Pharmacologic Interventions Statins

Natural Cholesterol Guide

Lower Cholesterol Book

Get Instant Access

The statins are reversible, competitive 3-hydroxy-3-meth-ylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. HMG-CoA reductase is the rate-limiting step for cholesterol biosynthesis in the liver and systemic tissues. Statins are the most potent agents for reducing serum levels of LDL-C. The statins augment the elimination of atherogenic apoB100-con-taining lipoproteins (VLDL, VLDL remnants, and LDL) from plasma by upregulating the LDL receptor on the surface of hepatocytes. The statins also reduce VLDL secretion and stimulate apoprotein-AI expression and hepatic HDL secretion.

Many prospective, placebo-controlled clinical trials have shown that the statins significantly reduce rates of MI, stroke, and coronary and all-cause mortality in the primary prevention (Downs et al., 1998) and secondary prevention settings (Scandinavian Simvastatin Survival Study Group, 1994). Statins reduce the frequency of stable and unstable angina and decrease atheromatous plaque progression and, based on intravascular ultrasound measurement (Nissen et al., 2004), quantitative coronary angiography, and high-resolution magnetic resonance imaging (Corti et al., 2002), even stimulate some degree of plaque resorption. The statins reduce cardiovascular events in men and women, blacks and Hispanics, hypertensive and diabetic patients, smokers, and patients over age 70.

Seven statins are currently available. These drugs differ by potency and a number of pharmacokinetic properties. The choice of statin and its dosing depend on the magnitude of LDL-C and non-HDL-C reduction required (baseline vs. risk-stratified NCEP target). The LDL-C-lowering efficacy of the statins is as follows (e.g., Jones et al., 2003): Rosuvastatin (Crestor): 45%-63% (5-40 mg daily) Atorvastatin (Lipitor): 26%-60% (10-80 mg daily) Simvastatin (Zocor): 26%-47% (10-80 mg daily) Lovastatin (Mevacor): 21%-42% (10-80 mg daily) Fluvastatin (Lescol): 22%-36% (10-20 mg daily) Pitavastatin (Livalo): 32%-43% (1-4 mg daily) Pravastatin (Pravachol): 22%-34% (10-80 mg daily)

Each doubling of a statin's dose yields an additional 6% reduction, on average, in serum LDL-C ("rule of 6s"). Patients who are heterozygous or homozygous for familial hyper-cholesterolemia frequently require high potency statins at their highest doses coupled to stringent restriction in dietary lipid ingestion and the addition of one or more other lipid-lowering agents. The statins induce significant reductions in serum TG levels (typically 10%-25%) and modest elevations in serum HDL-C (2%-14%). Unlike the other statins, atorvastatin therapy is associated with decreasing capacity for raising HDL-C as a function of increasing doses. In patients with high baseline serum TG levels (>300 mg/dL), simvastatin and rosuvastatin raise HDL-C up to 18% and 22%, respectively.

The statins display significant differences in their pharma-cokinetic profiles. Because of their relatively short half-life (1-4 hours), lovastatin, fluvastatin, pravastatin, and simvas-tatin should be taken after the evening meal in order to intercept the peak activity of HMG-CoA reductase, which occurs around midnight. Rosuvastatin and atorvastatin can be taken at any time during the day or night because of their long half-life (~19 and 14 hours, respectively). The coadministra-tion of drugs or compounds that inhibit cytochrome P450 3A4 (macrolide antibiotics [erythromycin, clarithromycin], azole-type antifungals [ketoconazole, itraconazole], cyclo-sporine, HIV protease inhibitors, nefazodone, >1 qt grapefruit juice daily) with atorvastatin, simvastatin, and lovastatin is contraindicated because these statins depend on this P450 isozyme for oxidative modification and elimination (Neu-vonen et al., 1998). CYP3A4 inhibition is associated with increased risk for myopathy and hepatotoxicity. The dose of

