Hyperlipidemia
in Understanding Pharmacology for Pharmacy TechniciansKEY TERMS AND DEFINITIONS
| Atherosclerosis | a condition in which arteries have lost their elasticity (hardened) as a result of plaque deposits. |
| Atherosclerotic plaque | an accumulation of cholesterol and cells that can block the flow of blood through a vessel. |
| Bile acid sequestrants (BAS) | a class of hyperlipidemia agents that bind to bile acids in the gastrointestinal tract. To produce new bile acid, the liver removes cholesterol from the blood stream, lowering LDL. |
| Cholesterol | a lipid used in the production of hormones, bile salts, and cell membranes that contributes to atherosclerotic plaque formation when levels are high. |
| Chylomicrons | a very large lipoprotein that contains 90% triglycerides and 5% cholesterol. |
| High density lipoprotein (HDL) | the good cholesterol that contains 5% triglyceride, 25% cholesterol, and 50% protein. |
| Hyperlipidemia | elevated levels of one or more lipoproteins in the blood. |
| Lipids | molecules, including fats, cholesterols, steroids, and others, that are usually insoluble in water. |
| Lipoprotein | a spherical particle made up of hundreds of lipid and protein molecules. |
| Low density lipoprotein (LDL) | the bad cholesterol that contains 6% triglyceride and 65% cholesterol. LDL is highly likely to cause atherosclerosis. |
| Triglyceride | a lipid that is the storage form of fatty acids, used as an energy source. |
| Very low density lipoprotein (VLDL) | a lipoprotein that contains 60% triglyceride and 12% cholesterol. |
LEARNING OBJECTIVES
After completing this chapter, you should be able to
Define hyperlipidemia and recognize its causes, symptoms, and consequences.
Identify tests for hyperlipidemias and recognize the conditions under which they are done.
Distinguish between total cholesterol, LDL, HDL, VLDL, and triglycerides, know the meaning of each acronym, and recognize target values for each.
List nonpharmacologic treatments recommended for each type of hyperlipidemia.
List the classes of medications used in the treatment of hyperlipidemia and their basic mechanisms of action.
Identify agents and common side effects from each class of medications used to treat hyperlipidemias.
The term lipid is used to describe a wide variety of compounds in the human body. At desired concentrations, these molecules serve many important purposes. One type of lipid, known as a phospholipid, is responsible for making up the cell membranes of nearly every cell in the body, while others, called steroids, are versatile hormones that are integral parts of the reproductive, immune, renal, cardiovascular, and central nervous systems. Some lipids are essential nutrients, such as vitamins A, D, E, and K, that must be obtained from the diet because the body cannot create them on its own. But perhaps the most widely discussed and researched lipid is cholesterol. Like other lipids, cholesterol is vital to the function of the human body; however, more than 50% of American adults have hyperlipidemia or elevated (inappropriately high) levels of lipids in their bloodstreams. When levels rise, whether due to genetics or lifestyle, the chance of developing atherosclerotic plaques increases sharply, along with the risk for cardiovascular diseases, stroke, and other health problems.
The types, synthesis, and functions of cholesterol are reviewed in this chapter, followed by an examination of the development of atherosclerotic plaques. Next, the techniques used to measure cholesterol levels in the blood and the classification of these results are discussed. Finally, the various treatments, both pharmacological and nonpharmacological, are explored.
CASE STUDY
J. H. is a 48-year-old male who has just had an annual checkup with his primary care physician. His past medical history includes a diagnosis of hypertension. He does not smoke and has no family history of heart disease, though he is overweight. Each year, a blood test has been performed to measure J. H.’s cholesterol. In the past, these levels have been acceptable, but today J. H. learns that his total cholesterol is measured as 285 mg/dL, his HDL is 45 mg/dL, and his triglycerides are 210 mg/dL. His physician has informed him that he has hyperlipidemia. J. H. has now arrived at the pharmacy with a prescription for simvastatin 40 mg at bedtime.
Pathophysiology of Hyperlipidemia
The Role of Cholesterol and Triglycerides in Homeostasis
As described above, there are many different types of lipids present in the body. Cholesterol and triglycerides are the two major lipids involved in the development of atherosclerotic plaques. Normally, cholesterol is an important component of cell membranes throughout the body. This rigid molecule provides a backbone and structure to an otherwise disorganized collection of phospholipids, the major component of the cell membrane. It is also an important ingredient in the formation of a number of hormones and the bile acids, compounds that help the body absorb fat from the gastrointestinal tract. Triglycerides, on the other hand, are the storage form of fatty acids in the bloodstream. They can be used as an energy source when the body’s glucose is running low.
CASE?
J. H. is confused about where he got the cholesterol measured in his blood test. Describe the two main sources of cholesterol.
