HDL Cholesterol

Author : Dr Robert Rosenson cardiologist University of Michigan School of Medicine Ann Arbor

2008-07-10

Low levels of high density lipoprotein (HDL)-cholesterol (HDL-C) are defined as less than 40 mg/dL (<1.03 mmol/L) according to current National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines [1] (see High Cholesterol Knol). By this definition, low HDL-C levels are relatively common in the United States, occurring in approximately 35% of men and 15% of women in the general population [2]. Comparatively, patients with coronary heart disease (CHD) are even more likely to have low HDL-C. Low HDL-C levels (<35 mg/dL) (<0.90 mmol/L) are more common in men with CHD compared with those without CHD (50% vs. 30%, respectively).
HDL Cholesterol: an inverse risk predictor for CVD  
Low HDL-C levels can confer additional risk for cardiovascular disease (CVD) irrespective of total cholesterol levels. An independent reduction in CHD risk of 2% to 3% has been estimated for every 1-mg/dL (0.03-mmol/L) increase in HDL-C. In a 12-year follow-up of the Framingham study, individuals with high HDL-C (80th percentile) were at 50% lower risk of CHD than those with low HDL-C (20th percentile) [3]. Similarly, the Prospective Cardiovascular Münster study participants with HDL-C ≥35 mg/dL (>0.90 mmol/L) were found to have 4-times less risk of CHD at 6-year follow-up than patients with HDL-C <35 mg/dL (<0.90 mmol/L) [4]. 
Importantly, baseline HDL-C level has been shown in several statin trials to predict CVD risk [5]. For example, the Treating to New Targets (TNT) trial included 9,770 stable coronary heart disease patients with mean LDL-C levels <70 mg/dL (<1.81 mmol/L). Low HDL-C levels in that subgroup remained a significant predictor of major cardiovascular events. The cardiovascular event rate was 40% lower for patients in the highest quintile (>55 mg/dL) (>1.42 mmol/L) versus the lowest quintile (<38 mg/dL) (<0.98 mmol/L) of HDL-C [6]. 
Figure 1
Multiple Risk Factor Adjusted Analysis of the Relationship between Major Cardiovascular Events and Categories of HDL Cholesterol Levels in Coronary Heart Disease Patients with LDL-C Levels <70 mg/dL [6]

Anti-atherogenic properties of HDL particles
Atherosclerosis is one form of hardening of the arteries that involves large arteries. This disorder of large arteries is responsible for most arterial disease in industrialized societies. The clinical complications of atherosclerosis may lead to heart attack, stroke, lower extremity arterial disease and aneurysms. The ability of HDL particles to protect against atherosclerosis is believed to be the result of numerous anti-atherogenic properties as described in the next sections.

HDL plays a pivotal role in reverse cholesterol transport (RCT), a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed [7]. The steps involved in RCT are depicted in the figure (figure 2).
Figure 2
Reverse cholesterol transport (RCT) [7]

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very low density lipoprotein (VLDL) and low density lipoprotein (LDL) from the liver (white arrows). Apo A-1 is synthesized by the liver and, after interaction with ABCA1, is secreted into plasma as lipid-poor apo A-1 (yellow arrow). In RCT, newly synthesized lipid-poor apo A-1 interacts with ABCA1, removing excess cellular cholesterol and forming pre-beta-HDL (green arrow). Pre-beta-HDL is converted into mature alpha-HDL by lecithin cholesterol: acyltransferase (LCAT) (black arrow). HDL-C is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic SR-B1 (blue arrow), or the transfer of cholesteryl ester by CETP to VLDL-LDL, with uptake by the liver through the LDL receptor (red arrows).

• Another protein, ABCA1 (also called cholesterol efflux regulatory protein [CERP]), also plays an important role in the HDL-mediated uptake of cellular cholesterol by promoting the transfer of intracellular cholesterol to the cell membrane. ABCA1 expression on the cell surface is induced by cholesterol loading and reduced after the cholesterol has been removed by apolipoproteins.
• After acquisition of free cholesterol by HDL, the cholesterol is esterified to cholesterol esters by lecithin: cholesterol acyl transferase (LCAT), a plasma enzyme that is activated primarily by apo A-I. By a similar mechanism, HDL can act as an acceptor for cholesterol released during lipolysis of triglyceride-containing lipoproteins.
• Lipid transfer proteins, such as cholesteryl ester transfer protein facilitate movement of the cholesterol esters to apo B-containing lipoproteins (VLDL, IDL, and LDL). This cholesterol can then be delivered to the tissues for steroid synthesis or storage. 

While RCT is often cited as the primary anti-atherogenic mechanism, HDL also protects LDL particles from oxidation. Oxidized LDL increases atherosclerosis by several mechanisms, such as facilitating the transformation of macrophages into foam cells (see High Cholesterol Knol). Additional mechanisms by which HDL may confer protection against atherosclerosis include the inhibited production of the proteins on the lining of the blood vessels that tether inflammatory cells to the vessel wall thereby stopping the migration of these inflammatory cells into the vessel walls, and reduced platelet activation, which are the primary cells involved in blood clotting. HDL can also improve vessel wall dilation and reduced stickiness of blood platelets to the vessel wall. It was recently shown that HDL carries a previously unidentified range of proteins that may contribute to its anti-inflammatory and cardioprotective activities.