Figure 27-2 Gastrointestinal absorption of dietary and biliary lipid and cholesterol. In the gastrointestinal tract, cholesterol and triglycerides arising from biliary and dietary sources are assimilated with bile salts and phospholipids to form micelles. Micelles transport cholesterol and lipid to the jejunal brush border. Along the enterocyte surface, the sterol transporter known as Niemann Pick C1 Like 1 (NPC1L1) protein is responsible for importing cholesterol and phytosterols into the neurocyte. Once internalized, the cholesterol is esterified to cholesterol esters via the activity of acyl-CoA acyltransferase (ACAT). The esterified cholesterol is packaged with triglycerides, phospholipids, and apoprotein B48 (ApoB48) to form chylomicrons in an assimilation reaction catalyzed by microsomal transfer protein (MTP). The chylomicrons are released into gastrointestinal lacteals which conduct these lipoproteins into the central circulation. Excess intracellular sterols can be excreted back into the GI tract via the activity of the sterol exporter complex ABCG5/G8 (ATP-binding membrane cassette transporter G5/G8). (Reproduced with permission from Toth PP, Davidson MH. Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 2005;5:455-462.)

Knee Plica Exercises

Figure 27-2 Gastrointestinal absorption of dietary and biliary lipid and cholesterol. In the gastrointestinal tract, cholesterol and triglycerides arising from biliary and dietary sources are assimilated with bile salts and phospholipids to form micelles. Micelles transport cholesterol and lipid to the jejunal brush border. Along the enterocyte surface, the sterol transporter known as Niemann Pick C1 Like 1 (NPC1L1) protein is responsible for importing cholesterol and phytosterols into the neurocyte. Once internalized, the cholesterol is esterified to cholesterol esters via the activity of acyl-CoA acyltransferase (ACAT). The esterified cholesterol is packaged with triglycerides, phospholipids, and apoprotein B48 (ApoB48) to form chylomicrons in an assimilation reaction catalyzed by microsomal transfer protein (MTP). The chylomicrons are released into gastrointestinal lacteals which conduct these lipoproteins into the central circulation. Excess intracellular sterols can be excreted back into the GI tract via the activity of the sterol exporter complex ABCG5/G8 (ATP-binding membrane cassette transporter G5/G8). (Reproduced with permission from Toth PP, Davidson MH. Cholesterol absorption blockade with ezetimibe. Curr Drug Targets Cardiovasc Haematol Disord 2005;5:455-462.)

simvastatin should be 20 mg or less daily in patients being treated with amiodarone or verapamil.

Although there is some concern about the potential toxicity of statins, their benefits significantly outweigh their risks. Liver toxicity can occur and is defined as an alanine transaminase (ALT) elevation of three times or more the upper limit of normal (ULN) on two occasions at least 1 month apart. The average risk of hepatotoxicity from statin therapy is approximately 1%, but risk increases as a function of increasing doses. Mild elevations in serum transaminase levels early during the course of therapy are relatively common and usually resolve spontaneously. If hepatotoxicity develops, statin therapy should be discontinued until transaminase levels normalize and therapy with a different statin can be initiated. There is no documented evidence that the statins increase risk for liver failure. The most important adverse event associated with statin therapy is rhabdomyolysis, myoglobinuria, and renal failure. The risk for rhabdomyolysis is less than 0.1%. Symptoms of rhabdomyolysis include worsening muscle pain, proximal weakness, nausea and vomiting, and brownish-red discoloration of urine. The statins can cause myalgia. If a patient develops myalgia or muscle weakness, a serum creatine kinase (CK) level can be obtained. The diagnosis of myopathy is made when CK levels exceed 10 times ULN. When assessing myalgia, it is important to evaluate patients for pain caused by arthritis, tendinopathy, fibromyalgia, and muscle strain induced by exertion.