Cholesterol and triglycerides are obtained from two sources, those that the body creates and those that are consumed in the diet. The liver is the main source of production for both these lipids, though cholesterol can also be synthesized by nearly every cell in the body. For this reason, dietary sources are largely unnecessary, as the body can create enough of a supply to function. Whether they are synthesized or consumed, cholesterol and triglycerides must be transported throughout the body on molecules called lipoproteins. These small, spherical molecules travel around the body either delivering cholesterol to cells in need or returning excess cholesterol to the liver to be recycled. Lipoproteins are classified on the basis of their densities and are divided into four major classes: chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL).
The largest of the lipoproteins is the chylomicron. Its main function is to transport triglycerides that are produced from dietary fats, and it is composed primarily of dietary triglycerides. After picking up the triglycerides from the small intestines, chylomicrons travel through the circulatory system to the adipose (fatty) tissue. There, enzymes release the triglycerides from their transporter to be stored in fat cells for later use. After all the triglycerides have reached their destination, the liver will remove the chylomicrons from the circulation until they are needed. After a fast of 8–12 hours, chylomicrons are usually completely absent from the bloodstream. To transport triglycerides being produced by the liver, the body uses VLDL molecules. In a process similar to the one described for the chylomicron, VLDL picks up excess triglycerides in the liver and transports them to the adipose tissue for storage. Unlike the chylomicron, the VLDL molecule can also transport limited amounts of other lipids, with 50% of its composition being triglycerides, 20% being phospholipids, and 20% being cholesterol. After VLDL has delivered its contents to the adipose tissue, half of the remnants are absorbed by the liver, while the other half is used to create LDL molecules.
The major carrier of cholesterol in the bloodstream is the LDL particle. It is made up of 70% cholesterol and 15% phospholipids. Commonly referred to as bad cholesterol, LDL particles are the lipoprotein most likely to contribute to atherosclerosis. After sufficient cholesterol has been delivered to the cells of the body, excess LDL particles can begin depositing cholesterol into the smooth muscle of the vascular system. Whether caused by a genetic deficiency or high dietary intake of cholesterol, an elevated LDL level is the first step toward the development of heart disease.
Finally, the smallest of the lipoproteins is the HDL particle. It is made of 5% triglycerides, 30% phospholipids, and 20% cholesterol, with the remainder being protein. These dense particles travel around the body and remove excess cholesterol from cells, returning it to the liver to be eliminated. For this reason, these lipoproteins are typically referred to as good cholesterol. Elevated levels of HDL are associated with a decreased risk of developing heart disease.
CASE?
J. H. has heard that there are good and bad types of cholesterol. List the proper name of each lipid particle and explain the differences between them.
Atherosclerosis
Perhaps the most worrisome result of hyperlipidemia is the development of atherosclerosis. The process begins after the circulating LDL particles have delivered a sufficient supply of cholesterol to the cells of the body. Any excess LDL remaining in the bloodstream will begin to deposit into the smooth muscle surrounding the blood vessels, especially in areas of vascular damage. Once beneath the smooth muscle, the LDL particles attract the attention of the immune system. In an effort to remove the particles, white blood cells attempt to digest the cholesterol and are converted into foam cells, causing further irritation in the area. This initial process results in the formation of fatty streaks, which are deposits of cholesterol and foam cells in blood vessel walls. For some patients, the process may end at this stage, with only minimally elevated risks of adverse cardiovascular events. In fact, most people older than 20 years of age have some evidence of fatty streak deposits in their blood vessels. For others, however, the atherosclerosis will progress. As the irritation in the area continues to build and more white blood cells are attracted, the walls of the blood vessel will begin to change. Attempting to wall off the inflamed fatty streak, smooth muscle cells, platelets, and collagen begin to bulge into the middle of the blood vessel, forming a true atherosclerotic plaque (see Figure 17-1).
Atherosclerosis is the buildup of a waxy plaque on the inside of blood vessels.
A number of risk factors for the progression from fatty streak to atherosclerotic plaque have been identified. Some of these risk factors are classified as nonmodifiable, meaning they are characteristics that a patient cannot change. A patient’s age contributes to the likelihood of plaque formation, with men older than 45 years and women older than 55 years or in premature menopause at highest risk. Additionally, a patient’s gender is also an important risk factor, as men are at an increased risk. Finally, a patient’s genetics plays a very important role in determining his or her risk for developing atherosclerosis. Clinicians will ask if a patient has any first-degree relatives, meaning a parent or sibling, who suffered an early cardiac death.
Other risk factors, however, are modifiable, meaning patients can make decisions that will affect their risk of developing atherosclerosis. These include smoking, body weight, physical activity levels, diet, diabetes, hypertension, and hyperlipidemia. Studies are underway to identify new risk factors, such as the size of LDL particles, number of cholesterol receptors, and chronic inflammation markers, which may be important tools to evaluate risk in the future. In addition to these risk factors, cardiovascular risk calculators, such as the ASCVD Risk Score, Framingham, Reynolds, and QRISK calculators, are used to estimate a patient’s risk of having an event over a specified number of years.