CAUSES OF LOW PLASMA HDL
Low HDL levels can occur in one of three ways: impaired synthesis of apo A-I (apo A-I deficiency, apo A-I/C-III deficiency, apo A-I structural variants); increased turnover or catabolism (familial HDL deficiency and Tangier disease); or enzymatic changes affecting HDL metabolism. The enzymatic changes are either genetically determined or, as with decreased activity of lipoprotein lipase, secondary to insulin resistance.
Low HDL-C levels: A marker of atherogenic dyslipoproteinemia?
LDL also consists of a heterogeneous spectrum of particles that differ in size, density, and composition. Elevated concentrations of small LDL particles are associated with a greater risk for CHD and are frequently found in patients with type 2 diabetes or metabolic syndrome [8]. Furthermore, evidence suggests that the CHD risk associated with low HDL-C may, in part, reflect a previously unrecognized shift in LDL size from large LDL to small LDL particles. Data from the Framingham Offspring Study showed that, in individuals with low HDL-C (<40 mg/dL) (<1.03 mmol/L), there was a substantial increase in the level of small LDL particles [9] [Figure 3]. 
Additionally, the lipoprotein profile in patients with type 2 diabetes or metabolic syndrome may be characterized by the formation of small, dense HDL with altered physicochemical properties, such as abnormal composition (triglyceride-rich) and dysfunctional anti-atherogenic activity. Thus, while HDL-C level is a strong, independent, and inverse predictor of CVD, other factors that are closely associated with low HDL-C levels may also contribute to CVD risk.
Figure 3
Framingham Offspring Study: Clinical Implications of the Disconnect Between LDL-C and LDL Particles in Patients with Low HDL-C [9] 

HDL-C and existing guideline recommendations
The NCEP guidelines recognize elevated LDL-C as the primary target for lipid modification [1] (see High Cholesterol Knol). Recommended targets reflect clear evidence from clinical trials that large reductions in LDL-C are associated with significant decreases in CV events. Nonetheless, the guidelines do recognize the importance of low HDL-C as a CHD risk factor and state that:

• In addition to intensive LDL-C lowering, risk assessment should cover high triglyceride and low HDL-C levels (low HDL-C being defined as <40 mg/dL) (<1.03 mmol/L).
• Low HDL-C modifies the goal for LDL-C lowering and should be used as a risk factor to estimate the 10-year CHD risk.
• HDL-C is a secondary therapeutic target in patients with isolated low HDL-C (where triglycerides are ≥200 mg/dL (>2.26 mmol/L) or as a component of the metabolic syndrome).

However, NCEP guidelines have not established a target level for HDL-C [1]. This is likely due to the absence of pharmacotherapies that can robustly raise HDL-C and a consequent lack of direct evidence from clinical outcomes trials. In contrast, other influential guidelines do suggest target levels for HDL-C. The American Diabetes Association recommends an optimal target of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women with type 2 diabetes [10]. Similarly, a target of ≥40 mg/dL (>1.03 mmol/L) is recommended by the Expert Group on HDL-C as a goal for patients with CVD and those without clinical CVD at high risk (eg, patients with type 2 diabetes or metabolic syndrome) [11]. As has been the case with LDL-C targets, HDL-C targets will be reassessed as more clinical trial data emerges.
What are the current therapeutic options for raising LOW HDL-C levels?
Treatment of low HDL-C disorders — Treatment of low HDL disorders involve both lifestyle modifications and appropriate medications [1,5,10,11]. Exercise, weight loss (in overweight subjects), smoking cessation, and substitution of monounsaturated for saturated fatty acids all can raise HDL-C.
Figure 4
Efficacy of Lifestyle Strategies for Increasing HDL-C [5]

Different classes of hypolipidemic drugs have different effects on HDL-C as described in the next sections.
Nicotinic Acid (Niacin)
Nicotinic acid is the most effective HDL-C–raising drug currently available, and it also favorably affects LDL-C, LDL particle size, and triglyceride levels. Extended-release form of nicotinic acid 3,000 mg has been shown to increase HDL-C by 30% in patients with primary hyperlipidemia, although a pooled analysis of randomized trials using various nicotinic acid preparations indicates HDL increases by an average of 16% [Figure 5] [12]. Nicotinic acid is, however, associated with tolerability problems, side-effects include disruption of glucose control and liver toxicity and skin flushing that can occur in up to 80% of patients [12]. The extended-release formulation has improved tolerance, producing significantly less flushing than immediate-release nicotinic acid.
 Figure 5
Summary data of nicotinic acid (niacin) effects on HDL-C [12]

Fibrates or Fibric Acid Derivatives
Fibrates (peroxisome proliferator-activated receptor-alpha agonists) stimulate the formation of HDL in the serum by increasing the expression of proteins involved in HDL metabolism (for example, apolipoproteins A-I and A-II, ABCA1, and SR-B1). Fibrates can increase HDL-C an average of 10% [Figure 6] as well as substantially lower triglyceride levels [12]. Beneficial changes in the size and distribution of HDL and LDL subclasses are also produced [8]. Gemfibrozil, for example, raises the HDL concentration via both direct stimulation of the hepatic synthesis of apo A-I and reduced cholesterol transfer from HDL to VLDL due to a decline in VLDL levels.
Figure 6
Summary data of fibrate effects on HDL-C [12]

Statins
Statins produce small increases in HDL-C (5% to 15%) in addition to a significant impact on LDL-C. The underlying mechanism is not well understood, but may involve a reduction in CETP activity.
Figure 7
Percent Change in HDL-C Across Statin Treatment in Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) (Week 6) [13]

