[PCSK9] Inhibitors)
Alirocumab [Praluent] and evolocumab [Repatha] compose a new type of drug class used for patients with high LDL
carries some risk. Methylmercury can cause heart disease as well as neurologic damage, manifesting as tremor, numbness, tingling, altered vision, and impaired concentration. Exposure in utero or during early childhood can lead to developmental delay, blindness, and seizures. With dioxin and PCBs, carci- nogenesis is the major concern. Does this mean we should avoid eating fish?
No. For postmenopausal women and for men who are middle-aged or older, the benefits of fish outweigh the risks. For women who are pregnant or breast-feeding, fish consumption should be limited to 12 ounces a week, and certain species—swordfish, king mackerel, shark, and golden snapper, all of which may have high levels of methylmercury—should be avoided entirely.
Young children should limit fish consumption too. For people who like salmon, dioxin exposure can be reduced by eating wild salmon, which contains much less dioxin than farm-raised salmon. Exposure to all contaminants can be reduced by using fish-oil supplements, which have much less contamination than fish themselves.
Lovaza
Lovaza is the brand name for the first preparation of omega-3-acid ethyl esters approved by the FDA. The product, available only by prescription, contains a combination of EPA and DHA. Lovaza is approved as an adjunct to dietary measures to reduce very high levels of TGs (500 mg/dL or greater). When used alone, Lovaza can reduce TG levels by 20% to 50%. Combining it with simvastatin produces a further decrease. Because large doses of omega-3 fatty acids can impair platelet function, leading to prolonged bleeding time, the product should be used with care in patients taking anticoagulants or antiplatelet drugs, including aspirin. Lovaza is supplied in 1-gm, liquid-filled, soft-gelatin capsules that contain approximately 465 mg of EPA and approximately 375 mg of DHA. The recommended dosage is 4 gm/day, taken either all at once (4 capsules) or in two doses (2 capsules twice a day).
Plant Stanol and Sterol Esters
Stanol esters and sterol esters, which are analogs of cholesterol, can reduce intestinal absorption of cholesterol (by 10%) and can thereby reduce levels of LDL cholesterol (by 14%). These compounds do not affect HDL levels or TG levels. ATP III recommends adding plant stanols or sterols to the diet if the basic TLC diet fails to reduce LDL cholesterol to the target level. Where can you get plant stanols and sterols? Two good sources are the Benecol brand of margarine and soft spreads sold under the brand name Promise.
Cholestin
Cholestin is the brand name for a dietary supplement that can lower cholesterol levels. The product is made from rice fermented with red yeast. Its principal active ingredient—lovastatin—is identical to the active ingredient in Mevacor, a brand-name, cholesterol-lowering drug. In addition to lovastatin, Cholestin contains at least seven other HMG-CoA reductase inhibitors (statins).
Several clinical trials have demonstrated that Cholestin can lower cholesterol levels, although none has studied its effects on CV events. In a trial conducted at Tufts University School of Medicine, Cholestin reduced total cholesterol by 11.4% and LDL cholesterol by 21%, and increased HDL cholesterol by 14.6%. Similarly, in a study conducted at the University of California at Los Angeles Medical School, Cholestin reduced total cholesterol by 16% and LDL cholesterol by 22%. Whether Cholestin also reduces the incidence of ASCVD is unknown.
Information on Cholestin is lacking in four important areas: clinical benefits, adverse effects, drug interactions, and precise mechanism of action. As noted, there are no data on the ability of Cholestin to reduce the risk of MI, stroke, or any other CV event. In contrast, the clinical benefits of prescription statins (lovastatin and all the others) are fully documented. There is little or no information on the adverse effects or drug interactions of Cholestin. In contrast, the safety (and hazards) of prescription statins, as well as their drug interactions, have been studied extensively.
The mechanism by which Cholestin lowers cholesterol levels is only partly understood. The recommended daily dose of Cholestin contains only 5 mg of lovastatin and varying doses of other HMG-CoA reductase inhibitors, compared with 10 mg for the lowest recommended dose of Mevacor. Hence, it seems unlikely that the statins in Cholestin can fully account for the supple- ment’s ability to reduce cholesterol levels. This implies that Cholestin has one or more active ingredients that have not yet been identified. What they are and how they may work is a mystery.