Ezetimibe

Dietary and biliary sources contribute significantly to serum levels of cholesterol (Fig. 27-2). Although plant sterols and stanols block gastrointestinal (GI) cholesterol absorption, ezetimibe (Zetia) is the first member of a class of lipid-lowering drugs known as cholesterol absorption inhibitors. Mechanistically, ezetimibe inhibits the Niemann-Pick C1 Like-1 protein, which mediates cholesterol and phytosterol transport along the brush border of the jejunal enterocyte (Altmann et al., 2004; Davis et al., 2004). After glucuronida-tion, ezetimibe undergoes enterohepatic recirculation with negligible systemic exposure. The half-life of ezetimibe is approximately 22 hours. When dosed at 10 mg once daily, ezetimibe reduces serum LDL-C on average by 20%, but up to 24% of patients experience a reduction of 25% or greater (Ballantyne et al., 2004; Davidson et al., 2002). Ezetimibe also decreases TGs by up to 8% and raises HDL-C by up to 4%. Ezetimibe does not decrease the absorption of bile acids, steroid hormones (ethinyl estradiol, progesterone), or such fat-soluble vitamins as vitamins A, D, E, or a- and p-carotenes.

The risk of hepatotoxicity with ezetimibe is almost identical to placebo (0.5% vs. 0.3%), and there is no documented evidence of increased risk for myopathy. Fixed-dose ezetimibe is also available in combination with increasing doses of simvastatin (Vytorin; 10/10, 10/20, 10/40, 10/80 mg daily). Ezetimibe can also be safely used in combination with other statins (Toth and Davidson, 2005). The ezetimibe provides additive changes in lipoprotein levels to that observed with statin therapy. The addition of ezetimibe to a statin regimen substantially reduces the likelihood of needing to titrate the statin.

Bile Acid-Binding Resins

The bile acid sequestration agents (BASAs) are orally administered anion-exchange resins that bind bile acids in the GI tract and prevent them from being reabsorbed into the enterohepatic circulation. These drugs reduce serum LDL-C by two mechanisms: (1) increased catabolism of cholesterol secondary to the upregulation of 7-a-hydroxylase, the rate-limiting enzyme for the conversion of cholesterol into bile acids; and (2) increased expression of LDL receptors on the hepatocyte surface, which augments the clearance of apoB100-containing lipoproteins from plasma. At maximum doses, the BASA can reduce serum LDL-C by 15% to 30% and increase HDL-C by 3% to 5%. It is recommended that these drugs be used in conjunction with a statin whenever possible because BASA therapy increases HMG-CoA reductase activity in the liver, which leads to increased hepatic biosynthesis of cholesterol, thereby offsetting the effects of the BASA over time. The BASAs are contraindicated in patients with serum TG levels greater than 400 mg/dL because these agents can exacerbate hypertriglyceridemia.

There are currently three different BASAs available: cho-lestyramine (Questran; 4-24 g in 2-3 divided doses daily), colestipol (Colestid; 5-30 g in 2-3 divided doses daily), and colesevelam (Welchol; 1250 mg 2-3 times daily). The development of constipation, flatulence, and bloating is relatively frequent, although colesevelam has the most favorable side-effect profile of the three available BASAs. Increasing water and soluble-fiber ingestion ameliorates some of the difficulty with constipation. The BASA bind negatively charged molecules in a nonspecific manner. Consequently, they can decrease the absorption of warfarin, phenobarbital, thiazide diuretics, digitalis, p-blockers, thyroxine, statins, fibrates, and ezetimibe. These medications should be taken 1 hour before or 4 hours after the ingestion of BASA. The BASA can reduce the absorption of fat-soluble vitamins. Colesevelam also has an indication to reduce serum glycated hemoglobin levels in patients with diabetes mellitus.

Fibrates

The fibrates are fibric acid derivatives that exert a number of effects on lipoprotein metabolism. These agents reduce serum TG levels by 25% to 50% and raise HDL-C by 10% to 20%. Fibrates activate lipoprotein lipase (LPL) by reducing levels of apoprotein CIII (inhibitor of LPL) and increasing levels of apoprotein CII (activator of LPL) (Fruchart et al., 1999). This stimulates TG hydrolysis in chylomicrons and VLDL. Fibrates increase HDL-C by two mechanisms. First, the fibrates are PPAR-a agonists and stimulate increased hepatic expression of apoproteins AI and AII. Second, by activating LPL, surface coat mass derived from VLDL is ultimately used to assimilate HDL in serum. In some patients, fibrate therapy may be associated with an increase in serum LDL-C ("p" effect) secondary to increased enzymatic conversion of VLDL to LDL. This effect may diminish over time as the patient increases the expression of hepatic LDL receptors.

The fibrates are particularly valuable for treating dyslipid-emia in patients with a combination of hypertriglyceridemia and low HDL-C. In this patient type, post hoc evaluations of data from two studies (Helsinki Heart Study and Bezafibrate Infarction Prevention Study) have demonstrated substantial cardiovascular event rate reductions using fibrate therapy (Bezafibrate Infarction Prevention Study Group, 2000; Manninen et al., 1988). In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), men with CAD and low HDL (mean, 31 mg/dL) were treated with either gemfibrozil

(600 mg orally twice daily) or placebo over a 5-year follow-up period (Robins et al., 2001). With a 6% elevation in HDL, no change in LDL, and a 31% decrease in TGs, gemfibrozil therapy resulted in a 22% reduction in the composite end point of all-cause mortality and nonfatal MI versus placebo (Rubins et al., 1999). Gemfibrozil therapy also reduced the risk of stroke and transient ischemic attacks by 31% and 59%, respectively (Rubins et al., 2001). Diabetic patients in VA-HIT treated with gemfibrozil had a 32% reduction in the combined end point (41% in CHD death and 40% in stroke) (Rubins et al., 2002). Fibrates have been shown to exert many of the same pleiotropic effects as statins and to reduce atheromatous plaque progression in native coronary vessels and in coronary venous bypass grafts (Diabetes Atherosclerosis Intervention Study Investigators, 2001; Ericsson et al., 1996).

As with the statins, fibrates are associated with a low incidence of myopathy and mild elevations in serum transami-nases. Fibrate therapy can increase the risk for cholelithiasis and elevate prothrombin time by displacing warfarin from albumin-binding sites. The periodic monitoring of serum transaminases (6-12 weeks after initiating therapy and twice annually thereafter) is recommended. The two most common fibrates are gemfibrozil (Lopid; 600 mg twice daily) and fenofibrate (Tricor; 54 or 160 mg daily). Bezafibrate is available in Europe and is dosed at 400 mg daily. The use of therapies combining a statin and fibrate is becoming more commonplace in clinical practice, especially as the incidence of complex dyslipidemias increases (Davidson and Toth, 2004). Gemfibrozil significantly reduces the glucuronidation of statins, which decreases their elimination (Backman et al., 2002; Prueksaritanont et al., 2002a, 2002b). This increases the risk for myopathy/rhabdomy-olysis and hepatotoxicity. When used in combination with gemfibrozil, the doses for simvastatin and rosuvastatin should not exceed 10 mg daily. In general, when embarking on combination therapy, fenofibrate is a safer choice because it does not adversely impact the glucuronidation of the statins (Bergman et al., 2004). Fenofibric acid (Tri-lipix) is indicated for use in combination with statin therapy. Although there are no clinical trial data yet available to assess the effect of statin-fibrate combination therapy on cardiovascular morbidity and mortality, the efficacy of feno-fibrate used in combination with simvastatin compared with simvastatin monotherapy is being tested in diabetic patients in the Action to Control Cardiovascular Risk in Diabetes Trial (http://www.nhlbi.nih.gov/health/prof/heart/ other/accord/).

When serum TGs do not normalize in response to a low-fat diet and fibrate therapy, the physician should consider adding other agents. Patients with severe hypertriglyceride-mia frequently possess mutations in LPL that reduce its lipo-lytic activity. The addition of orlistat (Xenical; 120 mg with meals) can reduce the absorption of dietary fat and thus the circulating levels of chylomicrons and TGs. The addition of fish oil should also be considered.

Fish Oils

Fish oil capsules enriched with omega-3 (eicosapentaenoic acid) and omega-6 (docosahexaenoic acid) fatty acids can reduce serum triglyceride and VLDL levels and raise HDL-C

in a dose-dependent manner. The omega-3 fatty acids inhibit the enzyme diacylglycerol acyltransferase-2, thereby reducing intrahepatic TG biosynthesis. They also stimulate mitochondrial beta-oxidation of fatty acids, decrease VLDL production and biosynthesis, and stimulate TG hydrolysis by LPL (Toth et al., 2009). Dietary supplementation with the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been shown to lower the risk of death, nonfatal coronary events, and stroke after MI (GISSI-Prevenzione Investigators, 1999). In several clinical trials, PUFAs have been shown to reduce TG levels by 20% to 30%, and up to 50% in patients with severe hypertriglyceridemia (TG >500 mg/dL) (O'Keefe and Harris, 2000).

The Japan EPA Lipid Intervention Study (JELIS) evaluated whether the addition of fish oils to patients already taking a statin would provide incremental risk reduction. Approximately 19,000 Japanese men and women with hypercholes-terolemia were prospectively randomized to statin therapy with or without 1800 mg/day of EPA (Yokoyama et al., 2007). Combination therapy resulted in an additional 19% reduction in major coronary events at 4.6 years of follow-up compared to statin monotherapy.

Niacin

Niacin, or nicotinic acid, is a B vitamin that exerts multiple beneficial effects on lipoprotein metabolism. In contrast to statins and fibrates, niacin does not stimulate hepatic biosynthesis of HDL. Niacin appears to block HDL particle uptake and catabolism by hepatocytes without adversely impacting reverse cholesterol transport. This helps to increase circulating levels of HDL. Niacin reduces hepatic VLDL and TG secretion according to two mechanisms: (1) it decreases the flux of fatty acids from adipose tissue to the liver by inhibiting lipase activity; and (2) it inhibits TG formation within hepatocytes by inhibiting diacylglycerol acyltransferase. Niacin also reduces serum LDL-C concentrations by increasing the catabolism of apoB100. Consequently, niacin beneficially impacts all components of the lipoprotein profile.

When used as monotherapy at 3.0 g daily, crystalline nia-cin significantly reduced the incidence of MI and stroke in patients with established CAD in the Coronary Drug Project (1975). In the HDL-Atherosclerosis Treatment Study (HATS), combinations of high-dose niacin (2-4 g with simvastatin) reduced cardiovascular morbidity and mortality by up to 90% compared to placebo (Brown et al., 2001). This combination therapy also induced atheromatous plaque stabilization over a 3-year follow-up. Niacin should be started at a low dose and gradually titrated upward based on the results of follow-up lipid panels. When evaluated as a function of dose (500-2000 mg daily), Niaspan induces the following changes in serum lipid levels: LDL-C, 3% to 16% reduction; TGs, 5% to 32% reduction; HDL-C, 10% to 24% elevation (Capuzzi et al., 1998).

Niacin therapy is associated with a number of side-effects. The most common side-effect with niacin is cutaneous flushing; its incidence can be reduced by taking a 325-mg tablet of aspirin 1 hour before taking niacin. The flushing is prostaglandin mediated. Limiting fat intake for 2 to 3 hours before taking niacin also helps as fat is a source of arachidonic acid, the substrate for cyclooxygenase. Nias-pan is a sustained-release preparation of niacin associated with less flushing. Other side effects include bloating, pruritus, acanthosis nigricans, transient disturbances in glyce-mic control, and increased serum concentrations of uric acid. Niacin appears to increase rates of proximal tubular reuptake of urate from the glomerular ultrafiltrate. Niacin is available as a combination pill with lovastatin (Advicor; 500/20, 1000/20, and 2000/40 mg) or simvastatin (Simcor; 500/20,750/20, and 1000/20 mg) with the two drugs in each combination pill providing additive changes in serum lipoprotein levels.

KEY TREATMENT

Statins, fibrates, niacin, omega-3 fish oils, and bile acid sequestration agents to treat dyslipidemia reduce cardiovascular morbidity significantly (SOR: A).

Statins are the most efficacious drugs currently available for reducing serum levels of LDL and significantly impact risk for both cardiovascular morbidity and mortality (SOR: A). The omega-3 fish oils also appear to impact cardiovascular mortality, although the evidence is not as strong as with statins (SOR: A). Fibrates have the greatest capacity to reduce serum TGs and reduce cardiovascular morbidity (MI and stroke). The fibrates have not yet been shown to beneficially impact mortality as an independent end point in clinical trials. The fibrates have been shown to reduce rates of atherosclerotic disease progression in both diabetic and nondiabetic patients with CAD (SOR: A). Niacin raises serum levels of HDL significantly better than other currently available antilipidemic medications, and it also reduces LDL, TGs, and lipoprotein(a) (SOR: A).

Therapy with combinations of drugs (statin-fibrate, statin-niacin, fibrate-niacin, statin-ezetimibe) is frequently required in patients with mixed forms of dyslipidemia and increases the likelihood of therapeutic success. The addition of niacin or omega-3 fish oils to statin therapy does provide incremental cardiovascular risk reduction over statin therapy alone (SOR: A).

The impact of fibrate and ezetimibe adjuvant therapy with a statin is currently being evaluated in prospective, randomized clinical trials.

POTENTIAL FOR HARM

Antilipidemic agents can induce hepatotoxicity and myopathy (SOR: A).

Statins and fibrates may induce transient elevations in serum transaminases and should be discontinued if levels exceed three times ULN. If levels are below this threshold, monitor liver function tests because transaminase levels usually decrease and trend toward normal spontaneously. Often, these drugs are discontinued prematurely to the detriment of patient care (SOR: A). When combining a statin with a fibrate, use of gemfibrozil should be discouraged because it impairs the glucuronidation and elimination of the statins to varying degrees. This can result in increased risk for hepatotoxicity and rhabdomyolysis (SOR: A). Fenofibrate and fenofibric acid are safer choices in this context. Patients complaining of myalgias or weakness, especially if escalating, should be monitored for myopathy. The statins and fibrates should be discontinued if serum CK levels exceed 10 times ULN (SOR: A). However, myalgias are common and not necessarily attributable to statin and fibrate use.

In patients presenting with rhabdomyolysis, antilipidemic medications should be discontinued immediately. Patients should be hospitalized, hydrated with intravenous fluids, and provided supportive care.

Table 27-3 JNC-7 Blood Pressure (BP) Classification

Classification

Systolic (mm Hg)

Diastolic (mm Hg)

Lifestyle Modification

Drug Therapy

Normal

<120

and <8

Yes

Usually no treatment

Prehypertension

120-139

and 80-89

Yes

Yes, for compelling JNC-7 indications

Stage 1 hypertension

140-159

or 90-99

Yes

Yes

Stage 1 hypertension

>160

or>100

Yes

Yes

From Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).

Was this article helpful?

0 0
Lose 10 Pounds Naturally

Lose 10 Pounds Naturally

Studies show obesity may soon overtake tobacco as the leading cause of death in America. Are you ready to drop those extra pounds you've been carrying around? Awesome. Let's start off with a couple positive don't. You don't need to jump on a diet craze and you don't need to start exercising for hours each day.

Get My Free Ebook


Post a comment