LC is a 51-year-old female with a history of CHD (stent placement in the left anterior descending coronary artery 3 years prior) and type 2 diabetes who is referred to you for follow-up of her cholesterol. She is taking simvastatin 20 mg once daily in the evening for her cholesterol, metformin 2,000 mg once daily in the evening, and pioglitizone 15 mg once daily for diabetes. Her diabetes is well controlled. Her laboratory test results are within normal limits, except for her fasting lipid profile: total cholesterol 215 mg/dL (5.57 mmol/L), triglycerides 135 mg/dL (1.53 mmol/L), HDL cholesterol 51 mg/dL (1.32 mmol/L), and LDL cholesterol 137 mg/dL (3.55 mmol/L).
What is your assessment ofLC's cholesterol results?
Identify treatment goals forLC.
Assess LC's risk for statin-induced side effects.
Design a treatment plan forLC.
Cholestyramine, colestipol, and colesevelam are the bile acid-binding resins or sequestrants (BAS) currently available in the United States. Resins are highly charged molecules that bind to bile acids (which are produced from cholesterol) in the gut. The resin-bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol resulting in an upregulation of LDL receptors to replenish hepatocellular stores which then result in a decrease in serum cholesterol. Resins have been shown
to reduce CHD events in patients without CHD.
Resins are moderately effective in lowering LDL cholesterol but do not lower triglycerides (Table 12-8). Moreover, in patients with elevated triglycerides, the use of a resin may worsen the condition. This may be due to a compensatory increase in HMG-CoA reductase activity and results in an increase in assembly and secretion of VLDL. The increase in HMG-CoA reductase activity can be blocked with a statin, resulting in enhanced reductions in serum lipids (see section on combination therapy). Resins reduce LDL cholesterol from 15% to 30%, with a modest increase in HDL cholesterol (3%-5%) (Table 12-8). Resins are most often used as adjuncts to statins in patients who require additional lowering of LDL cholesterol. Because these drugs are not absorbed, adverse effects are limited to the GI tract (Table 12-9). About 20% of patients taking cholestyramine or colestipol report constipation and symptoms such as flatulence and bloating. A large number of patients stop therapy because of this. Resins should be started at the lowest dose and escalated slowly over weeks to months as tolerated until the desired response is obtained. Patients should be instructed to prepare the powder formulations in 6 to 8 ounces (approximately 180-240 mL) of noncarbonated fluids, usually juice (enhances palatability) or water. Fluid intake should be increased to minimize constipation. Colesevelam is better tolerated with fewer gastrointestinal side effects, although it is more expensive. All resins have the potential to prevent the absorption of other drugs such as digoxin, warfarin, thyrox-ine, thiazides, P-blockers, fat-soluble vitamins, and folic acid. Potential drug interactions can be avoided by taking a resin either 1 hour before or 4 hours after these other agents. Colesevelam appears less likely than the older agents to reduce drug absorption, and the manufacturer does state that colesevelam has to be dosed hours apart from other medications that have been tested in in vitro binding or in vivo drug interaction testing or with postmarketing reports to interact. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow
therapeutic index, should be administered at least 4 hours prior to colesevelam. The time until maximum effect on lipids for resins is generally 2 to 4 weeks.
Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of Apo B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 12-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-Apo A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 12-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3
Several different niacin formulations are available: niacin immediate-release (IR),
niacin sustained-release (SR), and niacin extended-release (ER). ' These formulations differ in terms of dissolution and absorption rates, metabolism, efficacy, and side effects. Limitations of niacin IR and SR are flushing and hepatotoxicity, respectively. These differences appear related to the dissolution and absorption rates of niacin formulations and its subsequent metabolism. Niacin IR is available by prescription (Ni-
acor) as well as a dietary supplement which is not regulated by the FDA. Currently, there are no FDA-approved niacin SR products; thus, all SR products are available only as dietary supplements.
Niacin IR is usually completely absorbed within 1 to 2 hours; thus, it quickly saturates a high-affinity, low-capacity metabolic pathway, and the majority of the drug is metabolized by a second low-affinity, high-capacity system with metabolites associ-
ated with flushing. Conversely, absorption of niacin SR may exceed 12 hours. Because niacin SR is absorbed over 12 or more hours, the high-affinity pathway metabolizes the majority of the drug, resulting in the production of metabolites associated with hepatotoxicity. Niacin ER was developed as a once-daily formulation to be taken at bedtime, with the goal of reducing the incidence of flushing without increasing the risk of hepatotoxicity. Niacin ER (Niaspan) is the only long-acting niacin product approved by the FDA for dyslipidemia. Niacin ER has an absorption rate of 8 to 12 hours, intermediate to niacin IR and SR, and therefore balances metabolism more evenly over the high-affinity, low-capacity pathway and the low-affinity, high-capacity pathway. Furthermore, taking niacin ER at bedtime can minimize the impact of flushing.