HDL-C in Clinical Trials of LDL-C Lowering with Statin Therapy
Additional support for the treatment of low HDL-C is provided by inference from clinical trials of LDL-C lowering strategies in which patients were further stratified by change in HDL-C. Although the effect of these small changes in HDL-C on reducing CHD risk is difficult to determine, given the larger simultaneous decreases in LDL-C, evidence suggests that the reduction in morbidity seen in at least some statin trials can be partly attributed to changes in HDL-C [5]. Furthermore, statins may be especially beneficial in individuals with low HDL-C at baseline. In the AFCAPS/TexCAPS study, lovastatin 20 to 40 mg/day increased HDL-C by 6% after 1 year in patients with an average risk for CHD [14]. Individuals whose baseline HDL-C was <40 mg/dL (<1.03 mmol/L) experienced a 3-fold reduction (45% to 15%) in risk for first-time, CHD-related events after 5.2 years compared with those with HDL-C ≥40 mg/dL (>1.03 mmol/L).
More recently, a pooled analysis of four prospective studies [Reversal of Atherosclerosis with Lipitor (REVERSAL), Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT), Acyl-CoA: Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation Study (ACTIVATE), and A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID)] that used intravascular ultrasound (IVUS) to determine changes in atherosclerotic progression in statin-treated patients with angiographic coronary disease showed that a ≥5% reduction in atheroma volume was observed in those patients in which a 7% increase in HDL-C was accompanied by a reduction in LDL-C to <87.5 mg/dL (<2.26 mmol/L) [15]. Despite these observations, no significant difference was found with regard to clinical events.
EFFECT OF INCREASING HDL-CHOLESTEROL ON CLINICAL OUTCOMES
Two studies have found that raising HDL-C in patients with a low baseline serum concentration may be effective for the prevention of recurrent CHD events:
The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) included 2531 with CHD who had an LDL-C (<140 mg/dL or <3.62 mmol/L), an HDL-C (<40 mg/dL or <1.03 mmol/L), and triglycerides <300 mg/dL (<3.38 mmol/L); the patients were randomly assigned to treatment with gemfibrozil or placebo [16]. At one year, the following differences in plasma lipids were noted in the gemfibrozil group:

• The average HDL-C level was 6 percent higher (34 versus 32 mg/dL for placebo [0.88 versus 0.83 mmol/L])
• The average total cholesterol was 4 percent lower (170 versus 177 mg/dL [4.39 versus 4.57 mmol/L])
• The mean triglyceride concentration was 31 percent lower (115 versus 166 mg/dL [1.30 versus 1.87 mmol/L])

These differences persisted throughout the study and the mean LDL-C concentration was the same in both groups. At five years, the combined primary end point of cardiac death and nonfatal myocardial infarction occurred less often in the gemfibrozil-treated group (17.3 versus 21.7 percent for placebo). Patients taking gemfibrozil also had a lower rate of stroke (4.6 versus 6 percent for placebo), transient ischemic attacks (1.7 versus 4.2 percent), and carotid endarterectomy (1.3 versus 3.5 percent).
Multiple risk factor adjusted analysis of the VA-HIT trial found that the reduction in nonfatal myocardial infarction and cardiac death was strongly correlated with the serum HDL-C concentration achieved with gemfibrozil therapy independent of changes in LDL-C or triglycerides [17]. 
Table 1
Gemofibrozil Treatment Effects in VA-HIT [17]

Variable (change)	Relative Risk (95%CI)	P Value
Baseline
HDL-C (5.0 mg/dL)	0.93 (0.85 – 1.02)	0.13
Triglycerides (50 mg/dL)	1.06 (0.99 – 1.14)	0.11
LDL-C 25 (25 mg/dL)	1.06 (0.96 – 1.17)	0.26
During Treatment
HDL-C (5.0 mg/dL)	0.89 (0.81 – 0.98)	0.02
Triglycerides (50 mg/dL)	1.03 (0.96 – 1.11)	0.48
LDL-C 25 (25 mg/dL)	1.09 (0.98 – 1.21)	0.13

In accordance with the interrelationships between low HDL-C levels, low levels of small HDL and high levels of small LDL particles were even more predictive of cardiovascular events in VA-HIT [17]. 
Table 2
Lipoprotein Particles predict Coronary Heart Disease Events

Variable	Baseline RR (1 SD Change)	On-Trial RR (1 SD Change)
HDL Particle (total)	0.78**	0.71***
Large HDL Particles	0.98	0.94
Small HDL Particles	0.82**	0.74***
LDL Particles (total)	1.20**	1.28***
Large LDL Particles	1.08	1.06
Small LDL Particles	1.11	1.17*
LDL Size	0.97	0.96
* p<0.05, ** p< 0.01, *** p<0.001

The HDL Atherosclerosis Treatment Study (HATS) was a second study that suggested additional cardiovascular benefits may be observed in patients with low HDL-C by combining a statin (which not only lowers LDL-C but may have additional cardiovascular benefits beyond lipid lowering) with a drug that increases HDL-C [18]. This three year trial included 160 patients with clinical and angiographic evidence of CHD who had an HDL-C less than 35 mg/dL (0.90 mmol/L) and an LDL-C less than 145 mg/dL (3.75 mmol/L) [18]. In the simvastatin plus niacin group the LDL-C fell by 42% and the HDL-C increased by 20%. Compared with placebo, patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event (death, myocardial infarction, stroke, or revascularization) and experienced angiographic regression (compared with progression for the placebo group) of the most significant coronary stenosis.
The ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2 study was a randomized trial that examined the effects of extended-release (ER) nicotinic acid 1000 mg daily in 167 patients with known CHD and an HDL-C concentration below 45 mg/dL (1.16 mmol/L) who were already receiving a statin [19]. Patients treated with ER nicotinic acid experienced a mean increase in HDL-C of 8 mg/dL (0.21 mmol/L) and, compared with those receiving placebo, had a trend toward decreased progression of carotid intima-media thickness.
Summary
Low HDL-C currently represents one of the strongest independent predictors of CHD risk. Targeting HDL-C is a promising strategy for combating CVD, and one that may help address the residual CV risk in statin-treated patients. In particular, pharmacologic elevation of HDL-C may also be associated with additional beneficial effects, such as a reduction in overall LDL particle number. This results from the redistribution of highly-atherogenic, cholesterol-depleted small LDL to larger, less atherogenic, cholesterol-enriched LDL particles that improves LDL particle-LDL receptor interaction and facilitates LDL clearance. However, there remains a lack of trial data confirming the clinical benefit of independently raising HDL-C to protective levels.
References

1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486.
2. Johnson, CL, Rifkind, BM, Sempos, CT, Carroll, MD, Bachorik, PS, Briefel, RR, Gordon, DJ, Burt, VL, Brown, CD, Lippel, K, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002.
3. Castelli, WP, Garrison, RJ, Wilson, PW, Abbott, RD, Kalousdian, S, Kannel, WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835.
4. Assman G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996; 124 Suppl:S11.
5. Rosenson RS. Low High-density lipoprotein cholesterol and cardiovascular disease: risk reduction with statin therapy. Am Heart J. 2006;151:556-563.
6. Barter, P, Gotto, AM, LaRosa, JC, Maroni, J, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301.
7. Brewer, HB, Jr., Increasing HDL Cholesterol Levels. N Engl J Med. 2004;350:1491.
8. Kathiresan, S, Otvos, JD, Sullivan, LM, Keyes, MJ, Schaefer, EJ, Wilson, PW, D'Agostino, RB, Vasan, RS, Robins, SJ. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006;113:20.
9. Otvos, JD, Jeyarajah, EJ, Cromwell, WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90:22i.
10. Haffner, SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27 Suppl 1:S68.
11. Gotto, AM Jr, Brinton, EA. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol 2004; 43:717.
12. Birjmohun, RS, Hutten, BA, Kastelein, JJ, Stroes, ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2005;45:185.
13. Jones, PH, Davidson, MH, Stein, EA, Bays, HE, McKenny, JM. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial), Am J Cardiol 2003;92:152.
14. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAP/TexCAPS. Air force/Texas Coronary Atherosclerosis Prevention Study JAMA 1998;279:1615.
15. Nicholls, SJ, Tuzcu, EM, Sipahi, I, Grasso, AW, Schoenhagen, P, Hu, T, Wolski, K, Crowe, T, Desai, MY, Hazen, SL, Kapadia, SR, Nissen, SE. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499.
16. Rubins, HB, Robins, SJ, Collins, D, et al, for the Veterans Affairs High-density lipoprotein cholesterol Intervention Trial study group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341:410.
17. Otvos, JD, Collins, D, Freedman, DS, et al. Low-density lipoprotein particles subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-density lipoprotein Intervention Trial. Circulation 2006;113:1556.
18. Brown, BG, Zhao, XQ, Chait, A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583.
19. Taylor, AJ, Sullenberger, LE, Lee, HJ, et al. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2. A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512.

High cholesterol

Author : Dr Robert Rosenson cardiologist University of Michigan School of Medicine Ann Arbor

2008-10-16

Introduction — Lipids, such as cholesterol and triglycerides, are fats that are an integral part of cells, and that may dissolve in alcohol, but are insoluble in water. They are thus insoluble in the blood. In order for lipids to be transported in blood, they are packaged as lipoprotein. Lipoproteins have a shell of phospholipids and proteins that allow them to dissolve in blood. The lipids, transported as lipoprotein, are transported to various tissues for energy utilization, lipid deposition, steroid hormone production, and bile acid formation.

High cholesterol is a major modifiable risk factor for cardiovascular diseases, and it is essential that the informed consumer understand the importance of an elevated cholesterol, as a risk factor for cardiovascular diseases; target levels of cholesterol that may necessitate treatment of high cholesterol levels; and treatments available to lower blood cholesterol levels. In this High Cholesterol Knol these topics will be reviewed.

TWO PATHWAYS CONTRIBUTE TO BLOOD CHOLESTEROL LEVELS —Lipoprotein metabolism involves two pathways: exogenous, or originating outside of the blood system, and endogenous, referring to those originating within the blood system.

EXOGENOUS PATHWAY OF LIPID METABOLISM — The exogenous pathway starts with the intestinal absorption of dietary cholesterol and fatty acids (Figure 1).

Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides (and cholesterol is esterified), to form cholesterol esters. Triglycerides and cholesterol are packaged intracellularly as chylomicrons. The main apolipoprotein is B-48, but C-II and E are acquired as the chylomicrons enter the circulation. Apolipoprotein B-48 permits lipid binding to the chylomicron.

ENDOGENOUS PATHWAY OF LIPID METABOLISM — The endogenous pathway starts with the synthesis of VLDL by the liver. (Figure 1)

Figure 1
Cholesterol Levels Are Affected by Multiple Organ Systems:
Net Cholesterol Balance in Humans

VLDL particles contain a core of triglycerides (60 percent by mass) and cholesterol esters (20 percent by mass). The surface apolipoproteins for VLDL include apolipoprotein C-II which acts as an activator or cofactor for lipoprotein lipase, apolipoprotein C-III which inhibits the LPL enzyme, and apolipoprotein B-100 and E which serve as recognition sites or ligands for the apolipoprotein B/E (LDL) receptor.

Low density lipoprotein — LDL particles contain a core of cholesterol esters, lesser amounts of triglyceride, and are enriched in apolipoprotein B-100, which is the ligand for binding to the apolipoprotein B/E (LDL) receptor. LDL can be internalized by hepatic and nonhepatic tissues. Hepatic LDL cholesterol can be converted to bile acids and secreted into the intestinal lumen. LDL cholesterol internalized by nonhepatic tissues can be used for hormone production, cell membrane synthesis, or stored in the esterified form.

Circulating LDL can also enter macrophages and some other tissues through the unregulated scavenger receptor. This pathway can result in excess accumulation of intracellular cholesterol and the formation of cholesterol-enriched cells (called foam cells) that contribute to the formation of fatty deposits, inflammatory cells and smooth muscle cells in the lining of the arteries, called atheromatous plaques.

Lipoprotein(a) — Lipoprotein(a) or Lp(a) is a specialized form of LDL that is assembled extracellularly from apolipoprotein (a) and LDL. Apolipoprotein (a) is bound to apolipoprotein B-100 on the surface of LDL by disulfide bridges.