CASE?
List J. H.’s risk factors for developing atherosclerosis. Which are nonmodifiable? What can J. H. do to change the modifiable ones?
PRACTICE POINT
Cardiovascular risk calculators are available at several online sites. A reliable starting point is the website of the American Heart Association (www.heart.org), where one can enter the search term “risk calculator.”
CASE?
J. H. is wondering if following the treatment plan he got from his physician is worth the trouble, because he is currently feeling no symptoms. Describe the risks to J. H. if his new diagnosis goes untreated.
If left untreated, protruding atherosclerotic plaques will eventually decrease blood flow through the narrowing, hardening blood vessel, leading to potentially life-threatening consequences that depend on the location of the plaque. Atherosclerosis of coronary arteries puts patients at risk of developing ischemic heart disease and acute coronary syndromes. If they are present in the arteries supplying the brain with oxygen, patients may develop a stroke. In the rest of the vascular system, blocked arteries may lead to symptoms of atherosclerosis of arteries in the arms or legs that leads to painful cramping and decreased muscle function (termed peripheral vascular disease) or decreased blood flow to vital organs like the kidneys, spleen, or gastrointestinal tract. But perhaps one of the most unnerving characteristics of atherosclerosis is the possibility that patients may not experience any symptoms to warn them of a potentially life-threatening event on the horizon.
Diagnosis of Hyperlipidemia
The Lipid Profile
To identify patients with hyperlipidemia, a measurement of the levels of various lipoproteins in the blood must be performed. This blood test is commonly referred to as the lipid panel. In the past, the measurement used to define lipid status was the total cholesterol. This number is determined by adding levels of LDL, HDL, and VLDL into one value. The benefit of this strategy is that patients were not required to fast before obtaining a measurement. The drawbacks, however, were numerous. It is now understood that total cholesterol, alone, does not accurately reflect a patient’s risks. Clinicians must look at levels of each lipoprotein individually to assess the patient’s status, though the process for obtaining these individual measurements is more complex. Levels of total cholesterol, HDL, and triglycerides can be measured directly in the blood. Next, the triglyceride value must be converted into an estimate of VLDL. Recall that triglycerides are carried by two lipoproteins, chylomicrons and VLDL particles. To get an accurate estimate of VLDL, patients must fast for 8–12 hours before having blood drawn for a lipid panel. This ensures that any triglycerides present in the bloodstream are traveling on VLDL particles and not the temporary chylomicrons. If a patient does not fast, the presence of chylomicrons will affect the measurement of triglycerides and the calculation of LDL, falsely elevating the results. To estimate VLDL levels, the triglycerides of a fasting lipid panel are divided by 5. To obtain a calculated LDL value, the Friedewald formula is used (see Figure 17-2). This entails subtracting the measured HDL and the estimated VLDL levels from the measured total cholesterol.
The Friedewald equation for calculating LDL cholesterol values.
CASE?
What is J. H.’s calculated LDL level from the values reported to him?
Types of Hyperlipidemia
After the lipid panel has been evaluated, clinicians will attempt to classify patients by type of hyperlipidemia. There are two overarching categories into which patients may fall, either primary or secondary hyperlipidemia. In the case of primary hyperlipidemia, the underlying cause of the disorder is the patient’s genetics. At least six different genetic defects have been identified, including deficiencies in the enzyme responsible for cleaving cholesterol from LDL, lacking LDL receptors, excess production of lipoproteins, and abnormal metabolism of lipoproteins. The end result is moderate to extreme elevations in one or more lipoproteins. Treatments can also vary from diet and medication therapy to complete liver transplant.
Much more common than the primary hyperlipidemias, secondary hyperlipidemia is the result of other causes. The most common of these are a diet high in cholesterol and saturated fats and a sedentary lifestyle, leading to being overweight or suffering from obesity. Other secondary causes of hyperlipidemia include certain medications, such as antipsychotics, antivirals, and steroids, and disease states, such as type 2 diabetes, hypothyroidism, and chronic kidney disease.
Treatment
For patients with hyperlipidemia, the primary goal is to decrease the risk of developing serious complications due to the development of atherosclerosis. To accomplish this, clinicians will typically begin with lifestyle modifications, such as diet, physical activity, and weight loss. Because lifestyle changes are usually difficult to achieve, pharmacological treatment is added if goal cholesterol levels are not reached with diet and exercise alone. Since LDL is most likely to cause atherosclerosis, the first goal is to bring this value down to acceptable levels. Once this goal is met, HDL and triglycerides can be treated to further minimize the risk of having an adverse cardiovascular event.
Nonpharmacological Treatment
The Therapeutic Lifestyle Changes Diet
The therapeutic lifestyle changes (TLC) diet focuses on reducing dietary saturated fat and cholesterol while promoting a healthy weight loss. The TLC diet recommends that <7% of calories are acquired through saturated fat consumption, as opposed to the typical American diet that receives 11%–17% of calories from these sources. By slowly incorporating healthier options, such as substituting lean meats and skim milk for beef and whole milk, these lifestyle changes are more likely to remain a part of the patient’s daily habits. In addition to restricting saturated fats, the TLC diet restricts cholesterol intake to <200 mg/day. As described above, the body can produce enough cholesterol to maintain homeostasis, making dietary cholesterol largely unnecessary. By keeping intake low, LDL cholesterol levels are reduced while HDL levels may increase. As a potential substitute for harmful saturated fats and cholesterol, the TLC diet recommends increasing intake of mono- and polyunsaturated fats, commonly known as the “healthy fats,” to 10%–20% of the calories consumed in a day. Found in olives, many seeds, and nuts, the healthy fats can further decrease LDL cholesterol.
CASE?
What type of diet might be best to help J. H. reach his cholesterol goals?
In addition to dietary restrictions, the TLC diet offers a number of options that may be incorporated into the diet to augment LDL reductions. Increasing the amount of soluble fiber in the diet, found in oats, beans, and other plants, to at least 5–10 g daily can reduce LDL by 5%. Consuming 10–15 g daily may cause even larger reductions in LDL. The plant sterols and stanols isolated from soybeans can help reduce the absorption of cholesterol in the gastrointestinal tract. Studies have shown that 2 g daily can reduce cholesterol levels by up to 10%, though higher intake did not result in a greater reduction. Various margarine-like products are available that use plant sterols and stanols to help control LDL levels. It should be noted, however, that these options should be considered as add-on therapy to the dietary options outlined above and not as substitutes for reducing intake of saturated fats and cholesterol.
Other Lifestyle Modifications
In addition to dietary changes, guidelines exist for physical activity and weight loss. Studies have shown that physical activity can cause important changes to lipid metabolism and functioning. Over the long term, exercise causes a reduction in triglycerides, increases HDL, and leads to larger LDL particles that are less likely to contribute to atherosclerosis. To obtain these benefits, it is recommended that at least 30 minutes of moderate physical activity is performed on a near-daily basis. Coupling the dietary and physical activity recommendations will likely lead to another important goal in the treatment of hyperlipidemia: weight loss. Though the emphasis should be placed on the types of food eaten and the amount of physical activity performed, weight loss, itself, can improve a patient’s lipid profile. Reductions of as little as 10 pounds can lower LDL and triglycerides while increasing HDL. In general, an initial weight loss goal of 10% of a patient’s current weight should be reached over a 6-month period.
The use of alcohol and tobacco has also been examined. Studies have shown that moderate alcohol consumption may actually reduce the risk of heart disease by increasing HDL particles slightly. Moderate intake has been defined as no more than two servings per day for men or no more than one serving per day for women. Patients must be cautioned that consuming more than the recommended amount may actually increase triglyceride levels and contribute to liver damage and cirrhosis. For patients who use tobacco, evidence suggests that not only are HDL levels reduced and LDL levels elevated, but the particles are more prone to cause atherosclerosis. All patients reporting tobacco use should be encouraged to quit, without regard to their lipid status.
CASE?
What are three lifestyle changes that J. H.’s physician might recommend to improve his hyperlipidemia?
Pharmacologic Treatment
HMG-CoA Reductase Inhibitors
Often called the statins, the HMG-CoA reductase inhibitors block the function of an important enzyme used in the production of cholesterol. As the body produces less cholesterol, LDL levels begin to drop, possibly by as much as 55%. In addition to dropping LDL cholesterol, triglyceride levels may also fall by up to 30% while HDL levels may rise 15%. Though these favorable effects on the lipid profile are important features of the statin medications, many experts have theorized that there are other benefits of statin use beyond their lipid-lowering effect. The so-called pleiotropic effects of statins range from reducing inflammation to stabilizing atherosclerotic plaques, making them more organized and less likely to rupture. Taken together, their powerful LDL-lowering ability, pleiotropic effects, and benefit on other components of the lipid profile have made the statins the drug of choice for many of the hyperlipidemias.
ALERT!
Statins are usually discontinued for pregnant patients when the risk to the fetus may outweigh possible benefits to the mother. Other agents described later in this chapter, such as the bile acid sequestrants, are considered first line in pregnancy because they are not absorbed into the body, so would be less likely to harm an unborn child.
The agents in this class include atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin, pitavastatin (Livalo, Zypitamag), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor—see Medication Table 17-1; Medication Tables are located at the end of the chapter). Though many of these medications are available as generics, pitavastatin is brand name only. Clinicians will recommend that they are taken once daily at bedtime to ensure high blood concentrations when the body’s cholesterol production is at its peak, during the night (though the some of the newer agents can be taken at any time of day). Depending on which agent and dose is chosen, the effect on LDL levels can vary greatly. See Table 17-1 for a summary of the relative effects of the different doses of the statins.
Potency of Reduction of Low Density Lipoprotein (LDL) for Various Statins1a
Statin |
Daily Dose |
||
|---|---|---|---|
Low Intensity (< 30% LDL Reduction) |
Moderate Intensity (30%–49% LDL Reduction) |
High-Intensity (> 50% LDL Reduction) |
|
Atorvastatin (a TORE va sta tin) |
10–20 mg |
40–80 mg |
|
Fluvastatin (FLOO va sta tin) |
20–40 mg |
80 mg |
|
Lovastatin (LOE va sta tin) |
20 mg |
40–80 mg |
|
Pitavastatin (pit A va stat in) |
1–4 mg |
||
Pravastatin (PRA va stat in) |
10–20 mg |
40–80 mg |
|
Rosuvastatin (roe SOO va sta tin) |
5–10 mg |
20–40 mg |
|
Simvastatin (SIM va stat in) |
10 mg |
20–40 mg |
|
Pronunciations have been adapted with permission from USP Dictionary of USAN and International Drug Names (USP Dictionary) © 2022.
PRACTICE POINT
Since it is thought that the body synthesizes most cholesterol at night, it is generally recommended that statins be taken at bedtime. Atorvastatin, pitavastatin, and rosuvastatin, however, are longer-acting statins that can be taken any time during the day and retain their effectiveness.
As a class, these medications are fairly well tolerated; however, side effects can occur. One of the most frequently reported side effects is myalgia, or muscle pain, reported in 1%–10% of patients. Patients especially at risk for this adverse event are older adults, patients taking high doses of statins, patients of Asian descent, or those taking other medications that may cause myalgia, such as the fibrates and niacin products also used to treat hyperlipidemia. Clinicians will monitor patients with myalgia closely as it may be a warning sign for a more serious side effect of statin use, called myopathy. This condition is the coupling of muscle pain with an elevation in creatinine kinase levels, an enzyme that is released when muscle tissue is severely damaged. If allowed to progress, myopathy could lead to rhabdomyolysis, a widespread breakdown of muscle fibers that can cause kidney failure and death. All patients who experience unexplained muscle pain should be instructed to call their healthcare providers so that they may be evaluated for these serious side effects. In addition to their effects on muscle tissue, statins may also cause damage to the liver. To avoid this, clinicians will monitor blood levels of liver enzymes. These liver function tests (LFTs) will rise if there is damage to the liver and alert the clinician to stop the offending agent.
ALERT!
Patients should be warned to avoid drinking large amounts of grapefruit juice with statins. This drug–diet interaction can lead to higher levels of statin in the blood and increased risk of side effects.
PRACTICE POINT
Prescribers will choose the appropriate statin dosage based on patient risk factors. Those at highest risk for a myocardial infarction, stroke, or other event tend to receive high-intensity statin therapy (such as atorvastatin 80 mg or rosuvastatin 40 mg daily) to lower LDL by >50%. Patients at lower risk or those who develop side effects to statin therapy tend to receive lower-intensity statin therapy (eg, simvastatin or pravastatin 10 mg daily).
PRACTICE POINT
The pharmacist may counsel patients to watch out for dark brown urine while taking statins. This can be an early warning sign of rhabdomyolysis.
CASE?
What are the common side effects of the medication prescribed to J. H.?
Niacin
Niacin is a B vitamin that, at high doses, can have a favorable effect on each component of the lipid profile. It is thought that niacin’s action comes from its ability to inhibit fat breakdown, lowering the amount of fatty acids being delivered to the liver to make lipoproteins. Reductions in LDL tend to be smaller than is seen with the statins, likely dropping by 5%–25%, but the effect on triglyceride and HDL can be dramatic, lowering triglycerides by 20%–40% and increasing HDL up to 35%.
Though niacin has a beneficial effect on each part of the lipid profile, side effects often limit its use. The first, and most bothersome, side effect is known as flushing, a sensation of heat and redness of the face, neck, chest, or body a few hours after a dose of niacin is given. This is the result of vasodilation in the face and neck as niacin levels begin to rise in the body. Though a tolerance to the effect sometimes develops with time, the sensation is unlikely to fully disappear. Gastrointestinal complaints, such as nausea, vomiting, diarrhea, and heartburn, are common, as well. In some patients, symptoms of myopathy can present, similar to those experienced by some statin users. Others may see elevations in blood glucose, making niacin difficult to use in patients with diabetes. Finally, clinicians must closely monitor liver function tests in patients taking niacin products as hepatic injury is a common issue, especially at higher doses.
PRACTICE POINT
The pharmacist or prescriber may recommend taking 325 mg of aspirin 30 minutes before administering a dose of niacin to help reduce the severity of flushing.
Niacin is available in three different formulations, each with a slightly different side effect profile and dosing regimen. The first is an immediate-release tablet or capsule that is available over the counter (Niacor, vitamin B3) started as a once daily dose but increased weekly until the patient is taking it three times a day. The usual target dose is 500 mg three times daily. If lipid profile goals are not met at this dosage, further escalation to doses up to 2 g three times daily may be attempted, though it is unlikely most patients will tolerate these higher doses. The benefit of using immediate-release forms of niacin is that liver damage is unlikely to occur. However, the immediate-release products cause the largest amount of flushing, a consequence that most patients cannot tolerate (see Medication Table 17-1).
Also available over the counter is a sustained-release niacin product (Slo-Niacin). This sustained-release preparation is taken twice daily in doses starting at 500 mg, which can be increased to 1 g if the patient needs and can tolerate the higher dosage. In addition to the benefit of fewer daily doses, sustained-release niacin also reduces the risk of developing flushing. However, these agents should be used with extreme caution and only under the supervision of a healthcare provider because a significant increased risk of liver damage has been discovered.
The final formulation of niacin is an extended-release product (Niaspan). Available only with a prescription, extended-release niacin is absorbed more slowly than an immediate-release product but more rapidly than the sustained-release versions. The result is a lower risk of flushing and little to no risk of liver damage. Dosing typically begins at 500 mg at bedtime and is increased each month by 500 mg to a target of 1–2 g each night. Recently, data from studies suggest that using niacin may not decrease the risk of having heart attacks or strokes in patients with hyperlipidemia so the utility of these agents has been called into question.
ALERT!
Many over-the-counter niacin products are labeled as FLUSH FREE. These supplements are not equivalent to the niacin products outlined above and do not have a role in treating hyperlipidemia.
Fibrates
The fibrates are medications that target primarily triglycerides. Through a series of complex steps, they encourage the breakdown and removal of chylomicrons and VLDL particles from the bloodstream while reducing their production in the liver. They also may have a small role in increasing HDL levels. Reduction in LDL levels, however, is usually modest and the fibrates may even lead to increased LDL in some populations. The newer agents in this class, fenofibrate products (Tricor, Trilipix, and others), are dosed once daily, while the older agent, gemfibrozil (Lopid), is dosed twice daily. For patients with poor kidney function, doses should be reduced to avoid accumulation and the development of side effects. Many different formulations of fenofibrate exist and are available as generic medications. Gemfibrozil is available generically, as well. In general, this class of hyperlipidemia medications is very well tolerated; however, gemfibrozil is associated with slightly higher incidence of upset stomach, myopathy, and liver damage than the fenofibrate products and also carries a higher risk of interacting with statins (see Medication Table 17-1).
PRACTICE POINT
The many different formulations of fenofibrate have slightly different doses and release mechanisms; therefore, they are not interchangeable.
ALERT!
Patients may not gain the full effect of the fibrates until they have completed 6–8 weeks of therapy.
Cholesterol Absorption Inhibitors
The only agent from the class known as the cholesterol absorption inhibitors currently available is ezetimibe (Zetia). This newer class of hyperlipidemia medication, available as a generic and dosed 10 mg once daily, inhibits a cholesterol transporter in the small intestine. The result is a drop in cholesterol absorption by up to 50%, leading to a modest 18% reduction in circulating LDL particles. Because of this relatively small decrease in LDL and no significant effect on other parts of the lipid profile, ezetimibe is usually used as an adjunctive treatment for patients unable to meet their cholesterol goals on other hyperlipidemia treatments. It may also be used in patients who cannot tolerate statins due to adverse events, as it is very well tolerated. Few case reports of muscle-related side effects have been reported with ezetimibe (see Medication Table 17-1).
PRACTICE POINT
Ezetimibe is available in combination with simvastatin for patients who have been unable to reach their cholesterol goals on statins alone. The ezetimibe dose in each of these is 10 mg, but the combination is available in a variety of simvastatin doses. Labeled strengths are 10/10, 10/20, 10/40, and 10/80, with the second number being the dose, in milligrams, of simvastatin.
Omega 3 Fatty Acids
The omega 3 fatty acids are polyunsaturated fats found in oily fish (such as salmon or tuna). When taken at high doses, these substances interfere with the liver’s ability to produce VLDL particles, thus reducing serum triglyceride concentrations. Though they are found in certain plants, as well, all available evidence of cardiovascular risk benefit come from fish sources. Available as over-the-counter supplements (various fish oil preparations) and one prescription strength formulation (Lovaza), doses of up to 4 g/day are required to lower triglycerides by up to 50%. As doses approach the 3 g/day threshold, the incidence of adverse effects, including bloating, fishy taste, belching, and indigestion, increases though these agents are generally well tolerated (see Medication Table 17-1).
Bile Acid Sequestrants
Historically, the first agents used to treat hyperlipidemia were the bile acid sequestrants (BAS). When this class of medications is ingested, no drug is absorbed into the bloodstream. Instead, the drug travels through the digestive system binding the bile acids. The bile acids are molecules produced by the liver that are responsible for breaking down and transporting fats from the diet. Bile acid sequestrants can reduce the amount of bile acid by as much as 40%. Sensing this decrease, the body is stimulated to produce new bile acid. Cholesterol is collected from the bloodstream and returned to the liver where it can be reprocessed into new bile acid. The result is a decrease in circulating LDL by up to 25%, with little to no change in the other components of the lipid panel.
The use of bile acid sequestrants has declined in favor of more effective, easier to administer, and more tolerable medications such as the statins. Though they do not get absorbed into the systemic circulation, the gastrointestinal side effects of these agents lead to a > 40% discontinuation rate. Constipation, flatulence, bloating, and abdominal pain are all likely occurrences as the adsorbed bile acid is eliminated through the feces. In addition to these side effects, administering other medications along with the bile acid sequestrants can lead to significant interactions, as some medications and vitamins become bound to the molecules, and are not absorbed. To avoid this issue, all other medications must be administered at least 1 hour before or 4 hours after a dose of the bile acid sequestrants is administered.
The agents in this class of hyperlipidemia medications are cholestyramine (Questran), colestipol (Colestid), and colesevelam (Welchol). Cholestyramine and colestipol are dosed at 4–5 g and titrated to a maximum dose of 24–30 g/day, respectively. The newer agent colesevelam is dosed at 3.75 g/day. These products are all available in powdered form to be mixed with liquids. Colestipol and colesevelam are also available as oral tablets. Theoretically, the lower dose used with colesevelam reduces the likelihood of the serious gastrointestinal side effects seen with the older bile acid sequestrants (see Medication Table 17-1).
ALERT!
Bile acid sequestrants may bind other drugs in the gastrointestinal tract, interfering with their absorption. It is generally recommended that patients take other medications at least 1 hour before or 4–6 hours after the bile acid sequestrant doses to avoid this issue.
PRACTICE POINT
The powdered or granule BAS products are available in both bulk containers (with a scoop used to measure the dose) and in packets (with premeasured doses). Technicians must be sure the label directions are appropriate for the packaging being dispensed. Powders and granules are never taken dry—they must be mixed according to the packager’s directions in a glass of water or other appropriate liquid (including soups or juices) or soft food (such as oatmeal or applesauce). Even the tablet forms should be taken with plenty of liquid or moist food.
Proprotein Convertase Sutilisin-Kexin Type 9 Inhibitors
The newest class of medication aimed at lowering blood cholesterol levels are the proprotein convertase sutilisin-kexin type 9 (PCSK9) inhibitors. Agents in this class include evolocumab (Repatha) and alirocumab (Praluent), which are available only as brand name injections administered every 2 or 4 weeks. These antibodies bind to an enzyme that would normally promote the degradation of LDL receptors in the liver. In the process, the liver will remove more LDL from the bloodstream. When compared to other medications that treat hyperlipidemia, the PCSK9 inhibitors are very effective at lowering LDL (up to a 76% reduction in many patients), though their higher costs have limited their use. In most cases, these agents are reserved for patients who have elevated LDL levels despite multiple other medications prescribed at their maximum tolerated doses.
CASE?
After 6 months of lifestyle modifications and treatment with simvastatin, J. H. returns to his primary care physician’s office and has a lipid panel checked. His LDL is now at goal, but his triglycerides remain slightly elevated. What add-on therapy might the physician prescribe for J. H.? Describe its mechanism of action and potential side effects.
SUMMARY
Cholesterol is an important ingredient in the production of a number of vital substances needed to maintain homeostasis. The body can both produce cholesterol and obtain it through dietary sources. For the typical American, the amount of cholesterol obtained in the diet far exceeds what the body requires, resulting in excess low density lipoprotein (LDL) particles circulating in the bloodstream. When the LDL has delivered sufficient cholesterol to the tissues, leftover particles will begin to deposit into the smooth muscle surrounding the vasculature. This is the first step in the development of atherosclerosis, a hardening and narrowing of the blood vessels. If allowed to continue, the affected blood vessel may become completely blocked or the plaque may rupture, sending fragments and blood clots traveling downstream to smaller vessels that may become blocked, as well. Depending on the affected vessel, the consequences can range from decreased blood flow and organ dysfunction to stroke, myocardial infarction, and death. To reduce the risk of forming deadly plaques, clinicians monitor patients’ serum cholesterol levels with a lipid panel. This lab test can give an early warning for patients at risk of developing atherosclerosis. If the levels of cholesterol must be reduced, a combination of lifestyle changes and pharmacological treatment can be initiated to bring the disease under control and reduce the risk of life-threatening consequences.
REFERENCES
- 1.↑
Grundy SM, Stone NJ, Bailey AL, et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139(25):e1082–e1143.
CHAPTER RESOURCES
Barrett KE, Barman SM, Brooks HL, et al.Ganong’s Review of Medical Physiology. 26th ed. New York, NY: McGraw-Hill; 2019.
DiPiro JT, Yee GC, Posey M, et al.Pharmacotherapy: A Pathophysiological Approach. 11th ed. New York, NY: McGraw-Hill; 2020.
The American Heart Association website. Available at http://www.heart.org. Accessed June 22, 2022.
REVIEW QUESTIONS
Define the terms lipid, cholesterol, and hyperlipidemia.
List the steps involved in the formation of an atherosclerotic plaque.
Calculate the LDL of a patient with a total cholesterol level of 170 mg/dL, HDL of 28 mg/dL, and triglycerides of 250 mg/dL.
Describe the differences between primary and secondary hyperlipidemias.
Describe the mechanism of action of the statins.
MEDICATION TABLE
Hyperlipidemia Pharmacotherapy2
CLASS Generic Name (pronunciation) |
Brand Name |
Route |
Forms |
Dose |
Notes |
|---|---|---|---|---|---|
Bile Acid Sequestrants |
|||||
Cholestyramine (koe LESS tir a meen) |
Questran, Questran Light, Prevalite |
Oral |
Powder |
4–12 g 1–2 times daily |
Significant gastrointestinal side effects limit use; the lower doses needed with colesevelam may reduce this risk |
Colesevelam (koh le SEV e lam) |
Welchol |
Oral |
Tablet |
3.75 g once daily |
|
Colestipol (koe LES ti pole) |
Colestid |
Oral |
Powder |
5–15 g 1–2 times daily (doses may be divided) |
|
Oral |
Tablet |
2–16 g 1–2 times daily |
|||
Cholesterol Absorbtion Inhibitors |
|||||
Ezetimibe (ez ET i mibe) |
Zetia |
Oral |
Tablet |
10 mg once daily |
No proven cardiovascular risk reduction |
Fibrates |
|||||
Fenofibrate (fen oh FYE brate) |
Antara |
Oral |
Capsule |
30–200 mg once daily |
Primarily target is triglycerides |
Lipofen |
Oral |
Capsule |
50–150 mg once daily |
||
Tricor |
Oral |
Tablet |
48–145 mg once daily |
||
Trilipix |
Oral |
Capsule |
45–135 mg once daily |
||
Gemfibrozil (jem FI broe zil) |
Lopid |
Oral |
Tablet |
600 mg 2 times daily |
More likely to interact with statins |
Niacin |
|||||
Niacin immediate release (NYE a sin) |
Niacor |
Oral |
Tablet |
250 mg–2 g 3 times daily |
Flushing most common with immediate-release form |
Niacin extended release (NYE a sin) |
Niaspan |
Oral |
Tablet |
500 mg–2 g at bedtime |
|
Niacin sustained release (NYE a sin) |
Slo Niacin |
Oral |
Tablet |
500 mg–1 g 2 times daily |
Liver injury most common with sustained-release form |
Omega 3 Fatty Acids |
|||||
Omega 3 fatty acids (oh MAY ga) |
Fish oil |
Oral |
Capsule |
3 g once daily |
Primarily target triglycerides |
Lovaza |
Oral |
Capsule |
4 g once daily |
||
Icosapent Ethyl (eye KOE sa pent ETH il) |
Vascepa |
Oral |
Capsule |
2 g 2 times daily |
|
Proprotein Convertase Sutilisin Kexin Type 9 (PCSK9) Inhibitors |
|||||
Alirocumab (al i ROK ue mab) |
Praluent |
SUBQ |
Solution |
75–150 mg every 2 weeks or 300 mg every 4 weeks |
|
Evolocumab (e voe LOK ue mab) |
Repatha |
SUBQ |
Solution |
140 mg every 2 weeks or 420 mg every 4 weeks |
|
Statins |
|||||
Atorvastatin (a TORE va sta tin) |
Lipitor |
Oral |
Tablet |
10–80 mg once daily |
Pleiotropic effects may give added benefits; often dosed at bedtime for maximal effect |
Lovastatin (LOE va sta tin) |
Mevacor |
Oral |
Tablet |
20–80 mg once daily |
|
Pitavastatin (pit A va stat in) |
Livalo |
Oral |
Tablet |
1–4 mg once daily |
|
Pravastatin (PRA va stat in) |
Pravachol |
Oral |
Tablet |
10–80 mg once daily |
|
Rosuvastatin (roe SOO va sta tin) |
Crestor |
Oral |
Tablet |
5–40 mg once daily |
|
Simvastatin (SIM va stat in) |
Zocor |
Oral |
Tablet |
20–80 mg once daily |
|
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