Niacin use is limited by cutaneous reactions such as flushing and pruritus of the face and body. The use of aspirin or a nonsteroidal anti-inflammatory drug (NSAID) 30 minutes prior to taking niacin can help alleviate these reactions, as they are mediated by an increase in prostaglandin D2. In addition, taking niacin with food and avoiding hot liquids at the time niacin is taken is helpful in minimizing flushing and pruritus.
In general, niacin reduces LDL cholesterol from 5% to 25%, reduces triglycerides by 20% to 50%, and increases HDL cholesterol by 15% to 35% (Table 12-8). Niacin has been shown to reduce CHD events and total mortality.36 as well as the progres-
sion of atherosclerosis when combined with a statin.
However, several clinical trials have shown that niacin can be used safely and effect-
ively in patients with diabetes. Due to the high cardiovascular risk of patients with diabetes, the benefits of improving the lipid profile appear to outweigh any adjustment in diabetic medication(s) that is needed. 9
Niacin should be instituted at the lowest dose and gradually titrated to a maximum dose of 2 g daily for ER and SR products and no more than 5 g daily for IR products. FDA-approved niacin products are preferred because of product consistency. Moreover, niacin products labeled as "no flush" don't contain nicotinic acid and
therefore have no therapeutic role in the treatment of lipid disorders. The time until maximum effect on lipids for niacins is generally 3 to 5 weeks.
The predominant effects of fibrates are a decrease in triglyceride levels by 20% to 50% and an increase in HDL cholesterol levels by 9% to 30% (Table 12-8). The effect on LDL cholesterol is less predictable. In patients with high triglycerides, however, LDL cholesterol may increase. Fibrates increase the size and reduce the density of LDL particles much like niacin. Fibrates are the most effective triglyceride-lowering drugs and are used primarily in patients with elevated triglycerides and low HDL cholesterol.
Fibrates work by reducing Apos B, C-III (an inhibitor of LPL), and E, and increasing Apos A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these Apos result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL.
Clinical trials of fibrate therapy in patients with elevated cholesterol and no history of CHD demonstrated a reduction in CHD incidence, although less than the reduction attained with statin therapy.40 In addition, a large study of men with CHD, low HDL cholesterol, low LDL cholesterol, and elevated triglycerides demonstrated a 24% reduction in the risk of death from CHD, nonfatal MI, and stroke with gemfibrozil.41 Fibrates may be appropriate in the prevention of CHD events for patients with established CHD, low HDL cholesterol, and triglycerides below 200 mg/dL (2.26 mmol/ L). However, LDL-lowering therapy should be the primary target if LDL cholesterol is elevated. Evidence of a reduction in CHD risk among patients with established CHD has not been demonstrated with fenofibrate.
The fibric acid derivatives are generally well tolerated. The most common adverse effects include dyspepsia, abdominal pain, diarrhea, flatulence, rash, muscle pain, and fatigue (Table 12-9). Myopathy and rhabdomyolysis can occur, and the risk appears to increase with renal insufficiency or concurrent statin therapy. If a fibrate is used with a statin, fenofibrate is preferred because it appears to inhibit the glucuronidation of the statin hydroxy and moiety less than gemfibrozil, allowing greater renal clearance of the statins.2 ,42 A CK level should be checked before therapy is started and if symptoms occur. Liver dysfunction has been reported, and LFTs should be monitored. Fibrates increase cholesterol in the bile and have caused gallbladder and bile duct disorders, such as cholelithiasis and cholecystitis. Unlike niacin, these agents do not increase glucose or uric acid levels. Fibrates are contraindicated in patients with gallbladder disease, liver dysfunction, or severe kidney dysfunction. The risk of bleeding is increased in patients taking both a fibrate and warfarin. The time until maximum effect on lipids is generally 2 weeks for fenofibrate and 3 to 4 weeks for gemfibrozil.
03FAs (eicosapentaenoic acid and docosahexaenoic acid), the predominant fatty acids in the oil of cold-water fish, lower triglycerides by as much as 35% when taken in large amounts. Fish oil supplements may be useful for patients with high triglycerides despite diet, alcohol restriction, and fibrate therapy. This effect may be modulated through PPAR-a and a reduction in Apo B-100 secretion. 03FAs reduce platelet aggregation and have antiarrhythmic properties, and therefore their use has been associated with a reduction in MI and sudden cardiac death, respectively.43
Prescription grade 03FAs are FDA approved at a dose of 4 g daily for the treatment of elevated triglycerides. Use of high-quality 03FAs free of contaminants such as mercury and organic pollutants should be encouraged when using these agents. Common side effects associated with 03FAs are diarrhea and excess bleeding. Patients taking anticoagulant or antiplatelet agents should be monitored more closely when consuming these products because excessive amounts of 03FAs (e.g., greater than 3 g daily) may lead to bleeding and may increase the risk of hemorrhagic stroke.
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