LIPOPROTEINS AND ATHEROSCLEROSIS — Abnormal lipoprotein metabolism is a major predisposing factor to atherosclerosis. Atherosclerosis is one form of hardening of the arteries that involves large arteries. This disorder of large arteries is responsible for most arterial disease in industrialized societies. The clinical complications of atherosclerosis may lead to heart attack, stroke, lower extremity arterial disease and aneurysms.

Low density lipoprotein —Elevated plasma concentrations of apolipoprotein B-100 containing lipoproteins can induce the development of atherosclerosis even in the absence of other risk factors.

When LDL-cholesterol (LDL-C) levels are increased, unregulated uptake via the scavenger pathway leads to excess accumulation of modified LDL within macrophages [1]. Foam cells can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall.

Oxidatively modified LDL can cause disruption of the endothelial cell surface and impairs endothelial function, reducing the release of nitric oxide (NO), which is a major mediator of endothelium-dependent vasodilation. In addition, oxidized LDL induces programmed cell death of vascular smooth muscle and endothelial cells. High levels of cholesterol also increase endothelial production of oxygen free radicals, which may bind to and inactivate NO.

DISORDERS OF CHOLESTEROL METABOLISM — There are a variety of different lipid disorders (dyslipidemias) that can occur as either a primary event or secondary to some underlying disease. The primary dyslipidemias are associated with overproduction and/or impaired removal of lipoproteins. The latter defect can be induced by an abnormality in either the lipoprotein itself or in the lipoprotein receptor. There are a number of different disorders of LDL metabolism, which vary according to the underlying defect and the clinical presentation.

IDENTIFICATION OF PATIENTS AT RISK FOR CORONARY HEART DISEASE

ATP III recommendations for risk assessment — The Third Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) recommendations for the treatment of hypercholesterolemia are based upon the LDL-C fraction and are influenced by the presence of Coronary Heart Disease (CHD) and the number of cardiac risk factors [2]. There are five major steps to determining an individual's risk category, which serves as the basis for the treatment guidelines.

Step 1 —Obtain a fasting lipid profile. The lipid profile is ordered by the health care practitioner. The lipid profile should be obtained in the fasting state or a minimum of 12 hours after the last meal. The measurement of blood lipids on fasting samples minimizes the acute effects of diet on increasing blood triglyceride levels that may distort the LDL-C calculation. Other important considerations that ensure accuracy of the lipid profile should minimize changes in blood volume that result from vigorous exercise before the test, excess dehydration that may occur on a hot humid day, and prolonged standing as you wait for the test. The last consideration is the effects of inflammation on the blood lipids and lipoproteins. If you have an infection (cold virus, bacterial or fungal infection), surgery, major physical trauma or a recent heart attack, the fasting lipid profile should be deferred until six weeks after those conditions have resolved.

From the measured total cholesterol, triglycerides and HDL cholesterol, calculate the LDL-C fraction according to the formula:

LDL-C = Total cholesterol – VLDL-C (estimated as 0.2x triglyceride) – HDL-C

The formula is considered valid when levels are less than 400mg/dL (4.52mmol/L); when the fasting triglyceride levels are >400mg/dL (4.52mmol/L) the LDL-C may be measured by direct methods.

Step 2 —Establish the presence of CHD equivalents. These CHD risk factors that place the patient at similar risk for CHD events as a history of CHD itself. These risk equivalents include [2]:

• Diabetes mellitus
• Symptomatic carotid artery disease
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Multiple risk factors that confer a 10-year risk of CHD >20 percent (refer to “Step 4”.

Although not specifically identified by ATP III as CHD equivalents, chronic renal insufficiency (defined by a plasma creatinine concentration that exceeds 1.5 mg/dL [133 µmol/L] or an estimated glomerular filtration rate that is < 60 mL/min per 1.73 m2) is considered to be a CHD equivalent by other professional societies.

Step 3 — Major CHD factors other than LDL-C are identified:

• Age (men ≥45 years, women ≥55 years)
• Cigarette smoking
• Hypertension (BP ≥140/90 or taking antihypertensive medication)
• Low HDL-cholesterol (HDL-C) (<40 mg/dL [1.03 mmol/L])
• Family history of premature CHD (in males first degree relatives <55 years, in females first degree relative <65 years)

HDL-C ≥60 mg/dL (1.55 mmol/L) counts as a "negative" risk factor; its presence removes one risk factor from the total count. (see HDL Knol)

Step 4 — If two or more risk factors other than LDL-C (as defined in step 3) are present in a patient without CHD or a CHD equivalent (as defined in step 2), the 10-year risk of CHD is assessed using the ATP III modification of the Framingham risk tables (www.nhlbi.nih.gov). The risk score does not need to be assessed in people without CHD who have 0 to 1 risk factors since individuals in this category have a 10-year risk of CHD that is <10 percent.

The Framingham CHD predictor has been validated for prediction of CHD events in white men and women and black men and women, but it overestimated risk among Japanese American, Hispanic men, and Native American women [3]. Several studies have suggested that the Framingham criteria also overestimated the risk in European and Asian populations [4,5].

Step 5 —The last step in risk assessment is to determine the risk category that establishes the LDL-C goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy as shown in tables 1 and 2.

Table 1
ATP III LDL-C goals and cutpoints for therapeutic lifestyle changes and drug therapy in different risk categories [2]

Risk category	LDL-C goal	LDL-C level at which to initiate therapeutic lifestyle changes	LDL-C level at which to consider drug therapy
Coronary heart disease (CHD) or CHD risk equivalent (10-year risk >20 percent)*	<100 mg/dL (2.58 mmol/L)	≥100 mg/dL (2.58 mmol/L)	≥130 mg/dL (3.36 mmol/L); drug optional at 100 to 129 mg/dL (2.58 to 3.33 mmol/L)•
2 or more risk factors (10-year risk ≤20 percent)†	≤130 mg/dL (3.36 mmol/L)	≥130 mg/dL (3.36 mmol/L)	10-year risk 10 to 20 percent: >130 mg/dL (3.36 mmol/L) 10-year risk <10 percent: ≥160 mg/dL (4.13 mmol/L)
0 to 1 risk factor◊	≤160 mg/dL (4.13 mmol/L)	≥160 mg/dL (4.13 mmol/L)	190 mg/dL (4.91 mmol/L); LDL-C lowering drug optional at 160 to 189 mg/dL (4.13 to 4.88 mmol/L)

* CHD risk equivalents defined in text. Ten-year risk is defined by Framingham risk score (see text).
•Some authorities recommend use of LDL-C lowering drugs in this category if LDL-C <100 mg/dL (2.58 mmol/L) cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C (e.g., nicotinic acid or fibrate). Clinical judgment may also call for deferring drug therapy in this subcategory.
†Risk factors that modify LDL-C goals include cigarette smoking; hypertension (BP 140/90 mmHg or on antihypertensive medication); low HDL-C mg/dL [1.03 mmol/L]); family history of premature CHD (CHD in male first degree relative <55 years or CHD in female first degree relative <65 years); age (men 45 years; women 55 years). HDL-C >60 mg/dL (>1.55 mmol/L) counts as a negative risk factor; its presence removes one risk factor from the total count.
◊Almost all people with 0 to 1 risk factor have a 10-year risk <10 percent; thus, 10-year risk assessment in people with 0 to 1 risk factor is not necessary.

Table 2
Proposed modification of ATP III LDL-C goals and cutpoints for therapeutic lifestyle changes and drug therapy in different risk categories [6]

Risk category	LDL-C goal	LDL-C level at which to initiate therapeutic lifestyle changes	LDL-C level at which to consider drug therapy*
High risk: Coronary heart disease (CHD) or CHD risk equivalent (10-year risk >20 percent)•	<100 mg/dL (2.58 mmol/L); optional goal <70 mg/dL (1.82 mmol/L) in very high risk†	≥100 mg/dL (2.58 mmol/L)◊	100 mg/dL (2.58 mmol/L)§; <100 mg/dL (2.58 mmol/L) consider drug options
Moderately high risk: 2 or more risk factors (10-year risk 10 to 20 percent)¥	<130 mg/dL (3.36 mmol/L)	≥130 mg/dL (3.36 mmol/L)◊	≥130 mg/dL (3.36 mmol/L); 100 to 129 mg/dL consider drug options¦
Moderate risk: 2 or more risk factors (10-year risk <10 percent)¥	<130 mg/dL (3.36 mmol/L)	≥130 mg/dL (3.36 mmol/L)	≥160 mg/dL (4.13 mmol/L)
Lower risk: 0 to 1 risk factor**	<160 mg/dL (4.13 mmol/L)	≥160 mg/dL (4.13 mmol/L)	≥190 mg/dL (4.91 mmol/L); 160 to 189 mg/dL consider drug options

* When LDL-C lowering drug therapy is given, it is advised that the intensity of therapy be sufficient to achieve at minimum a 30 to 40 percent reduction in LDL-C level.
•CHD risk equivalents include noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease), and diabetes. Ten-year risk defined by modified Framingham risk score.
†Very high risk favors the optional LDL-C goal of <70 mg/dL (1.82 mmol/L) and, in patients with high triglycerides, non-HDL-C goal of <100 mg/dL.
◊Any individual at high or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, hypertriglyceridemia, low HDL-C [<40 mg/dL (1.04 mmol/L)], or metabolic syndrome is a candidate for therapeutic lifestyle changes to modify these risk factors independent of LDL-C level.
§ If baseline LDL-C is <100 mg/dL (2.58 mmol/L), institution of an LDL-C lowering drug is an option. This can be combined with a fibrate or nicotinic acid if a high-risk person has hypertriglyceridemia or low HDL-C (<40 mg/dL (1.04 mmol/L).
¥ Risk factors that modify LDL-C goals include cigarette smoking; hypertension (BP 140/90 mmHg or on antihypertensive medication)s; low HDL-C (<40 mg/dL [1.03 mmol/L]); family history of premature CHD (CHD in male first degree relative <55 years or CHD in female first degree relative <65 years); age (men 45 years; women 55 years). HDL-C- 60 mg/dL (>1.55 mmol/L) counts as a negative risk factor; its presence removes one risk factor from the total count.
Optional LDL-C goal <100 mg/dL (2.58 mmol/L).
¦ For moderately high risk persons with LDL-C of 100 to 129 mg/dL (2.58 to 3.35 mmol/L) at baseline or after lifestyle changes, initiation of an LDL-C lowering drug to achieve an LDL-C <100mg/dL is an option.
** Almost all people with 0 to 1 risk factor have a 10-year risk <10 percent; thus, 10-year risk assessment in people with 0 to 1 risk factor is not necessary.

Therapeutic lifestyle changes refer to the adaptation of a healthy lifestyle. The main features of therapeutic lifestyle changes include:

• Reduced intake of saturated and trans fats to less than 7 percent of total calories and cholesterol to less than 200 mg daily.
• Increased intake of LDL-C lowering dietary fibers as found in plant stanols and sterols (2 grams daily) and viscous soluble fiber (10-25 grams daily)
• Weight reduction in overweight individuals
• Increased physicial activity.

The approximate effects of dietary modification on LDL-C reduction are described in Table 3. 

Table 3
Approximate and Cumulative LDL Cholesterol Reduction Achievable By Dietary Modification [2]

Dietary Component	Dietary Change	Approximate LDL Reduction
Major
Saturated Fat	<7% of calories	8-10%
Dietary cholesterol	<200 mg/day	3-5%
Weight reduction	Lose 10 lbs	5-8%
Other LDL-lowering options
Viscous fiber	5-10 g/day	3-5%
Plant sterol/ stanol esters	2 g/day	6-15%
Cumulative estimate		20-30%

A more detailed description of the nutrient content of the therapeutic lifelstyle changes diet is provided in Table 5.

Importance of other risk factors — A number of other risk factors for CHD have been suggested by population data, such as obesity, physical inactivity, impaired fasting glucose, markers for inflammation, and abnormalities of blood clotting or thrombosis. Since there has been no evidence from controlled trials that targeting these risk factors improves outcomes, their presence does not influence current guidelines for cholesterol lowering. Nonetheless, ATP III suggests that these factors can be used to modify clinical decision-making in some circumstances [2].

Non-HDL-C — Non-HDL-C is defined as the difference between the total cholesterol and HDL-C. Non-HDL-C includes all cholesterol present in lipoprotein particles that is considered atherogenic, including LDL-C, lipoprotein(a), intermediate-density lipoprotein, and very-low-density lipoprotein. It has been suggested that the non-HDL-C fraction may be a better tool for risk assessment than LDL-C.

ATP III identifies the non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides (≥200 mg/dL [2.26 mmol/L]) [2]. The goal for situation is a concentration that is 30 mg/dL (0.78 mmol/L) higher than that for LDL-C as show in Table 4.

Table 4
Non-HDL-C goals [2]

Risk category	Non-HDL-C goal, mg/dL (mmol/L)
Coronary heart disease (CHD) or equivalent (10- year risk of CHD >20 percent)	<130 (3.36)
Two or more CHD risk factors and 10-year risk of CHD 20 percent	<160 (4.13)
0 to 1 CHD risk factor	<190 (4.91)

THERAPIES — All patients with high LDL-C should undergo lifestyle modifications in an effort to reduce the serum cholesterol. Many will not reach the goal level of cholesterol with these measures and will require drug therapy.

Lifestyle modifications —All patients with high LDL-C should undergo lifestyle modifications (therapeutic lifestyle changes as stated in ATP III) such as reductions in dietary total fat and saturated fat as shown in Table 5, weight loss in overweight patients, aerobic exercise, and plant stanols/sterols. 

Table 5
Nutrient composition of the therapeutic lifestyle changes diet

Nutrient	Recommended intake
Saturated fat*	<7 % of total calories
Polyunsaturated fat	Up to 10% of total calories
Monounsaturated fat	Up to 20% of total calories
Total fat	25 to 35% of total calories
Carbohydrate	50 to 60% of total calories
Fiber	20 to 30 g/day
Protein	Approximately 15% of total calories
Cholesterol	<200 mg/day
Total calories	Balance energy intake and expenditure to maintain desirable body weight and prevent weight gain

The United Kingdom Lipid Clinics Program of 2508 subjects found that, with diet alone, 60 percent of subjects had a mean reduction in body weight of 1.8 percent, which was associated with 5 to 7 percent reductions in serum total and LDL-C [7]. Other diets can lower LDL-C by as much as 30 percent.

The benefits of LDL-C lowering on coronary atherosclerosis may be evident within 6 to 12 months. The individual response to a cholesterol-lowering diet depends upon many factors that may be genetically determined; an increased body mass index is associated with less response to dietary change. Patients who are referred to a dietitian may have greater success in the short term with lowering LDL-C compared with patients who receive dietary counseling by physicians, although long-term compliance with dietary therapy is inadequate for both groups. As a result, there should be no hesitation in beginning a hypolipidemic drug regimen in patients who fulfill the criteria described above.

Drug therapy — Lipid-altering agents encompass several classes of drugs that include statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid, and cholesterol absorption inhibitors (eg, ezetimibe). These drugs differ with respect to mechanism of action and with respect to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and common adverse reactions are described in Table 6.

Table 6
Dose, side effects, and drug interactions of lipid lowering drugs

Drug class	Dose	Dosing	Major side effects and drug interactions
Statins (HMG CoA reductase inhibitors)
Atorvastatin	10-80 mg/day		Headache; nausea; sleep disturbance; elevations in liver function enzymes. Muscle aches and muscle damage, primarily when given with gemfibrozil or cyclosporine; myositis is also seen with severe renal insufficiency (CrCl* <30 mL/min). Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin and all but rosuvastatin raise digoxin levels; these interactions not seen with pravastatin or fluvastatin.
Fluvastatin	20-80 mg/day	BID* if dose >40 mg/day.
	80 mg SR/day
Lovastatin	20-80 mg/day	Take with evening meal. BID* if dose >20 mg/day.
Pravastatin	10-80 mg/day	Take at bedtime
Rosuvastatin	5-40 mg/day
Simvastatin	5-80 mg/day
Gemfibrozil	600 mg BID	30 to 60 min before meals.	Potentiates warfarin action. Absorption of gemfibrozil diminished by bile acid sequestrants.
Fenofibrate	160 mg/day**	Take with meals.** Use lower doses with renal insufficiency.	Skin rash, gastrointestinal (nausea, bloating, cramping) myalgia; lowers blood cyclosporine levels; potentially nephrotoxic in cyclosporine treated patients.
Nicotinic acid	1-12 g/day	Given with meals. Start with 100 mg BID* and titrate to 500 mg TID.* After 6 weeks, check lipids, glucose, liver function, and uric acid. Increase dose as needed.	Prostaglandin-mediated cutaneous flushing, headache, warm sensation, and pruritus; hyperpigmentation (particularly in intertriginous regions); acanthosis nigricans; dry skin; nausea; vomiting; diarrhea; and myositis.
Bile acid sequestrants
Cholestyramine	4-24 g/day	Take within 30 min of a meal. A double dose with dinner produces same lipid-lowering effect as BID* dosing.	Nausea, bloating, cramping, and constipation; elevations in hepatic transminases and alkaline phophatase. Impaired absorption of fat soluble vitamins, digoxin, warfarin, thiazides, -blockers, thyroxine, and phenobarbital.
Colestipol	5-30 g/day
Colesevelam	3.75 g/day	Take six tablets with meals QD* or divide 3 tablets BID	Similar
Cholesterol absorption inhibitors
Ezetimibe	10 mg/day		Increased transaminases in combination with statins

*BID: twice daily; QD: daily; TID: three times daily; SR: sustained release; CrCl: creatinine clearance.
**A micronized formulation of fenofibrate (145mg daily) may be taken without meals.

The range of expected changes in the lipid profile are listed in Table 7.

Table 7
Average effects of different classes of lipid lowering drugs on serum lipids

Drug class	Serum LDL cholesterol	Serum HDL cholesterol	Serum triglycerides
Bile acid sequestrants	↓15 to 30 percent	0 to slight increase	No change*
Nicotinic acid	↓10 to 25 percent	↑15 to 35 percent	↓25 to 30 percent
Statins (HMG CoA reductase inhibitors)	↓20 to 60 percent	↑5 to 10 percent	↓10 to 33 percent
Gemfibrozil	↓10 to 15 percent	↑15 to 25 percent	↓35 to 50 percent
Fenofibrate (micronized form)	↓6 to 20 percent	↑18 to 33 percent	↓41 to 53 percent
Cholesterol absorption inhibitors	↓17 percent	No change	No change

↑: Increase; ↓: Decrease.
* Serum triglyceride levels may increase in patients with preexisting hypertriglyceridemia (triglycerides 200mg/dL or 2.26mmol/L).

The statins are the only class of drugs to demonstrate clear improvements in overall mortality in primary and secondary prevention; follow-up from a clinical trial of niacin suggested some mortality benefits in secondary prevention [8]. Large trials of cholestyramine, clofibrate, and gemfibrozil in primary prevention not only failed to show mortality benefits but showed worrisome trends toward an increase in non-cardiac deaths. A large trial of fenofibrate in patients with diabetes (some of whom had known cardiovascular disease) found a non-significant increase in overall mortality [9]. A large trial of gemfibrozil in secondary prevention also failed to show any improvement in overall mortality, although cardiac mortality was reduced [10].

As such, statins are the first choice in virtually all patients with hypercholesterolemia in whom the goal is reduction of primary or secondary cardiovascular risk. If goal LDL-C levels cannot be attained with the use of a statin alone, it is uncertain whether the addition of other agents such as ezetimibe provides additional clinical benefit, even though LDL-C levels can be reduced further. This issue is discussed in detail separately.

Statins — Statins inhibit the rate limiting step in cholesterol production, hydroxyl-methyl-coenzyne A (HMG-CoA) reductase, and through negative feeback loops secondarily increase expression of LDL receptors on hepatic cells. The LDL particles are recognized by LDL receptors that allows for their uptake by the liver, exretion into bile and subsequently stool.The statins are the most commonly used drugs in the treatment of hypercholesterolemia. They are the most powerful drugs for lowering LDL-C, with reductions in the range of 20 to 60 percent.

Fibrates — Fibrates have modest effects on LDL-C that is considered to occur from a shift in the distribution of small dense LDL particles to large buoyant LDL particles that are more easily taken up by the LDL receptors. The major effects of the fibrates are to lower plasma triglyceride and raise HDL-C levels. They are effective for the treatment of hypertriglyceridemia and combined hyperlipidemia with or without low HDL-C or hypoalphalipoproteinemia. There is an increased risk of muscle toxicity in patients t aking a fibrate and a statin.

Nicotinic acid — Nicotinic acid acts in the liver to reduce production of VLDL apolipoprotein B and VLDL triglyceride. These VLDL components are processed to LDL particles as desribed earlier in the section Exogenous pathways of cholesterol metabolism. Nicotinic acid is effective in patients with hypercholesterolemia and in combined hyperlipidemia associated with normal and low levels of HDL-C (hypoalphalipoproteinemia). Modest VLDL-C and LDL-C lowering effects can occur at doses of 1.5 to 2.0 g/day, while doses above this amount (3 g/day) often produce greater effects. The HDL-C raising properties of nicotinic acid occur with dosages as low as 1 to 1.5 g/day.The use of nicotinic acid is often limited by poor tolerability.

Ezetimibe — Ezetimibe blocks a intestinal transporter responsible for active transport of dietary cholesterol across the wall of the intestine Ezetimibe modestly lowers the LDL-C when used alone but may have its greatest use in combination with statins, particularly when high-dose statins are not tolerated or the maximal tolerated dosage of the statin does not adequately allow the individual to achieve their minimal acceptable LDL-C target as described in Tables 1 and 2.

Bile acid sequestrants — Bile acid sequestrants bind the cholesterol enriched bile acids in the large intestine. Bile acid sequestrants are effective in patients with mild to moderate elevations of LDL-C. Low doses (8 g/day of cholestyramine or 10 g/day of colestipol) can reduce LDL-C by 10 to 15 percent. A more pronounced reduction (about 24 percent) is seen with colesevelam (6 tablets with dinner). Bile acid sequestrants are also effective when used in combination with a statin or nicotinic acid in patients with markedly elevated plasma levels of LDL-C. The use of a bile acid sequestrant is often limited by side effects.

Monitoring therapy — There are no reliable data on the optimal method of monitoring the effects of lipid-lowering therapy. ATP III recommends that the LDL-C be monitored every six weeks after the initiation of treatment until the LDL-C target is achieved. Thereafter, measurement every 6 to 12 months is reasonable in patients adherent to lifestyle modifications.

EFFECTS OF THERAPY — Cardiovascular benefits of cholesterol lowering with statin drugs have been demonstrated in various groups, including:

• