Pharmacologic Treatment of Dyslipidemia and Cardiovascular Disease

Jennifer G. Robinson

Extensive animal and clinical trial evidence has shown that lowering low-density lipoprotein cholesterol (LDL-C) slows the development of atherosclerotic disease and prevents clinical events. Although the vast majority of clinical data comes from the statin trials, other lipid-modifying drugs have been shown to have cardiovascular benefits. This chapter will review the appropriate use, mechanisms of action, lipid-modifying efficacy, safety, and data from morbidity and mortality trials for each drug class.

The third recommendations of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) identified two targets for the prevention of cardiovascular diseases, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) (Table 23.1) (1). More aggressive optional treatment goals were suggested in a 2004 update (2). LDL-C is the first target of therapy, with treatment goals based on the risk of a coronary heart disease (CHD) event in the next 10 years. In patients with elevated levels of triglycerides (TG) between 150 and 500 mg/dL, non-HDL-C is the second target of therapy. Non-HDL-C is calculated by subtracting HDL-C from total cholesterol and reflects circulating levels of atherogenic apolipoprotein B (apoB)-containing lipoproteins. The non-HDL-C goal is 30 mg/dL higher than the LDL-C goal. In patients with TG levels >500 mg/dL, prevention of pancreatitis is the objective. Once TG are <500 mg/dL, attention can turn to addressing LDL-C and non-HDL-C levels for cardiovascular prevention. Although low levels of HDL-C and high levels of TG are markers of increased cardiovascular risk, specific treatment targets have not been identified due to the lack of evidence that pharmacologically altering the levels of these two factors per se reduces cardiovascular risk. Cardiovascular prevention efforts in patients with low HDL-C should focus on lifestyle and drug therapy to achieve LDL-C and non-HDL-C goals.

Treatment strategies are similar for both LDL-C and non-HDL-C. All patients exceeding their cholesterol goals should be advised to undertake therapeutic lifestyle changes. In lowand moderate-risk patients, drug therapy should be initiated if LDL-C and non-HDL-C goals are not met after a maximum 3-month trial of lifestyle. In high-risk patients, drug therapy should be started simultaneously with lifestyle changes. Statins are the drug of choice for lowering LDL-C and non-HDL-C based on an extensive record of safely reducing cardiovascular events and total mortality. Niacin and bile acid sequestrants (BAS) as monotherapy have also been shown to reduce cardiovascular risk, although they are less effective and have rates of higher adverse effects than statins. Ezetimibe is a well-tolerated drug that lowers LDL-C and non-HDL-C but has not yet been shown to reduce cardiovascular risk in clinical trials. Fibrates are generally the first choice for TG lowering to prevent pancreatitis, although high doses of omega-3 fish oil, niacin, and statins are also effective. The mechanisms of action, efficacy, and safety for each class of drug will now be reviewed.

STATINS

Statins are the foundation of the cardiovascular prevention armamentarium. Consistent evidence from over 100,000 subjects in randomized clinical trials has demonstrated that statins reduce the risk of CHD and stroke in direct proportion to the magnitude of LDL-C lowering (3). Statins lower LDL-C levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in cholesterol synthesis (Fig. 23.1). Decreased intracellular cholesterol concentrations lead to upregulation of LDL receptors, thereby enhancing removal of circulating LDL-C. Downstream products of HMG-CoA also influence inflammatory, thrombotic, and vasodilatory factors. The importance of these “pleiotropic” effects for cardiovascular prevention remains to be determined (4) (see also Chapters 15 and 17). However, based on the evidence to date, it does not appear that statin pleiotropic effects are additive to the risk reduction expected from the degree of LDL-C lowering seen with other agents that reduce cardiovascular risk, such as diet, BAS, or ileal bypass surgery.

Efficacy

The initial statin dose should lower LDL-C by at least 30% to 40%. Starting doses of statins will generally achieve this magnitude of LDL-C reduction (atorvastatin 10 mg, fluvastatin 80 mg, lovastatin or pravastatin 40 mg, rosuvastatin 10 mg, simvastatin 40 mg). Reductions of 50% or more may be desirable, but on average this will require the highest doses of atorvastatin (40 to 80 mg), rosuvastatin (20 to 40 mg), or statins used in combination with another LDL-C-lowering agent. Each doubling of the statin dose will result in an additional 5% to 7% reduction in LDL-C and non-HDL-C. Statins raise HDL-C by 2% to 10% and lower TG in proportion to their LDL-C-lowering efficacy. Moderate doses of statins will lower TG by about 15% to 20%. The highest doses of atorvastatin, rosuvastatin, and simvastatin will lower TG by 25% to 30%, although reductions as high as 50% may occur in those with more severely elevated TG levels. While levels of HDL-C and TG remain predictive of cardiovascular risk in patients with
LDL-C levels at goal, it is not entirely clear whether the HDL-C increases or TG decreases from statin therapy contribute substantial additional benefit beyond that expected from LDL-C lowering.

TABLE 23.1 OVERVIEW OF LIPID TREATMENT GOALS AND STRATEGIES

		Elevated triglycerides (mg/dL)
		150-<200	200-<500	≥500
	First target LDL		Second target non-HDL
Objective	Prevent CVD		Prevent CVD	Prevent pancreatitis
Treatment goals	*High risk:* CHD/CHD risk equivalents^a <100 (optional <70) mg/dL Moderately high risk: ≧2 risk factors^b with 10-20% 10-year CHD risk^c <130 (optional <100) mg/dL Moderate risk: ≧2 risk factors^b with <10% 10-year CHD risk <130 mg/dL *Lower risk:* 0-1 risk factor <160 mg/dL (consider drug therapy LDL >190 mg/dL/optional LDL >160 mg/dL)		Non-HDL goal 30 mg/dL higher than LDL goal	Triglycerides <500 mg/dL
Treatment	Therapeutic lifestyle changes	Therapeutic lifestyle changes	Therapeutic lifestyle changes	Therapeutic lifestyle changes Very low fat (<15%) diet
Drug 1st choice	Statins		Statins	Fibrates
Drug add-on or	Niacin		Ezetimibe	Omega-3 fish oil
2nd choice	Bile acid sequestrant		Niacin	Niacin
	Ezetimibe		Fibrate
^aCHD includes a history of myocardial infarction, stable or unstable angina, coronary artery revascularization, or clinically significant myocardial ischemia; CHD risk equivalents include other cardiovascular disease such as peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease (stroke of carotid or intracerebral origin, transient ischemic attack, or >50% carotid artery stenosis), diabetes, and ≧2 risk factors with >20% 10-year CHD risk. ^bRisk factors include age (men ≧ 45 years, women ≧ 55 years), cigarette smoking, hypertension (blood pressure ≧ 140/90 mm Hg or antihypertensive therapy), low HDL-C (<40 mg/dL), and family history of premature CHD (onset in male first-degree relative < 55 years; first-degree female relative < 65 years). ^c10-year risk of nonfatal myocardial infarction and CHD death estimated by Framingham Scoring. LDL, low-density lipoprotein; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease.

Muscle Safety

Statins are very well tolerated by the majority of patients. Muscle complaints are common with statins, although usually are not related to statin use. The most serious concern with statins is the rare case of rhabdomyolysis. In properly selected patients participating in long-term clinical trials of statin therapy, myopathy (muscle symptoms with creatine kinase elevations >10 times the upper limit of normal) and rhabdomyolysis occurred in <0.2% of subjects, with the exception of a higher rate of approximately 0.5% observed with simvastatin 80 mg in one trial (5). Notably, currently marketed statins are much safer than low-dose aspirin, which has more than 200-fold higher rate of major bleeding than statins have of inducing rhabdomyolysis.

Risk of rhabdomyolysis is related to statin blood levels. Although very safe in properly selected patients, three statins metabolized by hepatic cytochrome P450 enzyme 3A4 have the most potential for drug interactions—atorvastatin, lovastatin, and simvastatin (Table 23.2). Concomitant use of these three statins with potent inhibitors of CYP 3A4 should be avoided, including use with azole antifungals (ketoconazole and itraconazole; alternative—fluconazole), macrolide antibiotics (erythromycin and clarithromycin; alternative—azithromycin), rifampin, and protease inhibitors (alternative—indinavir) (Table 23.3). Interactions with weaker CYP 3A4 inhibitors
amiodarone, calcium channel blockers diltiazem and verapamil (alternatives—amlodipine, nifedipine), and some antidepressants (alternatives—paroxetine, venlafaxine) have also been reported. Alternatives include rosuvastatin, which is minimally metabolized; pravastatin, which has no cytochrome P450 metabolism; and fluvastatin, which is metabolized by the 2C9 pathway. In four statins, glucuronidation has a major role in their metabolism, increasing the potential for their interaction with gemfibrozil (Table 23.2). Cyclosporine raises blood levels of virtually all statins by both cytochrome P450 and other
pathways, and low doses of statins should be titrated carefully if needed.

FIGURE 23.1 Overview of mechanisms of drug action. Statins inhibit the rate-limiting step in cholesterol synthesis, HMG-CoA reductase. Reduction in intrahepatic FC levels releases SREBP, which binds to the SRE in the promotor of the LDLR gene, increasing the number of LDLRs on the cell membrane, thereby increasing removal of LDL-C from plasma. BAS and EZE also lower plasma LDL-C by the same mechanism. BAS bind bile acids in the intestine, preventing uptake by the IBAT, interrupting the entero-hepatic circulation of biliary FC. EZE and other cholesterol absorption inhibitors act on the NPC1L1 transporter to prevent absorption of dietary and biliary cholesterol, interrupting the entero-hepatic circulation of biliary FC as well as CM assembly. These drugs also block uptake of plant sterols. Dietary sterol/stanols competitively inhibit the uptake of cholesterol. The efficacy of all three intestinally active agents is limited since SREBP also upregulates the gene for HMG-CoA reductase, resulting in a compensatory increase in cholesterol synthesis. The mechanisms of action for niacin have not been clearly elucidated. Niacin partially inhibits release of FFA from adipose and also increases LPL activity, enhancing removal of CM TG from plasma. Niacin decreases apoB synthesis, which lowers VLDL-C and IDL-C and plasma TG levels. Niacin increases HDL-C levels through decreased hepatic uptake, likely through the HUR and catabolism and also by lowering TG levels. Fibrates lower TG levels by decreasing VLDL secretion and increasing catabolism of TG-rich particles via several mechanisms. Fibrates reduce apoC-III production, which upregulates lipoprotein lipase-mediated lipolysis, increase cellular FFA uptake, as well as increase FFA catabolism. Fibrates increase HDL-C via the LXR/RXR heterodimer to upregulate the ABCA1 gene, inducing apoA-I and apoA-II synthesis. O-3 reduce the rate of VLDL synthesis through a number of putative mechanisms inhibiting release of FFA from adipose, inhibiting FFA synthesis, and increasing apoB degradation. ABC, ATP-binding cassette; ACAT, acyl cholesterol acyl transferase; apo B, apolipoprotein B; apo C, apolipoprotein C; B-48 or B-100, apolipoprotein B-48 or B-100; BAS, bile acid-sequestering agents; CE, cholesteryl esters; CETP, cholesterol ester transfer protein; CM, chylomicron; CMR, CM remnant; E, apolipoprotein E; EL, endothelial lipase; EZE, ezetimibe; FC, free cholesterol; FFA, free fatty acids; HDL-C, high-density lipoprotein cholesterol; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HL, hepatic lipase; HUR, holo-uptake receptor; IBAT, intestinal bile acid transporter; IDL-C, intermediate density lipoprotein cholesterol; LCAT, lecithin cholesterol acyl transferase; LDLR, low-density lipoprotein-receptor; LXR/RXR, liver X receptor/retinoid X receptor; LPL, lipoprotein lipase; LRP, LDL receptor-related protein 1; MTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-Pick C1-Like 1; O-3, Omega-3 fatty acids; PLTP, phospholipid transport protein; SR-BI, scavenger receptor class BI; SRE, sterol response element; SREBP, sterol regulatory element binding protein; TG, triglycerides; VLDL-C, very low density lipoprotein cholesterol. (see color insert.)

TABLE 23.2 SUMMARY OF COMPARATIVE PHARMACOKINETICS OF STATINS IN HEALTHY VOLUNTEERS

	Atorvastatin	Fluvastatin	Lovastatin	Pravastatin	Rosuvastatin	Simvastatin
Major metabolic enzyme	CYP3A4	CYP2C9	CYP3A4 glucuronidation	No CYP450 glucuronidation	Some CYP2C8 glucuronidation	CYP3A4 glucuronidation
Renal excretion (%)	≤2	<6	≥10	20	10	13
Prodrug	No	No	Yes	No	No	Yes
Lipophilicity (logP)	4.06	3.24	4.30	−0.23	—/33	4.68
Affinity for Pgp transporter	Yes	No	Yes	Yes	No	Yes
t_max (hr)	1.0-2.0	0.5-1.0	2.0-4.0	1.0-1.5	3.0-5.0	1.3-3.0
Absorption (%)	30	98	30-31	34	40-60	60-80
Hepatic first-pass metabolism (%)	20-30	40-70	40-70	50-70	50-70	50-80
Bioavailability (%)	12-14	29	<5	18	20	<5
Protein binding (%)	>98	>98	>95	43-54	88	95
Systemic active metabolites (no.)	Yes (2)	No	Yes (3)	No	Minimal	Yes (3)
T_1/2 (hr)	14-15	3.0	2.0	2.0	20	1.4-3.0