature atherosclerotic
disease.7,9
Polygenic hypercholesterolemia represents the largest group with approximately 36% of Americans diagnosed with this form of elevated cholesterol. These patients tend to have a number of defects, mostly related to nutritional and genetic factors, resulting in a less active B-E/LDL receptor. Cholesterol levels in these patients are approximately twice the normal
levels.9
Hypertriglyceridemia occurs in patients with high concentrations of VLDL or chylomicron particles. Most cases are mild and are primarily caused by increased VLDL secretion by the liver in patients who consume an excessive amount of calories or alcohol (diet-induced hypertriglyceridemia). VLDL secretion can also increase secondary to diabetes, obesity, or other medical problems (secondary hypertriglyceridemia). Primary hypertriglyceridemia occurs because of an overproduction of triglycerides and VLDL particles and is often associated with other medical conditions including diabetes and obesity. Hypertriglyceridemia is not usually an isolated condition. It tends to be associated with patients who have low concentrations of HDL cholesterol and elevated levels of LDL particles, posing the risk for
atherogenesis.9 Mixed hyperlipidemias are the most common forms of dyslipidemia where patients may have elevations in both triglyceride and cholesterol
levels.7,9
Familial combined hyperlipidemia occurs in approximately 1 of every 100 in the population where patients overproduce VLDL particles because of an increased production of apolipoprotein B. This increased production of VLDL particles can result in an elevated triglyceride level (since VLDL particles contain mostly triglycerides), an elevated cholesterol level (since VLDL particles may be converted to LDL particles, which are not cleared rapidly from the system and accumulate), or both an elevated triglyceride and cholesterol level (since the VLDL concentration is high enough that the content of both is
high).7,9 The features of familial combined hyperlipidemia may present differently in members of the same family and may even change in a given individual. In general, however, elevated apolipoprotein B concentrations and the presence of hypercholesterolemia or hypertriglyceridemia can be found in family members with
CAD.7
There may be a familial basis for the mixed hyperlipidemia, which may result from a deficiency of the lipoprotein lipase enzyme. This deficiency leads to a reduced ability to delipidize the triglyceride molecules from the VLDL and chylomicron particles. Depending on the situation, triglyceride levels can increase moderately or severely, placing the patient at risk for developing pancreatitis. Therefore, the goal of therapy for these patients is to reduce triglyceride concentrations to prevent
pancreatitis.9
Guidelines for the identification and treatment of patients with high blood cholesterol have been provided by the Adult Treatment Panel of the U.S. National Cholesterol Education Program (NCEP ATP II)
(Table 3).1 These guidelines provide the framework for most treatment decisions and are fundamental when devising a treatment regimen
(Figure 1 and Figure 2).1,3,7
Primary prevention refers to the prevention of CHD in individuals who are clinically free of CAD. For these patients, a total cholesterol level of 200 mg/dL or less is desirable, 200 to 239 mg/dL is borderline to high, and 240 mg/dL or above is considered high. Because of the possibility of having a low HDL cholesterol (<35 mg/dL) with any of these total cholesterol concentrations, it is important to measure HDL concentrations, especially since low HDL is a favorable CAD risk factor
(Table 4).7 The NCEP recommends that all individuals older than 19 years of age should have nonfasting total and HDL cholesterol concentrations measured at least every 5 years.
Patient education regarding lifestyle modification (diet, physical activity, and other risk-reducing activities) should be provided to patients to reduce risks for future CAD events by maintaining desirable total blood cholesterol and HDL cholesterol concentrations. Total and HDL cholesterol should be rechecked in 5 years. Individuals with low HDL cholesterol should undergo a fasting (9 to 12 hours) lipoprotein analysis, which measures total cholesterol, triglyceride, and HDL concentrations. If triglyceride levels are 400
mg/dL or less, the LDL concentration is calculated using the following equation:
LDL cholesterol = (total cholesterol – HDL cholesterol)
– (triglyceride/5)
However, the above equation loses accuracy as triglycerides increase above 200 mg/dL, and at levels greater than 400 mg/dL, the above calculation will yield a falsely low LDL cholesterol concentration. Although more costly, a direct LDL cholesterol measurement may be useful in the initial assessment of CHD patients whose fasting triglycerides are greater than 400 mg/dL, in patients with diabetes, and in persons with known vascular disease with triglycerides greater than 250 to 300
mg/dL.4
Persons with borderline to high total cholesterol (200 to 239 mg/dL), good HDL cholesterol levels, and fewer than two other CHD risk factors should be educated in lifestyle modifications and have their total and HDL cholesterol reevaluated in 1 to 2 years. Patients with borderline to high total cholesterol with low HDL cholesterol, or two or more risk factors, should undergo a fasting lipoprotein analysis. Those with a total cholesterol concentration of 240 mg/dL or higher are classified as high-risk for a future CHD event and should have a fasting lipoprotein analysis regardless of their HDL level.
Patients can be further stratified based on LDL concentrations (Table
5).3 Persons with desirable LDL cholesterol concentrations (<130 mg/dL) do not require further evaluation. Education and counseling on lifestyle modification designed for the general population can be provided, and reevaluation should take place in 5 years. Individuals with borderline to high risk levels (130 to 159 mg/dL) with fewer than two other CHD risk factors should be educated on appropriate lifestyle
modifications and reevaluated in 1 year. High-risk individuals with levels of 160 mg/dL or higher and two or more risk factors should be evaluated medically and initiated on an active cholesterol-lowering diet.
All patients should be assigned to a category based on the average of two LDL cholesterol readings. In addition, patients should always be evaluated for secondary causes of hypercholesterolemia, including hypothyroidism, nephrotic syndrome, diabetes mellitus, and various genetic forms of dyslipidemia. Pharmacists, with their expertise in medication, should focus on identifying potential drug therapies that may alter the lipid profile
(Table 6).7 The evaluation should also include any physical evidence of atherosclerotic disease and laboratory evaluations for renal, hepatic, and thyroid function, diabetes, as well as a urinalysis to identify
proteinuria.
As mentioned earlier, a patient with no known CHD or other atherosclerotic disease, and an LDL cholesterol of 160 mg/dL or above, with fewer than two CHD risk factors, or with a concentration of 130 mg/dL or higher and two or more CHD risk factors should begin lifestyle modifications with the goal of lowering their LDL cholesterol below the cutoff points. If, after an appropriate trial of lifestyle modifications of approximately 6 months, the LDL cholesterol remains elevated at 190 mg/dL or higher in patients with less than two CHD risk factors, or 160 mg/dL or higher in patients with two or more CHD risk factors, drug therapy should be considered. In healthy adult men younger than 35 years and premenopausal women, the critical LDL level for initiating drug therapy is 220 mg/dL or
higher.7
Secondary prevention refers to individuals who have evidence of CHD or other clinical atherosclerotic diseases. Like primary prevention, classification is based on LDL cholesterol levels. For patients with known atherosclerosis, an optimum LDL concentration is 100 mg/dL. If a patient with CHD has an optimum LDL concentration, lifestyle modification should be encouraged and a lipoprotein panel repeated every year. If the LDL cholesterol is above 100 mg/dL, the appropriate medical evaluation should be carried out and cholesterol-lowering therapy should be initiated.
In persons with known CHD, the goal is to reduce LDL to 100 mg/dL or below, which will slow the progression and perhaps cause regression of atherosclerotic lesions. If the LDL level is 100 mg/dL or above, maximum dietary therapy in addition to other lifestyle modifications should be initiated. If the level does not exceed 130 mg/dL, lifestyle modification alone can be continued. However, if the LDL is 130 mg/dL or greater, drug therapy should be added to lifestyle modifications to achieve target
goals.7
Nonpharmacologic Treatment
Lifestyle modifications should always be part of the treatment regimen for patients with dyslipidemia, regardless of pharmacologic intervention. The patient’s lifestyle should be thoroughly assessed, with simple methods of reducing cholesterol levels and risk of CHD as the main focus. Initial treatment should always include smoking cessation and control of other disease states, such as diabetes, obesity, and hypertension when
appropriate.1 Smoking and obesity are major causes of low HDL cholesterol levels. Likewise, decreased alcohol use is beneficial in most patients with hypertriglyceridemia and should be incorporated into their lifestyle
modifications.10
The Oslo Study Diet and Antismoking Trial evaluated the effect of lifestyle intervention on lipid levels and
CHD.11 A total of 1,232 healthy men at high risk for developing CHD as a result of hypercholesterolemia were enrolled and randomized to either a control group of no counseling intervention, or counseling on dietary habits and smoking cessation. During the 5 years of the study, total cholesterol levels in the intervention group decreased 13% from pretrial values compared with only 3% in the control group. In addition, after 102 months of follow-up, the intervention group had a significantly lower incidence of total coronary events, 25 versus 45 in the control group.
The two most commonly adopted lifestyle modifications involve diet and physical activity. Efforts to minimize the dietary intake of total fat, saturated fat, and cholesterol continue to be the cornerstone of treatment for dyslipidemias. Of the three fats mentioned, a reduction in saturated fat intake will most likely have the greatest effect on blood cholesterol concentrations, whereas reduction in total fat should lead to a reduction in total caloric intake, resulting in weight loss. It is suggested that only 30% of total daily calories should come from fats. Dietary cholesterol intake has a lesser effect on total and LDL cholesterol serum concentrations. For example, for every 600 mg of dietary cholesterol, cholesterol concentrations will only rise about 10 to 20
mg/dL.7
Initiation of drug therapy should be considered after 6 months of lifestyle modification. Although drug therapy is started, lifestyle modifications should be continued to enhance pharmacotherapy. In patients with severe dyslipidemia where the clinician does not feel that lipid levels will be normalized through diet alone, pharmacologic treatment may be initiated sooner. Clinical assessments of patients must be individualized even if it means deviating from the standard guidelines set by the
NCEP.10
After an adequate trial of nondrug interventions, initiation of pharmacotherapy will depend on
various factors, such as the type of dyslipidemia, efficacy of the drug, adverse-effect profile, patient compliance, and, ultimately, the cost of treatment. In general, the dose of any drug should be increased until the goal is reached, the maximum dose is reached, or the patient cannot tolerate the adverse effects. If the goal is not achieved after an adequate trial with one agent, a more effective agent from the same or a different category should be considered, or a different class of drug may be
added.1
There are four main classes of lipid-lowering drugs: the bile-acid sequestrants/resins, niacin/nicotinic acid, fibric-acid derivatives/fibrates, and the HMG-CoA reductase inhibitors (statins). These agents can be categorized by their site and mechanisms of action: agents that decrease triglycerides and LDL by reducing the hepatic synthesis of VLDL (niacin, atorvastatin, and high-dose simvastatin), agents that enhance VLDL triglyceride clearance (gemfibrozil and clofibrate), and agents that reduce hepatocellular cholesterol and enhance LDL receptor activity, increasing LDL clearance (statins and bile-acid sequestrants)
(Table
71,12).4
Cholestyramine (Questran) and colestipol (Colestid) are bile-acid–binding resins indicated for the treatment of hypercholesterolemia. These agents exchange an anion, usually sodium, for bile acids in the intestinal tract, forming a nonabsorbable complex. This interrupts the recycling of bile acids through the enterohepatic circulation, stimulating hepatic cells to convert more of the cholesterol pool into bile acids. Up-regulation of the B-E/LDL receptor occurs, enhancing the uptake of circulating lipoproteins by hepatic cells, thereby reducing the concentration of cholesterol.
Bile-acid sequestrants primarily affect LDL particles, causing an average 15% to 27% reduction in total and LDL cholesterol at high doses, and 10% to 23% reduction with 1 to 3 packets or scoops per day. The decrease in LDL appears to reduce the cholesterol content and the size of the LDL
particles.4 A 7- to 10-year, double-blind, randomized trial compared the effects of diet plus cholestyramine with diet plus placebo in 3,806 men without known CHD but an elevated cholesterol level of at least 265 mg/dL. The occurrence of nonfatal myocardial infarction or death from CHD was 8.6% in the placebo group as opposed to 7% in the cholestyramine group, a statistically significant
difference.13 Unfortunately however, resin therapy tends to raise triglyceride concentrations about 7% in the short term, and 2% to 3% after prolonged
therapy.7 Thus, they should be avoided in patients with mixed lipid
disorders.4
Cholestyramine and colestipol should be initiated with 1 to 2 doses (packets or scoops) per day, taken anytime without regard to meals. For additional reductions in cholesterol, 4 to 6 packets or scoops may be taken daily. However, most patients cannot tolerate a full therapeutic dose and usually achieve a significant reduction in cholesterol with 2 to 4 packs per
day.7 Compliance with the resins is usually less than 50% because of inconvenience and gastrointestinal
distress.4 Doses can be taken all at once for convenience, but divided doses are recommended to reduce gastrointestinal effects caused by increased bulk. The most common adverse effects involve the gastrointestinal tract and include abdominal pain, belching, bloating, gas, constipation, nausea, and heartburn. These side effects can be reduced by slowly titrating dosages so that the patient can accommodate to each dosage, or have the patient increase the intake of soluble fiber either with dietary changes or supplemental
compounds.7
The bile-acid sequestrants have the advantage of low toxicity, no systemic drug-drug interactions, and complementary effects on lipoprotein metabolism when added to other hypolipidemic agents. One should always remember to separate the time of resin administration from that of other drugs by approximately 2 hours because of the potential for the other drug to adsorb onto the
resin.7
Niacin (Niacor, Nicolar, niacin tablets) is an essential B vitamin that has lipid-regulating effects when administered at higher doses. The major mechanism of action appears to be the decreased release of VLDL, which in turn leads to decreased levels of IDL and LDL in the endogenous
cascade.10 In addition, niacin appears to reduce cholesterol concentrations through several mechanisms that include: reducing the hepatic synthesis of apolipoprotein B-containing particles, decreasing free fatty acid concentrations by inhibiting adipose tissue lipolysis, decreasing the synthesis of Lp(a), and decreasing the metabolism of HDL
particles.7 Niacin has the advantage of increasing HDL cholesterol more than any other
agent.14 Niacin is approved for the treatment of hypertriglyceridemia, hypercholesterolemia, and mixed
hyperlipidemias.1
To effectively lower lipid levels, niacin should be administered at dosages of 1.5 to 6 grams/day. Niacin reduces both the size and quantity of VLDL particles produced by the liver, causing the concentration of triglycerides to fall by approximately 20% to 50%. In addition, niacin can decrease LDL cholesterol by 10% to 25%, and increase HDL cholesterol by 15% to 35%. In the Coronary Drug Project Research Group, a placebo-controlled trial conducted in men with previous myocardial infarction, total mortality in the niacin group was significantly reduced by 11% at 15-year follow-up, which included almost 9 years after discontinuation of the study
drug.15,16 Although it offers many benefits, the majority of patients receiving niacin experience one or more side effects, which include flushing, tingling, itching, rash, and headaches, which are thought to be produced by prostaglandin-mediated vasodilation. To lessen these side effects, the dosage should be titrated slowly. Patients are also advised to take niacin with food or with a dose of 325 mg of aspirin 30 minutes before taking the niacin to reduce the prostaglandin-mediated vasodilation. Other significant adverse effects that can occur from niacin therapy include dyspepsia, diarrhea, flatulence, and elevations in blood glucose and uric acid
concentrations.7
Niacin has also been available in a sustained-release formulation to reduce the dosing frequency. Sustained-release niacin has been associated with hepatotoxicity, but it appears to be associated almost exclusively with the older sustained-release
formulations.17 This hepatotoxicity appears to be dose-related, most often occurs at daily doses greater than 2 grams, and is completely reversible once the drug is
discontinued.7,18,19 Several cases of fulminant hepatic failure have been reported in patients taking high-dose time-release niacin (>2
grams/day).20,21 A recent randomized, double-blind, placebo-controlled trial of 223 hypercholesterolemic patients comparing the newer Niaspan versus plain niacin at a dose of 1.5 grams/day demonstrated no clinically significant hepatic
dysfunction.22,23 In addition, adverse reactions, including general malaise, anorexia, and jaundice, have been reported after an abrupt change from the immediate- to sustained-release formulation. The dosages of the sustained-release formulation that caused these adverse effects were well above the usual recommended daily dose of 0.25 to 1 gram. There is approximately a threefold to sixfold difference in the upper limits of the recommended dosages of the sustained-release formulation (1 gram/day) as opposed to the immediate-release formulation (3 to 6 grams/day), which may be attributable to the differences in metabolic handling of the two formulations. As mentioned previously, niacin can cause blood glucose levels to rise, and is known to increase uric acid concentrations with the potential of precipitating gout. In a recent double-blind, placebo-controlled trial of 223 patients with hypercholesterolemia, plain niacin increased fasting plasma glucose levels 4.8%, while Niaspan increased levels by 4.5%. However, uric acid levels increased less, 6% with Niaspan versus 16% with plain niacin, a statistically significant
difference.22 Although the results of this study show that Niaspan may be safer for patients with other comorbid conditions, further studies are needed to evaluate if Niaspan offers any significant benefit over plain niacin for patients with diabetes or gout.
Niacin should be initiated at a dose of 100 mg twice daily for 1 week. If this is tolerated, the dose is increased to 200 mg twice daily for the following week. If the patient continues to tolerate the niacin, the dose is increased to 300 to 400 mg twice daily for 6 weeks. At this time, the patient should undergo a lipid profile and liver function tests prior to a clinic visit. If the patient continues to tolerate the niacin, and the lipid panel shows a positive response, the dosage is changed to 500 mg twice daily and the patient is reevaluated in 6 to 7
weeks.7
Currently, three fibrates are approved for use in the United States: clofibrate (Atromid-S), gemfibrozil (Lopid), and fenofibrate (Tricor). Fibrates primarily lower triglycerides by increasing the activity of lipoprotein lipase, which is responsible for the hydrolysis of triglycerides from VLDL to LDL particles. If the concentration of triglyceride-rich VLDL particles is elevated, rapid conversion to smaller IDL and LDL particles by lipoprotein lipase may overwhelm the system and cause an increase in LDL cholesterol. However, in individuals with normal to modestly elevated triglycerides, fibrates may produce a modest reduction in LDL cholesterol. In addition, fibric-acid derivatives offer the benefit of increasing HDL
cholesterol.7 In the Helsinki Heart Study, a 5-year, double-blind, placebo-controlled trial, 4,081 asymptomatic men with hypercholesterolemia were randomly assigned to receive gemfibrozil 600 mg twice daily or placebo. A 10% decrease in total cholesterol, 11% decrease in LDL cholesterol, and an 11% increase in HDL cholesterol occurred in patients treated with gemfibrozil, and was associated with a significant decrease in cardiac events after 5 years of
treatment.24
Clofibrate is rarely used because of a study reporting an increased mortality with clofibrate
use.25 Gemfibrozil, however, is prescribed at a usual dose of 600 mg twice daily. Fenofibrate (Tricor) is the most recent FDA-approved fibric- acid derivative, offering 67 mg of micronized fenofibrate in each oral capsule. This newly micronized formulation should be initiated at a dose of 67 mg/day, taken once daily with a meal, and increased gradually to a maximum dose of 3 capsules/day (201 mg) when necessary after repeat serum triglyceride estimations at 4 to 8
weeks.26,27 Although more direct comparisons are needed, fenofibrate may decrease LDL cholesterol more than gemfibrozil. Unfortunately, there are no data available on the effects of fenofibrate on
CHD.27
Side effects of the fibrates include myalgias, elevated liver function tests, gastrointestinal discomfort, and rashes. The most severe side effect is the ability of the fibrates to increase cholesterol in the bile, which can lead to an increase in gallstone
formation.7
The statins, or HMG-CoA reductase inhibitors, have taken a major role in the management of dyslipidemia, especially in the treatment of elevated LDL cholesterol. More specifically, this family of agents is considered first line for the treatment of hypercholesterolemia in patients who have failed to adequately respond to dietary
therapy.28 There are currently six FDA-approved HMG-CoA reductase inhibitors marketed in the United States. They all work by inhibiting HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the rate-limiting step in the biosynthesis of cholesterol. After administration, the HMG-CoA reductase inhibitors concentrate in the liver, the major site of cholesterol synthesis. All of the available HMG-CoA reductase inhibitors have the ability to decrease LDL and triglyceride levels, while increasing HDL cholesterol. Their main differences lie in their pharmacokinetic profiles, the amount of lipoprotein alterations, and cost. The statins are well tolerated, and there does not appear to be major differences in toxicity or adverse-effect profiles.
The HMG-CoA reductase inhibitors are currently used as adjuncts to diet therapy and in combination with other lipid-altering agents. They are also important in the treatment of dyslipidemia in patients with other comorbid conditions, such as diabetes. Experts have defined the ideal HMG-CoA reductase inhibitor as one that is well absorbed, reaches the liver unchanged, undergoes complete hepatic transformation, and is excreted via the hepatobiliary system. In addition, their once-daily dosing intervals, high efficacy, and tolerability with a low potential for drug interactions are other important
criteria.2 Of the six statins currently available, slight differences among them help determine the selection of the most appropriate statin for each patient.
The statins that are FDA-approved in the United States for the treatment of dyslipidemia are atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). Lovastatin is a natural product derived from the fungi Aspergillus terreus. Simvastatin and pravastatin are produced by chemical modification of lovastatin. These three compounds share a hydronaphthalene ring that interacts with the coenzyme A recognition site of HMG-CoA reductase. In addition, they have a hydroxy acid side chain that mimics
mevalonate.29 Fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor, is a mevalonolactone derivative of a fluorophenyl-substituted indole ring. In this case, the fluorophenyl indole moiety mimics coenzyme A in the interaction with HMG-CoA reductase, with the side chain mimicking
mevalonate.29 Atorvastatin and cerivastatin represent the new generation of highly purified, synthetic
statins.2 Of the six statins, lovastatin and simvastatin are provided as prodrugs, requiring hydrolysis to the corresponding beta-hydroxy acids for activity. Pravastatin, fluvastatin, and the new-generation atorvastatin and cerivastatin are all provided in their active
forms.29
The HMG-CoA reductase inhibitors are oral agents that competitively inhibit HMG-CoA reductase, the catalytic enzyme in the conversion of HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis
(Figure 2).9 This inhibition leads to the up-regulation of LDL receptors in the liver, enhancing LDL clearance from the
plasma.30 In addition, these agents may also reduce LDL production by decreasing the hepatic production of VLDL, and increasing the catabolism of VLDL remnants in the
plasma.31
In addition to their inhibitory mechanism in the biosynthesis of cholesterol, numerous clinical trials have demonstrated possible mechanisms for their beneficial effects on coronary events that involve endothelial function, plaque stabilization, and thrombogenicity. Under normal circumstances, the endothelium regulates vasomotor tone, thrombosis, fibrinolysis, inhibition of platelet activity, and inflammatory cell responses, all mediated through endothelium-derived relaxing factor. However, this regulatory process is impaired in patients with CHD. Various clinical trials that tested the effects of lovastatin, pravastatin, and simvastatin have indicated that a reduction of cholesterol with the statins improves this impaired endothelial
function.32-35
Furthermore, by improving this endothelial dysfunction, lovastatin was found to reduce myocardial ischemia in patients conducting their activities of daily
living.36
Similarly, the effects of the statins on plaque stabilization are currently being studied. The majority of coronary events are caused by coronary thrombosis, resulting from the breakage of an atherosclerotic plaque, which ultimately triggers platelet aggregation and thrombus formation. These vulnerable atherosclerotic plaques are characterized by a fibrous cap, made up of a lipid-rich core containing extracellular lipids and inflammatory cells that include macrophage foam cells. These cholesterol-laden foam cells increase density within the plaques and secrete proteinases that can weaken the fibrous cap, causing it to rupture and activate the coagulation cascade, leading to occlusion of the
vessels.37 It is postulated that statins can prevent this weakening of the fibrous cap by reducing the plaque’s rich lipid and inflammatory cell
content.38-40 In addition, HDL cholesterol, which is increased by the statins, has been implicated in enhancing this process by transporting cholesterol from lipid-rich lesions to the liver for
disposal.37,41
Finally, patients with CHD have hypersensitive platelets, increasing their risk of coronary thrombosis. Studies with pravastatin suggest that cholesterol reduction can decrease platelet aggregation caused by hypersensitive
platelets.42,43 Additional evidence indicates that pravastatin and simvastatin decrease thrombus generation. Further research is necessary to confirm this antithrombotic property in other
statins.44,45
The pharmacokinetic parameters of the HMG-CoA reductase inhibitors are shown in
Table 8.46-53 Overall, the pharmacokinetic profiles of the six statins are similar. However, there are a few differences among them that may influence the selection of one statin over the other for a particular patient.
Absorption. All six of the statins are absorbed rapidly following oral administration, achieving peak concentrations within 2 to 4
hours.46,54,55 Once absorbed, all of these drugs undergo extensive first-pass hepatic extraction, targeting them to the liver, their primary site of
action.29 This extensive first-pass metabolism can limit the absolute bioavailability of the parent drug, which is especially lower for lovastatin, simvastatin, and atorvastatin. As stated previously, lovastatin and simvastatin are provided as prodrugs, and therefore require activation to their active forms. However, the high degree of hepatic extraction may protect peripheral tissues from the adverse effects of these drugs by targeting most of the dose to the desired site of action, the
liver.29
Food taken concurrently
with drug administration may alter systemic bioavailability by altering either intestinal absorption or hepatic extraction. Lovastatin absorption is enhanced by food and can cause up to a 50% increase in systemic
bioavailability.29 On the other hand, fluvastatin and pravastatin have decreased bioavailability when taken with
meals.56-59 Both simvastatin and cerivastatin are not affected by
food.46,49,60 The manufacturer reports that food decreases the rate and extent of absorption of atorvastatin, but plasma concentrations do not correlate with the amount of drug that reaches the liver, and, therefore, it can be administered with or without
food.47,61
In general, the statins should be dosed in the evening because hepatic HMG-CoA reductase activity follows a circadian rhythm pattern and is higher in the evening than the
morning.62 In a recent open, randomized, crossover study of 31 healthy male volunteers, a single oral dose of cerivastatin 0.2 mg was given either in the morning or in the evening. After 4 weeks, the study reported that cerivastatin area under the curve values were significantly higher when taken in the evening instead of the
morning.63
Distribution. All the statins are highly concentrated in the liver. In addition, lovastatin, simvastatin, fluvastatin, atorvastatin, and cerivastatin are all >90% protein bound, primarily to plasma
proteins.46-50 This high level of protein binding may help protect peripheral tissues from the undesired adverse effects of these
drugs.29 Pravastatin is only 55% to 60% bound to plasma proteins but this is not considered significant and is unlikely to result in drug interactions caused by displacement of other drugs from
plasma.51,52 The newest statin, cerivastatin, is >99% protein bound, allowing only moderate penetration to peripheral
tissues.46
Although the statins are all highly protein bound, this effect appears to influence the volume of distribution the most for atorvastatin. The mean volume of distribution for atorvastatin is 565 L, which is significantly greater than the other statins. The unique hydroxy acid structure of atorvastatin limits distribution primarily to the liver, spleen, and adrenal glands, which may explain such a large volume of
distribution.47,64
Clearance. The mean plasma elimination half-lives for most of the statins range from approximately 1 to 3 hours. Atorvastatin has a much longer elimination half-life of approximately 14 hours, which has been proposed to be correlated with prolonged HMG-CoA reductase inhibition in
humans.65
Most of the statins are cleared nonrenally, and primarily hepatically. However, pravastatin appears to be cleared both renally and hepatically, almost at equal levels. Therefore, pravastatin may be beneficial in patients with hepatic disease because the drug can still be cleared
renally.66 Hepatic metabolism of the statins can result in active metabolites, which can contribute to the lipid-lowering effects of the drugs. All of the statins undergo hepatic metabolism, yielding active metabolites except for
fluvastatin.46-51
Significant Drug Interactions. Lovastatin, simvastatin, atorvastatin, and cerivastatin are metabolized through the cytochrome P-450 (CYP) 3A4 pathway. Cerivastatin is different from other statins in that it is a substrate for both CYP 3A4 and 2C8
pathways.67 This dual metabolic pathway may limit cerivastatin accumulation when CYP 3A4 inhibitors such as erythromycin are
coadministered.68 Pravastatin appears to go through the CYP pathway, but the manufacturer states that there is no significant metabolism. Because these drugs pass through the CYP pathway, they are subject to numerous drug interactions
(Table 8),46-53 with the most common involving food, warfarin, digoxin, cimetidine, and antacids. In addition, the concomitant use of cyclosporine, gemfibrozil, nicotinic acid, or erythromycin with a statin can increase the risk of myopathy, which is a rare side effect associated with the
statins.29
Bile-acid sequestrants, which are often administered in combination with the statins, have been shown to interfere with the absorption of pravastatin, cerivastatin, and
fluvastatin.56,69,70 Thus, when used together, HMG-CoA reductase inhibitors and the bile-acid sequestrants should not be taken at the same time. Although this interaction has not been studied with the other statins, this precaution should be applied when bile-acid sequestrants are used concurrently with any of the statins. Propranolol has been reported to decrease the systemic bioavailability of lovastatin and pravastatin by approximately
20%.53 Propranolol slows hepatic blood flow, which can enhance first-pass hepatic extraction of the HMG-CoA reductase inhibitors, causing a decrease in systemic
bioavailability.
Simvastatin, lovastatin, pravastatin, and fluvastatin have been shown to increase prothrombin time (PT) in patients treated with
warfarin.48-51 Cerivastatin and atorvastatin are the only two statins that do not interact with warfarin and do not affect
PT.71,72
Simvastatin, fluvastatin, and atorvastatin have been shown to increase digoxin levels, up to 20% for atorvastatin; therefore, digoxin levels should be monitored
carefully.60 Finally, antacids may be used by patients receiving statin therapy because of the gastrointestinal side effects. Unfortunately, there are not many studies reporting this interaction. The drug manufacturer cautions patients on pravastatin about this interaction, and a crossover study of 12 subjects receiving atorvastatin reported that magnesium hydroxide antacid decreased the mean plasma concentration of atorvastatin by 34%. However, this result did not alter LDL reduction, therefore, the researchers concluded that the interaction was not
significant.60 In contrast, Maalox did not alter the absorption of
cerivastatin.73
Cost considerations, side-effect profiles, a once-a-day dosing schedule, and compliance are all important considerations when selecting the appropriate statin for a patient
(Table 9).27 However, the most important factors to consider when deciding on the appropriate statin are which lipoproteins are elevated and the degree of lipoprotein reduction required to reach NCEP goals. Once this is determined, then the efficacy of each statin must be assessed to meet the needs of the patient
(Figure 5).74
The main clinical variable when assessing the efficacy of the HMG-CoA reductase inhibitors is plasma LDL cholesterol, which takes approximately 4 to 6 weeks to show a reduction following the initiation of treatment. Fluvastatin, lovastatin, pravastatin, and simvastatin have similar pharmacodynamic properties in that they can all reduce LDL by 20% to
35%.75 Atorvastatin, at doses ranging from 2.5 mg to 80 mg daily, can reduce LDL by 25% with the lowest dose and up to 60% with the maximal dose. Atorvastatin is the most potent and cost-effective agent available to lower LDL by more than
25%.76 The strong lipid-lowering effects of the statins have been established in a number of large clinical
trials.29,76-78 These trials show that statins can produce dose-dependent reductions in LDL of up to 60%, although reductions of 20% to 25% are more typical with the usual daily doses used in clinical practice for treating patients with
dyslipidemia.29 Significant reductions in LDL are accompanied by significant reductions in total cholesterol, triglycerides, and the various apolipoproteins, with modest increases in HDL cholesterol. The triglyceride-lowering feature of the statins is an advantageous feature of the newer compounds and has been attributed to their potent cholesterol-lowering effects in patients with elevated
triglycerides.29
The first published major secondary prevention trial was the Scandinavian Simvastatin Survival Study (4S), a randomized, double-blind, placebo-controlled trial in which 4,444 patients with hypercholesterolemia and established CHD received 20 to 40 mg simvastatin per day or placebo for 5 years. Compared with placebo, simvastatin-treated patients experienced a 25% decrease in total cholesterol, a 35% decrease in LDL, a 10% decrease in triglycerides, and an 8% increase in HDL. In addition, the treatment group showed significant reductions in risk of death and major coronary
events.79
A recent retrospective study evaluating the success of dosages of simvastatin lower than the recommended starting dose of 10 to 20 mg/day showed that percentages of patients at goal LDL were 98%, 89%, and 83% for patients taking 2.5, 5, and 10 mg/day, respectively. Thus, patients taking less than the recommended initial dosage of the agent still managed to have satisfactory lipid
control.80
The results from the 4S study were confirmed in the Cholesterol and Recurrent Events (CARE) study, a 5-year, double-blind, placebo-controlled trial in which lipid-lowering effects of 40 mg/day of pravastatin were evaluated in approximately 4,000 patients with normal cholesterol levels (mean LDL = 139 mg/dL) and CHD. Compared with placebo, pravastatin reduced LDL by 28% and total cholesterol by 20%. These lipid-lowering results were accompanied by significant decreases in cardiac events that included fatal and nonfatal myocardial infarction and
stroke.81 Similarly, the Regression Growth Evaluation Statin Study was a multicenter, double-blind, placebo-controlled trial of 885 patients with normal to moderately elevated cholesterol levels (total cholesterol between 155 and 310 mg/dL) and documented CHD. After 2 years, pravastatin therapy resulted in a 20% decrease in total cholesterol, a 29% decrease in LDL, a 10% increase in HDL, and a 7% decrease in
triglycerides.82
The Lipoprotein and Coronary Atherosclerosis Study was a double-blind, placebo-controlled trial that evaluated the effects of fluvastatin
20 mg twice a day in 429 patients with moderate LDL elevations (115 to 190 mg/dL) and demonstrable CHD. After 12 weeks, fluvastatin significantly improved lipid profiles by reducing total cholesterol by 18%, LDL by 26.5%, and triglycerides by 10%. HDL was increased by 5.5%. These results were further correlated with a decrease in the progression of atherosclerosis and
CHD.83
Two important primary prevention studies are the West of Scotland Coronary Prevention Study (WOSCOPS) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). WOSCOPS was a randomized, double-blind, placebo-controlled trial assessing the impact of 5 years of 40 mg/day of pravastatin therapy on the incidence of fatal and nonfatal myocardial infarction in patients with primary hypercholesterolemia. After 5 years, total cholesterol and LDL were decreased by 20% and 26%, respectively, which was associated with significant reduction in the risk of definite nonfatal myocardial infarction and death from cardiac
events.84
In the AFCAPS/TexCAPS trial, 6,605 healthy individuals (with total cholesterol 180 to 264 mg/dL, LDL 130 to 190 mg/dL, HDL ¨ 45 mg/dL, and triglycerides ¨ 400 mg/dL) received lovastatin 20 to 40 mg daily or placebo. After 5 years, lovastatin reduced LDL by 25%, increased HDL by 6%, reduced the incidence of coronary events by 37%, and reduced the incidence of unstable angina by
32%.85
Stein et al 86 studied the efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia. The statins have been widely studied and proven efficacious and safe in the treatment of adults with dyslipidemia. However, their effects in adolescents had not been thoroughly evaluated. This 1-year, double-blind, placebo-controlled, randomized trial in boys with familial hypercholesterolemia showed that lovastatin at doses of 10, 20, and 40 mg daily reduced LDL by 17%, 24%, and 27%, respectively. Thus, lovastatin was confirmed to reduce LDL effectively in adolescent boys, and no significant differences occurred in growth, hormonal, or nutritional status between lovastatin-treated and placebo
patients.86
Statins in Hypertriglyceridemia. Statins have been in clinical use for over a decade and, during this time, the focus for their use has been primarily to decrease LDL. However, it is clear that statin therapy is associated with reductions in VLDL triglyceride levels through their ability to inhibit the assembly and secretion of VLDL in inhibiting cholesterol
synthesis.87
Recently, numerous studies have been carried out to investigate the ability of the statins to lower triglycerides. The first two studies involving hypertriglyceridemic subjects treated with statins
involved simvastatin and atorvastatin.87 In the simvastatin-niacin comparison study, 180 subjects with combined hyperlipidemia (triglyceride 200 to 600 mg/dL and/or LDL 160 to 240 mg/dL) were randomized to receive either low-dose niacin or simvastatin 10 mg daily. After 17 weeks, triglycerides were decreased 26% compared with
baseline.88 In a second study, 52 individuals with baseline triglyceride > 350 mg/dL on diet therapy were randomized to double-blind therapy to receive either 5, 20, or 80 mg atorvastatin daily. After 4 weeks, triglycerides were decreased by 26.5%, 32.4%, and 45.8%, respectively. The investigators hypothesized that the triglyceride reduction with atorvastatin may be caused by an additional mechanism other than increased uptake of triglyceride-rich lipoproteins, such as IDL and remnants associated with the LDL receptor up-regulation known to occur with statins. They concluded that with atorvastatin, VLDL secretion was decreased as a result of decreased cholesterol production, which was required for normal VLDL
assembly.89
The recently presented Comparative Dose Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients with Hypercholesterolemia (CURVES) trial was a multicenter, open-label, randomized study performed over an 8-week period, comparing the efficacy and safety of simvastatin (10, 20, or 40 mg at bedtime), pravastatin (10, 20, or 40 mg at bedtime), atorvastatin (10, 20, 40, or 80 mg at bedtime), lovastatin (20 or 40 mg with evening meal), and fluvastatin (20 or 40 mg at bedtime) in 522 patients with LDL greater than 160 mg/dL. Subjects with triglyceride levels greater than 400 mg/dL were excluded. As an adjunct to dietary therapy, atorvastatin 10, 20, and 40 mg daily lowered LDL by 38% to 51% and had greater reductions in LDL than with fluvastatin, lovastatin, pravastatin, or simvastatin at the same milligram-per-milligram dose after 8 weeks of therapy. Atorvastatin 80 mg daily reduced LDL by 54% compared to 40% with lovastatin 40 mg twice daily. Atorvastatin 40 mg daily lowered triglyceride levels to a greater extent than fluvastatin, lovastatin, pravastatin, or simvastatin 40 mg daily. The LDL cholesterol goals were met in 64% of patients taking atorvastatin 10 mg daily, and 100% of the patients taking atorvastatin 80 mg daily. In comparison, 58%, 64%, 67%, and 73% of the patients reached their LDL goals at maximum dosages of fluvastatin, pravastatin, simvastatin, and lovastatin, respectively. This study was the first clinical trial to compare several statins at once. The CURVES study confirmed the superior LDL and triglyceride lowering of
atorvastatin.78
Cerivastatin, the newest HMG-CoA reductase inhibitor, was not studied in the CURVES study. However, it has been administered in clinical trials to more than 2,700 patients with primary hypercholesterolemia. In a recent multicenter pooled analysis of the efficacy and safety of cerivastatin, LDL cholesterol was reduced by 14.2% to 28.2% at doses of 0.025 to 0.2 mg/ day. At doses of 0.3 to 0.4 mg/day, LDL was decreased by 31.3% to 36.1%. In addition, cerivastatin produced significant reductions of up to 26.8% in total cholesterol, and reduced triglycerides by up to 36% with a dose of 0.4
mg/day.28 Cerivastatin is not only effective and well tolerated in the treatment of dyslipidemia, it also exemplifies high pharmacologic potency, which translates into efficacy at ultralow doses (0.1 to 0.3
mg/day).2 Therefore, the addition of cerivastatin to this family of hypolipidemic medications was a significant benefit, adding to the growing list of statins available for the treatment of dyslipidemia.
Overall, the statins are generally better tolerated than other lipid-lowering drugs and have an excellent safety record in long-term clinical
use.2,90,91 Clinically significant adverse effects are rare, and discontinuation rates due to drug-related adverse effects are similar to placebo, with a narrow range of 1% to
4.8%.29 Hepatotoxicity is the most common of the serious side effects, and was represented by increases in aspartate or alanine transaminase levels of three times the upper limit of normal in 0.1% of patients receiving 20 mg/day of lovastatin, 0.9% of those on 40 mg/day, and 1.5% of patients on 80 mg/day in the 48-week Expanded Clinical Evaluation of Lovastatin
trial.91 Similar dose-dependent elevations have been observed with other statins, including atorvastatin, but elevations in liver enzymes are almost always asymptomatic and resolve once the drug is
discontinued.92
Although rare, myopathy, leading to rhabdomyolysis and renal failure, is the most serious adverse effect associated with statin therapy and appears to be dose-related. Elevations in creatinine phosphokinase of >10 times the upper limit of normal, which is consistent with myopathy, occur less than 0.2% of the
time.29 However, concurrent therapy with erythromycin, cyclosporine, niacin, and fibric-acid derivatives can increase the risk of myopathy by 10% to 30% in patients receiving statin
therapy.77
In the recent CURVES study, the overall frequency of adverse events was similar between treatment groups. Approximately 10% of patients reported adverse events that may have been associated with treatment, most of which were mild to moderate in severity. The most common adverse events were myalgia, abdominal pain, diarrhea, flatulence, and nausea, all reported with an incidence of less than 2%. In addition, there were no incidences of persistent elevations in liver enzymes more than three times the upper limit, nor creatine phosphokinase levels more than three times the upper limit of
normal.78 However, most cases of significant elevations in serum transaminases have been reported to occur within the first 2 to 5 months of treatment, implying that this 8-week study was not long enough to detect such
elevations.78 This first trial comparing the lipid-lowering efficacy of all marketed HMG-CoA reductase inhibitors excluding cerivastatin confirmed the relative safety and favorable adverse-effect profile of the HMG-CoA reductase inhibitors.
Although no cases of teratogenesis related to HMG-CoA reductase inhibitors have been reported in humans, cholesterol synthesis is crucial for proliferating cells. Therefore, it should not be surprising to find HMG-CoA reductase inhibitors classified as pregnancy category X. Thus, all six of the statins should be considered as possibly teratogenic and should be avoided in
pregnancy.29
Numerous clinical trials have confirmed the benefits in morbidity and mortality related to cholesterol-lowering therapy with statins. However, the need for long-term, lifelong therapy with statins to prevent coronary events leads some to believe that statin therapy may, in fact, increase health care expenditures. Consequently, information from cost-effectiveness analyses can clarify the value of statin therapy in the prevention of events related to CAD.
Statin therapy has been demonstrated to be cost-effective in the secondary prevention of CAD. The pharmacoeconomic analysis of the 4S trial evaluated the impact of simvastatin therapy on health care resources for acute cardiovascular disease hospitalizations and cardiac revascularization procedures. Simvastatin decreased hospitalizations for acute cardiovascular disease, which included revascularization procedures, by 26%. The average length of stay for acute cardiovascular disease was 7.1 days in the simvastatin group as opposed to 7.9 days in the placebo group. In regards to length of stay and number of hospitalizations, simvastatin resulted in a 34% reduction in hospitalization days. The study concluded that simvastatin would lead to a reduction of $3,872 per patient over 5.4 years, and the cost of simvastatin therapy over 5.4 years would be $778, a favorable economic outcome supporting simvastatin therapy for secondary prevention of
CHD.93 Another economic measure based on the 4S data is the direct cost of simvastatin therapy per life-year saved, which ranged from $13,800 to $27,400 (1995 dollars), depending on age, gender, and baseline cholesterol
level.94 Thus, in the secondary prevention of CAD, simvastatin therapy ranged from being highly cost-effective (<$20,000/QALY
[quality-adjusted life-year]) to being relatively cost-effective ($20,000 to
$60,000/QALY).94
The cost-effectiveness of statins in the primary prevention of CAD has also been demonstrated based on data from the WOSCOPS study. This prospective, randomized, controlled trial of 6,595 participants was undertaken to assess the effects of pravastatin on hospital admissions in hypercholesterolemic middle-aged
men.95 Pravastatin 40 mg daily was found to reduce the number of subjects requiring hospital admissions for cardiovascular causes by 21% over a period of 4.9 years. In addition, pravastatin reduced the number of admissions per 1,000 subject-years for cardiovascular disease by 10.8 in all subjects, and resulted in 13.4 fewer admissions per 1,000 subject-years for all causes. Thus, the results confirm the benefits of pravastatin therapy on reducing health care costs attributable to hospital
admission.96 The cost per year of life saved varied between $16,000 and $32,000, thereby demonstrating the cost-effectiveness of pravastatin in the primary prevention of
CAD.97
The statins vary in potency and cost per percent reduction in LDL cholesterol. Thus, comparing the statins on a cost per percent reduction in LDL cholesterol basis demonstrates atorvastatin, cerivastatin, and fluvastatin to be the most efficient statins primarily because of the high
potency of atorvastatin, low acquisition cost of fluvastatin, and combined potency and low acquisition cost of cerivastatin
(Table 9 and Figure
6).96
The cost to reach NCEP goals in hypercholesterolemic patients was evaluated in a randomized, 54-week, 30-center, controlled trial, which compared atorvastatin, fluvastatin, lovastatin, and
simvastatin.98 Costs were considered from the perspective of insurers and managed care organizations and included cost of resources used to comply with NCEP guidelines and to evaluate and treat adverse events related to the treatment of hypercholesterolemia. Results of this study demonstrated that treatment with atorvastatin was associated with significantly lower annual total cost to reach NCEP goals ($1,064) than treatment with either fluvastatin ($1,542), lovastatin ($1,972), or simvastatin ($1,471). The lower cost was attributed to fewer required office visits, lower doses of HMG-CoA reductase inhibitor, and less adjuvant resin therapy. Patients with and without atherosclerotic disease had similar results.
In a recent meta-analysis of 56 trials (573 patients) with 101 statin monotherapy cohorts and 20 trials with 31 combination-therapy cohorts, Hilleman
et al reported that atorvastatin was the most effective monotherapy in reducing
LDL.99 Combination therapy was more effective in reducing LDL than monotherapy, but on the basis of cost per percentage of LDL reduction, combination therapy was frequently less cost-effective than monotherapy and was associated with a higher rate of nonadherence and drug-drug interactions. The researchers concluded that atorvastatin is the most cost-effective drug for high-risk patients (those with CHD), whereas fluvastatin is the most cost-effective agent for low-risk (< 2 risk factors for CHD) and moderate-risk (> 2 risk factors for CHD) patients.
In a recent randomized, nonblinded, crossover study assessing the efficacy of fluvastatin administered every other day versus an equivalent dose given daily in patients with hypercholesterolemia, it was found that fluvastatin 40 mg every other day is just as effective in lowering total cholesterol and LDL as fluvastatin 20 mg every
day.99 Thus, alternate-day dosing may be worth attempting in patients who do not require a large reduction in LDL since a significant cost savings would be realized. Since the price difference between 20- and 40-mg capsules is small, a patient would save approximately $230 annually taking 40 mg every other day.
Although the cost-effectiveness of treating hypercholesterolemia has been demonstrated in both the primary and secondary prevention of CHD, in general, the cost-effectiveness is generally heightened in the treatment of patients who are at greater risk for CHD. Additionally, given the apparent similarities in efficacy, safety, and outcomes of currently available statins, a major issue in selecting a statin for treatment is cost-effectiveness, which is primarily dependent on the potency and acquisition cost of each specific statin.
Combination therapy is often necessary in severe cases of dyslipidemia. The introduction of higher potency statins, such as atorvastatin, has largely decreased the need for combination therapy to lower LDL levels. However, statins may be combined with a variety of other hypolipidemic agents to obtain a synergistic effect by using agents that work through different mechanisms of action. The most widely used combination regimen involves a statin and a bile-acid sequestrant, which has been shown to be safe, complementary, cost-effective, and valuable in severe
hypercholesterolemia.69,100,101 The bile-acid sequestrant will interrupt the enterohepatic circulation of the cholesterol-rich bile salt pool, leading to increases in hepatic bile-acid synthesis and LDL receptor activity. Increased clearance of LDL from the circulation in conjunction with increased gastrointestinal loss of cholesterol will stimulate HMG-CoA reductase activity, increasing cholesterol synthesis and returning cholesterol levels to
normal.4 This increased synthesis of cholesterol may be partially inhibited by combining a statin with the resin, resulting in an enhanced reduction in
LDL.101 In a recent meta-analysis, combination therapy with cholestyramine and a statin (fluvastatin, lovastatin, pravastatin, or simvastatin) produced decreases of 55% in LDL, 27% to 43% in total cholesterol, and 2% to 15% in triglycerides. In addition, these combinations increased HDL by 7% to 17%. Combination therapy with a statin and a resin can impact lipid levels more significantly than either agent
alone.99
Statins have also been combined with fibric-acid derivatives that act primarily by increased catabolism of triglyceride-rich lipoproteins by stimulating lipoprotein lipase, resulting in enhanced VLDL degradation. However, if there is also a receptor defect, the increased LDL generated as an end product may not be cleared from the circulation. Therefore, the combination of a fibrate and a statin may alleviate this
effect.4 The controversial issue that remains to be addressed is whether these lipid-lowering benefits outweigh the potential risks of therapy. Both statins and fibric-acid derivatives have been linked individually to myopathy, and in combination, they can potentially accentuate this adverse event. However, the incidence of myopathy in patients taking the combination regimen is less than
1.0%.102 Therefore, the combination of a fibrate and a statin may be used cautiously in patients with mixed lipid disorders, with a low risk of muscle necrosis. The regimen should be discontinued at the first sign of muscle
ache.4
The combination of niacin 1,500 to 3,000 mg with a statin further reduces LDL by 10% to 15%, triglycerides by 10% to 30%, and increases HDL by 9% to 12%. This combination has the added benefit of reducing atherogenicity by reducing particle size and postprandial remnant accumulation. There is a risk of hepatic necrosis and rhabdomyolysis using this combination, but with careful monitoring, the risk is quite
low.103
Because atorvastatin has the most powerful LDL-lowering effect, with the added benefit of reducing triglycerides, combination therapy may not be necessary. Compliance is often a problem when patients are asked to take more medications, and the risk of drug interactions becomes an issue. Therefore, the treatment of dyslipidemia should always start with lifestyle modifications. If lipid-lowering responses are inadequate, then pharmacotherapy can be added to lifestyle modifications, but single drug therapy should always be maximized before the addition of a second agent to maximize compliance and minimize the chance of drug interactions and cost issues.
Dyslipidemia is a common disease state with general treatment guidelines and algorithms that can be applied to most patients. However, there are a few patient populations that require modification from these standard guidelines and need special attention, such as patients with diabetes and postmenopausal women.
Individuals diagnosed with diabetes mellitus have a twofold to fourfold higher risk of developing CHD than
nondiabetics.104 In addition, approximately 60% of patients with diabetes die from CHD, and 50% develop peripheral vascular disease and its
complications.7 Although the level of glycemia in these patients is strongly related to the development of microvascular complications, this relationship weakens when applied to macrovascular complications. The finding of increased cardiovascular risk factors before the onset of type 2 diabetes also suggests that aggressive screening for diabetes combined with strict glycemic control alone will not completely eliminate the increased risk of CHD in patients with diabetes. Thus, a multifactorial approach must be taken to prevent CHD in diabetic
patients.104
In individuals with type 1 diabetes, the highest frequency of dyslipidemia occurs in those with uncontrolled diabetes. In these patients, there is decreased activity of lipoprotein lipase, resulting in elevated VLDL and chylomicron concentrations, and a decrease in HDL. For some of these patients, insulin deficiency may result in defective LDL receptors, which can increase LDL
concentrations.7
The most common pattern of dyslipidemia in type 2 diabetes is elevated triglycerides with decreased HDL levels. The concentration of LDL however is not significantly different from those without diabetes. Patients with diabetes may have elevated levels of LDL and VLDL. However, those with type 2 diabetes tend to have smaller, more dense LDL particles, which may increase atherogenicity without an elevation in absolute LDL
concentrations.104 The median triglyceride level in patients with type 2 diabetes is less than 200 mg/dL, with 85% to 95% of patients below 400
mg/dL.105 The elevation in triglyceride levels can be explained by defective triglyceride metabolism, resulting in increased hepatic production of VLDL with decreased clearance of VLDL and chylomicron particles. The increased hepatic production of these particles is thought to be a result of excessive caloric intake and hyperinsulinemia, whereas the decreased clearance of VLDL and chylomicron particles results from decreased lipoprotein lipase activity caused by insulin resistance. The decreased level of HDL results from reduced levels of the most antiatherogenic type of HDL particle, causing the increased risk for CHD in these
patients.7 Few prospective studies of lipids and lipoproteins as predictors of CHD have been reported in individuals with diabetes, and the results have been contradictory. Observational studies have concluded that HDL may be the most reliable predictor of CHD in patients with type 2 diabetes, followed by triglyceride and total cholesterol
levels.104
There have not been any clinical trials on the effects of lipid-lowering agents on CHD specifically in patients with diabetes. However, a few clinical trials have included and reported the results of adult patients with type 2 diabetes. The 4S trial showed that simvastatin significantly reduced CHD incidence and total mortality in subjects with diabetes with elevated LDL and with previous clinical CHD. Similarly, the CARE study showed that pravastatin reduced CHD incidence in patients with diabetes, average LDL levels, and previous clinical CHD. Finally, the Helsinki Heart Study showed that gemfibrozil was associated with a reduction in CHD in those subjects with diabetes without prior
CHD.104 A multicenter, double-blind comparison found that simvastatin is useful in both combined mixed hyperlipidemia and isolated hypercholesterolemia in patients with primary dyslipidemia and non–insulin-dependent diabetes mellitus (NIDDM), whereas gemfibrozil can be used in patients with high triglyceride and low-to-normal LDL cholesterol
levels.106 In a randomized, double-blind, placebo-controlled study designed to evaluate the effect of fluvastatin on the lipid profiles of patients with hypertriglyceridemia resulting from NIDDM, fluvastatin was found to be effective for treating combined elevations of triglycerides and LDL in patients with
NIDDM.107
The treatment for a patient with diabetes and dyslipidemia is the same in regard to lifestyle modifications. The American Diabetes Association recommends nutritional therapy and physical activity in all patients with diabetes. Besides improving glucose control, physical activity will lead to decreased triglyceride and increased HDL cholesterol levels. There is a modest lowering of LDL levels and a decrease in insulin resistance. Therefore, lifestyle modifications are always an important component to all treatment
regimens.14
The categories of CHD risk by lipoprotein levels in patients with type 2 diabetes are shown in
Table 10.104 For diabetic patients, lipid levels should be measured annually in adult patients especially because of fluctuations in glucose control, and the effect this has on lipoprotein levels. If patients fall into the lower risk levels, lipid levels can be measured every 2 years. According to the American Diabetes Association, optimal lipoprotein levels for individuals with diabetes are LDL < 100 mg/dL, HDL > 45 mg/dL, and triglyceride level < 200 mg/dL. However, raising HDL levels through pharmacologic agents is very difficult in patients with diabetes, because the most effective agent for raising HDL is niacin, which can increase glucose levels. Therefore, the alternative for patients with diabetes are fibric-acid derivatives, which can raise HDL cholesterol levels without affecting glycemic
control.104
|
Table
10.
CHD Risk Stratification for Diabetics
|
| Risk |
LDL, mg/dL |
HDL, mg/dL |
Triglyceride, mg/dL |
| Low |
<100 |
>45 |
<200 |
| Borderline |
100–129 |
35–45 |
200–399 |
| High |
>130 |
<35 |
>400 |
CHD = coronary heart disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein.
Adapted from American Diabetes
Association: Clinical Practice Recommendations 1999.
www.diabetes.org.104 |
The decision to treat dyslipidemia in patients with diabetes depends on the LDL level of the patient, as well as their history of CHD, peripheral vascular disease (PVD), or coronary vascular disease (CVD). Drug therapy should be added to lifestyle modifications in patients with diabetes when LDL > 100 mg/dL for those with CHD, PVD, or CVD, and when LDL > 130 mg/dL for those without CHD, PVD, or CVD. The LDL goal for patients with diabetes is LDL < 100 mg/dL. In general, pharmacologic therapy should be initiated after lifestyle modifications are employed for 3 to 6 months. However, in patients with diabetes and clinical CVD or LDL > 200 mg/dL, drug therapy should be initiated in conjunction with diet
and physical activity.104
The treatment of diabetic dyslipidemia in adults has been prioritized as shown in
Table 11.104 For hypertriglyceridemia, the initial therapy is lifestyle modifications that include weight loss, increased physical activity, and a reduction in alcohol consumption. In severe cases (triglycerides > 1,000 mg/dL), severe dietary fat restriction (< 10% of calories) in addition to pharmacologic therapy is necessary to reduce the risk of pancreatitis. Improved glycemic control with the newer glucose-lowering agents has also been effective at reducing triglyceride levels and should be used aggressively before initiating fibric acids. The decision to start therapy at triglyceride levels between 200 to 400 mg/dL depends on the clinician. However, triglyceride levels above 400 mg/dL should be treated with medications. Unlike the case for triglycerides, improved glycemic control will only moderately reduce LDL levels; therefore, diabetic patients with high LDL and high glucose levels might receive glucose-lowering and statin therapy. In some studies, higher dose statins were moderately effective in decreasing triglyceride levels in subjects with triglyceride levels > 300
mg/dL.
Table 11. Order of Priorities
in the Treatment of
Diabetic Dyslipidemia
|
1) LDL Lowering*
• First Choice
HMG-CoA reductase inhibitor (statin)
• Second Choice
Bile-acid–binding resin or fenofibrate |
2) HDL Raising
• Weight loss, increased physical activity, smoking cessation
• Glycemic control
• Difficult except with niacin, which requires strict monitoring in
diabetics=>try fibrates |
3) Triglyceride Lowering
• First priority = Glycemic control
• Fibric-acid derivative
• Statins are moderately effective at high dose in hypertriglyceridemia with high LDL |
4) Combined Dyslipidemia
• First Choice
Better glycemic control plus high-dose statin
• Second Choice
Better glycemic control plus statin plus fibric acid
• Third Choice
Better glycemic control plus resin plus fibric acid
Better glycemic control plus statin plus niacin (close monitoring of glucose levels)
I.e.,the combination of statins with niacin, gemfibrozil, or fenofibrate may increase the risk of myositis
|
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
*Treatment of LDL is considered as the first priority for pharmacologic treatment of dyslipidemia.
Decision to treat high LDL before elevated triglyceride is based on clinical trial data indicating safety and
efficacy of the available agents.
Adapted from American Diabetes Association: Clinical Practice Recommendations 1999.
www.diabetes.org.104 |
When selecting the appropriate pharmacologic agents, several key issues are important to keep in mind that are specific for individuals with diabetes. Gemfibrozil should not be initiated alone in patients with diabetes who have both elevated triglycerides and LDL. Fenofibrate may be a better alternative because of its greater LDL-lowering effect. Although HDL is a powerful predictor of CHD in patients with diabetes, it is especially difficult to increase through drug therapy because niacin is relatively contraindicated in diabetic patients. Therefore, fibric acids may be a better alternative for diabetic patients for raising HDL in addition to lifestyle
modifications.104 The bile-acid sequestrants are not recommended as primary agents in diabetic patients because they can increase triglyceride levels, especially in those with hypertriglyceridemia. However, a bile-acid sequestrant can be beneficial when used in small doses with a fibric- acid derivative in patients with diabetes with mixed hyperlipidemia, or in combination with an HMG-CoA reductase inhibitor in patients with significantly elevated LDL concentrations.
The NCEP II guidelines recommend postmenopausal estrogen therapy, given in combination with progesterone if the uterus is present, in women with established CHD, PVD, and hyperlipidemia. Oral estrogens have shown to improve lipid profiles by reducing LDL by 10% to 15%, increasing HDL by 10%, and decreasing Lp(a) by approximately
25%.108,109
However, in a recent placebo-controlled, randomized trial, Heart and Estrogen/Progestin Replacement Study, 2,763 women with CHD showed no effect of daily estrogen and progestin for 4.1 years on survival or cardiovascular mortality and morbidity. In fact, the actively treated women showed an approximately threefold increase in thromboembolic events. Thus, postmenopausal use of estrogen and progesterone in dyslipidemia benefits lipid levels but may be associated with an increased risk of cardiac events in patients with preexisting CHD. Because the mean follow-up period was only 4.1 years, additional studies are needed to evaluate any long-term benefits of estrogen therapy in the treatment or prevention of hyperlipidemia and
CHD.110
Pharmacists can play an important role in the intervention, treatment, and prevention of dyslipidemia and CHD. One of the major problems associated with dyslipidemia is that it tends to be asymptomatic and works as a silent killer. Many individuals may not feel they need treatment. When treatment is implemented, compliance with lifestyle modifications and drug therapy is often not followed. As health care providers, pharmacists can participate in the detection of dyslipidemia and help identify the appropriate treatment options. In addition to counseling on the dosage, side effects, and possible drug-drug/drug-food interactions, pharmacists should always counsel patients on the disease process, and reinforce lifestyle modifications, with added emphasis on the benefits of intervention and compliance. Pharmacists can also help patients identify the most convenient and effective methods for adopting lifestyle modifications. The most important message pharmacists can relay to patients is that the management of dyslipidemia is not a short- term assignment with immediate, visible outcomes. Rather, it is a long-term process that should be integrated into one’s daily life.
Dyslipidemia continues to be the leading risk factor associated with CHD. Lipid modification by decreasing levels of circulating LDL, triglycerides, and increasing HDL levels in combination with lifestyle modifications is central in reducing the risks of CHD. With so many individuals diagnosed with dyslipidemia every year, it is crucial for the pharmacist to have a solid understanding of the disease state and the available treatment options for these patients. Although numerous pharmacologic therapies are available for the treatment of dyslipidemia, the statins are considered the primary therapeutic agents for the management of dyslipidemia in patients refractory to lifestyle modifications. However, they still remain underutilized. With the appropriate knowledge and understanding of these drugs, pharmacists can provide pharmaceutical care through interventions that may help prescribers select the appropriate agents for dyslipidemia and serve as front-line health care providers to the patients in the community.
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