What’s the bottom line? Until more is known about Cholestin, stick with statins—medications of proven safety and efficacy. Furthermore, for people with health insurance, using statins is cheaper: Most insurers will cover the cost of statins, but will not pay for Cholestin.
Despite the advantages of Vytorin, some authorities are concerned that the combination may be less beneficial than simvastatin alone. This concern is based on four facts:
• We have proof that simvastatin alone can decrease adverse outcomes (i.e., MI and other CV events).
• We have no proof that the combination can decrease adverse outcomes of elevated cholesterol (even though it can reduce levels of cholesterol).
• In addition to lowering cholesterol, statins have other beneficial actions (e.g., they often lower elevated TGs).
• When ezetimibe and simvastatin are combined, cholesterol goals can be met using simvastatin in reduced dosage (which is a problem for reasons discussed in the paragraph that follows).
Because the combination permits a reduction in simvastatin dosage, there is concern that although the target cholesterol goal may be reached, the reduction in adverse outcomes may be smaller than when cholesterol is lowered using simvastatin alone. Despite concerns, the FDA reviewed the evidence and determined that, although there was no significant change in carotid artery thickness after taking Vytorin, there was a significant decrease in LDL cho- lesterol in people taking Vytorin, which may decrease CV risk. For this reason, the FDA recommends that patients continue treatment on Vytorin.
Adverse Effects and Drug Interactions. Vytorin is generally well tolerated. However, myopathy is a concern (because both drugs can cause muscle injury). Concurrent use of a fibrate, which can also cause myopathy, increases risk. The risk of myopathy and other adverse effects is also increased by inhibitors of CYP3A4, the enzyme that inactivates simvastatin. Because Vytorin contains a statin, the product is contraindicated for women who are pregnant and for patients with liver disease.
Preparations, Dosage, and Administration. Vytorin tablets contain 10 mg of ezetimibe plus either 10, 20, 40, or 80 mg of simvastatin. The usual starting dosage is 10 mg ezetimibe/20 mg simvastatin each day. Dosing is done once daily, preferably in the evening. The simvastatin dosage can be increased as needed and tolerated.
Atorvastatin/Amlodipine [Caduet]
Atorvastatin and amlodipine (a calcium channel blocker) are available in fixed-dose combination tablets under the brand name Caduet. This is the first single product indicated for dyslipidemia combined with hypertension and/or angina. The combination has one advantage over taking each drug separately: fewer pills to swallow. Eleven amlodipine/atorvastatin combinations are available: 2.5 mg amlodipine with either 10, 20, or 40 mg atorvastatin;
5 mg amlodipine with either 10, 20, 40, or 80 mg atorvastatin; and 10 mg amlodipine with either 10, 20, 40, or 80 mg atorvastatin. Dosage is individual- ized on the basis of therapeutic response and tolerance of adverse effects. The pharmacology of amlodipine and other calcium channel blockers is discussed in Chapter 45.
Fish Oil
Consuming fatty fish or fish-oil supplements was once associated with a decreased risk of ASCVD and ASCVD-related death. Unfortunately, recent studies have revealed that consuming fish oil provides no advantage in the prevention of heart disease in high-risk populations. Yet, it is still believed that taking fish oil can reduce the incidence of heart dysrhythmias after MI or heart failure.
Fish oil may be beneficial in the prevention of heart dysrhythmias because it contains two “heart healthy” compounds: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both compounds are long-chain, omega-3 polyunsaturated fatty acids, with a methyl group at one end and a carboxyl group at the other. They are called omega-3 fatty acids because they have a double bond located three carbons in from the methyl terminus.
How do omega-3 fatty acids help us? The answer is unclear. Benefits of lower doses (850 mg to 1 gm) may result from reducing platelet aggregation;
reducing thrombosis (by effects on platelets and the vascular endothelium);
reducing inflammation (which may help stabilize atherosclerotic plaques);
and reducing blood pressure and cardiac dysrhythmias.
As the evidence is so new regarding lack of benefit in the primary prevention of heart disease, the American Heart Association still recommends eating at least two servings of fish a week. Fish with high concentrations of EPA and DHA are preferred. Among these are mackerel, halibut, herring, salmon, albacore tuna, and trout. The goal is to take in, on average, about 1 gm of fish oil a day.
Because fish concentrate certain environmental contaminants—especially methylmercury, dioxins, and polychlorinated biphenyls (PCBs)—eating fish
KEY POINTS
■ Lipoproteins are structures that transport lipids (cholesterol and triglycerides [TGs]) in blood.
■ Lipoproteins consist of a hydrophobic core, a hydrophilic shell, plus at least one apolipoprotein, which serves as a recognition site for receptors on cells.
■ Lipoproteins that contain apolipoprotein B-100 transport cholesterol and/or TGs from the liver to peripheral tissues.
■ Lipoproteins that contain apolipoproteins A-I or A-II transport cholesterol from peripheral tissues back to the liver.
■ There are three major types of lipoproteins: VLDLs (very- low-density lipoproteins), LDLs (low-density lipoproteins), and HDLs (high-density lipoproteins).
■ VLDLs transport TGs to peripheral tissues.
■ The contribution of VLDLs to ASCVD is unclear.
■ LDLs transport cholesterol to peripheral tissues.
■ Elevation of LDL cholesterol greatly increases the risk of ASCVD.
■ By reducing LDL cholesterol levels, we can arrest or reverse atherosclerosis, and can thereby reduce morbidity and mortality from ASCVD.
■ HDLs transport cholesterol back to the liver.
■ HDLs protect against ASCVD.
■ Atherogenesis is a chronic inflammatory process that begins with accumulation of LDLs beneath the arterial endothe- lium, followed by oxidation of LDLs.
■ All adults older than 20 years should be screened every 5 years for total cholesterol, LDL cholesterol, HDL choles- terol, and TGs.
■ Treatment of high LDL cholesterol is based on the indi- vidual’s 10-year risk of having a major coronary event.
■ Individuals with established ASCVD or an ASCVD risk equivalent (e.g., diabetes) are in the highest 10-year risk group.
■ Diet modification along with exercise is the primary method for reducing LDL cholesterol. Drugs are employed only if diet modification and exercise fail to reduce LDL cholesterol to the target level.
■ Therapy with cholesterol-lowering drugs must continue lifelong. If these drugs are withdrawn, cholesterol levels will return to pretreatment values.
■ Statins (HMG-CoA reductase inhibitors) are the most effective drugs for lowering LDL cholesterol, and they cause few adverse effects.
■ Statins can slow progression of ASCVD, decrease the number of adverse cardiac events, and reduce mortality.
■ Statins reduce LDL cholesterol levels by increasing the number of LDL receptors on hepatocytes, thereby enabling hepatocytes to remove more LDLs from the blood. The process by which LDL receptor number is increased begins with inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.
■ Four statins—atorvastatin, fluvastatin, lovastatin, and simvastatin—are metabolized by CYP3A4, and hence their levels can be increased by CYP3A4 inhibitors (e.g., cyclosporine, erythromycin, ketoconazole, ritonavir).
■ Statins can cause liver damage. Tests of liver function should be done at baseline and as clinically indicated thereafter.
■ Statins can cause myopathy. Patients who experience unusual muscle pain, soreness, tenderness, and/or weakness should inform their provider. A marker for muscle injury—
creatine kinase (CK)—should be measured at baseline, before starting the drug, and whenever signs or symptoms that could be due to myositis or myopathy develop.
■ Statins should not be used during pregnancy.
■ Bile-acid sequestrants (e.g., colesevelam) reduce LDL cho- lesterol levels by increasing the number of LDL receptors on hepatocytes. The mechanism is complex and begins with preventing reabsorption of bile acids in the intestine.
■ Bile-acid sequestrants are not absorbed from the GI tract, and hence do not cause systemic adverse effects. However, they can cause constipation and other GI effects. (GI effects with one agent—colesevelam—are minimal.)
■ Older bile-acid sequestrants form complexes with other drugs and thereby prevent their absorption. Accordingly, oral medications should be administered 1 hour before the sequestrant or 4 hours after. With a newer sequestrant—
colesevelam—these interactions are minimal.
■ Ezetimibe lowers LDL cholesterol by reducing cholesterol absorption in the small intestine.
■ Like the statins, ezetimibe can cause muscle injury.
■ Gemfibrozil and other fibrates are the most effective drugs for lowering TG levels.
■ Like the statins, the fibrates can cause muscle injury.
Please visit http://evolve.elsevier.com/Lehne for chapter- specific NCLEX® examination review questions.
Summary of Major Nursing Implications
aIMPLICATIONS THAT APPLY TO ALL DRUGS THAT LOWER LDL CHOLESTEROL
Preadministration Assessment Baseline Data
Obtain laboratory values for total cholesterol, LDL cholesterol, HDL cholesterol, and TGs (VLDLs).
Identifying ASCVD Risk Factors
The patient history and physical examination should identify ASCVD risk factors. These include smoking, advancing age, a personal history of ASCVD, reduced levels of HDL cho- lesterol (below 40 mg/dL), and hypertension.
In the past, diabetes was considered an ASCVD risk factor.
However, because the association between diabetes and
ASCVD is so strong, diabetes is now considered an ASCVD risk equivalent (i.e., it poses the same 10-year risk of a major coronary event as ASCVD itself).
Measures to Enhance Therapeutic Effects Diet Modification
Diet modification should precede and accompany drug therapy for elevated LDL cholesterol. Inform patients about the importance of diet in controlling cholesterol levels, and arrange for dietary counseling. Advise patients to limit consumption of cholesterol (to below 200 mg/day) and saturated fat (to below 7% of caloric intake). If these measures fail to reduce LDL cholesterol to the target level, advise patients to add soluble fiber and plant stanols or sterols to the regimen.
Exercise
Regular exercise can reduce LDL cholesterol and elevate HDL cholesterol, reducing the risk of ASCVD. Help the
patient establish an appropriate exercise program.
Reduction of ASCVD Risk Factors
Correctable ASCVD risk factors should be addressed. Encour-
age smokers to quit. Disease states that promote ASCVD—
diabetes mellitus and hypertension—must be treated.
Promoting Compliance
Drug therapy for elevated LDL cholesterol must continue lifelong; if drugs are withdrawn, cholesterol levels will return to pretreatment values. Inform patients about the need for continuous therapy, and encourage them to adhere to the prescribed regimen.
HMG-COA REDUCTASE INHIBITORS (STATINS) Atorvastatin
Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin
In addition to the implications discussed below, see earlier in this summary for implications that apply to all drugs that lower LDL cholesterol.
Preadministration Assessment Therapeutic Goal
Statins, in combination with diet modification and exercise, are used primarily to lower levels of LDL cholesterol.
Additional indications are shown in Table 50.7.
Baseline Data
Obtain a baseline lipid profile, consisting of total cholesterol, LDL cholesterol, HDL cholesterol, and TGs (VLDLs). Also, obtain baseline LFTs and a CK level.
Identifying High-Risk Patients
Statins are contraindicated for patients with viral or alcoholic hepatitis and for women who are pregnant.
Exercise caution in patients with nonalcoholic fatty liver disease, in those who consume alcohol to excess, and in those taking fibrates or ezetimibe or agents that inhibit CYP3A4 (e.g., cyclosporine, erythromycin, ketoconazole, ritonavir). Use rosuvastatin with caution in Asian patients.
Implementation: Administration Route
Oral.
Administration
Instruct patients to take lovastatin with the evening meal;
all other statins can be administered without regard to meals.
Advise patients that dosing in the evening is preferred for all statins.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Cholesterol levels should be monitored monthly early in treatment and at longer intervals thereafter.
Minimizing Adverse Effects
Statins are very well tolerated. Side effects are uncommon, and serious adverse effects—hepatotoxicity and myopathy—
are relatively rare.
Hepatotoxicity. Statins can injure the liver, but jaundice and other clinical signs are rare. Liver function should be assessed before treatment and as clinically indicated thereafter.
If serum transaminase becomes persistently excessive (more than 3 times the ULN), statins should be discontinued. Statins should be avoided in patients with alcoholic or viral hepatitis, but may be used in patients with nonalcoholic fatty liver disease.
Myopathy. Statins can cause muscle injury. If statins are not withdrawn, injury may progress to severe myositis or potentially fatal rhabdomyolysis. Inform patients about the risk of myopathy, and instruct them to notify the prescriber if unexplained muscle pain or tenderness develops. If muscle pain does develop, the CK level should be measured, and if it is more than 10 times the ULN, the statin should be withdrawn or changed.
Minimizing Adverse Interactions
The risk of myopathy is increased by (1) gemfibrozil, feno- fibrate, and ezetimibe, which promote myopathy themselves;
and by (2) inhibitors of CYP3A4—such as cyclosporine, macrolide antibiotics (e.g., erythromycin), azole antifungal drugs (e.g., ketoconazole), and HIV protease inhibitors (e.g., ritonavir)—which can cause statin levels to rise. The combina- tion of a statin with any of these drugs should be used with caution.
Use in Pregnancy
Statins are contraindicated during pregnancy. Inform women of childbearing age about the potential for fetal harm and warn them against becoming pregnant. If pregnancy occurs and the patient intends to continue the pregnancy, statins should be withdrawn.
Summary of Major Nursing Implications
a—cont’d
aPatient education information is highlighted as blue text.
BILE-ACID SEQUESTRANTS Cholestyramine
Colesevelam Colestipol
In addition to the implications discussed here, see earlier in this summary for implications that apply to all drugs that lower LDL cholesterol.
Preadministration Assessment Therapeutic Goal
Bile-acid sequestrants, in conjunction with diet modification and exercise (and a statin if necessary), are used to reduce elevated levels of LDL cholesterol.
Baseline Data
Obtain laboratory values for total cholesterol, LDL cholesterol, HDL cholesterol, and TGs (VLDLs).
Implementation: Administration Route
Oral.
Administration
Instruct patients to mix cholestyramine powder and colestipol granules with water, fruit juice, soup, or pulpy fruit (e.g., applesauce, crushed pineapple) to reduce the risk of esopha- geal irritation and impaction. Inform patients that the sequestrants are not water soluble, so the mixtures will be cloudy suspensions, not clear solutions.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Cholesterol levels should be monitored monthly early in treatment and at longer intervals thereafter.
Minimizing Adverse Effects
Constipation. Cholestyramine and colestipol—but not colesevelam—can cause constipation. Inform patients that constipation can be minimized by increasing dietary fiber and fluids. A mild laxative may be used if needed. Instruct patients taking cholestyramine or colestipol to notify the prescriber if constipation becomes bothersome, in which case a switch to colesevelam should be considered.
Vitamin Deficiency. Cholestyramine and colestipol—but not colesevelam—can impair absorption of fat-soluble vitamins (A, D, E, and K). Vitamin supplements may be required.
Colesevelam does not reduce vitamin absorption.
Minimizing Adverse Interactions
Cholestyramine and colestipol—but not colesevelam—can bind with other drugs and prevent their absorption. Advise patients to administer other medications 1 hour before these sequestrants or 4 hours after.
GEMFIBROZIL
Preadministration Assessment Therapeutic Goal
Gemfibrozil, in conjunction with diet modification, is used to reduce elevated levels of TGs (VLDLs). The drug is not very effective at lowering LDL cholesterol. It may also be used to raise low levels of HDL cholesterol.
Baseline Data
Obtain laboratory values for total cholesterol, LDL cholesterol, HDL cholesterol, and TGs (VLDLs).
Identifying High-Risk Patients
Gemfibrozil is contraindicated for patients with liver disease, severe renal dysfunction, and gallbladder disease.
Use with caution in patients taking statins or warfarin.
Implementation: Administration Route
Oral.
Administration
Instruct patients to administer gemfibrozil 30 minutes before the morning and evening meals.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Obtain periodic tests of blood lipids.
Minimizing Adverse Effects
Gallstones. Gemfibrozil increases gallstone development.
Inform patients about symptoms of gallbladder disease (e.g., upper abdominal discomfort, intolerance of fried foods, bloating), and instruct them to notify the prescriber if these develop.
Myopathy. Gemfibrozil can cause muscle damage. Warn
patients to report any signs of muscle injury, such as tender- ness, weakness, or unusual muscle pain.
Liver Disease. Gemfibrozil may disrupt liver function.
Cancer of the liver may also be a risk. Obtain periodic tests of liver function.
Minimizing Adverse Interactions
Warfarin. Gemfibrozil enhances the effects of warfarin, thereby increasing the risk of bleeding. Obtain more frequent measurements of prothrombin time and assess the patient for signs of bleeding. Reduction of warfarin dosage may be required, and reassessment and readjustment of the warfarin dosage may be needed if the fibrate is stopped.
Statins. Gemfibrozil and statins both cause muscle injury.
Risks rise when both are used. Use the combination with caution.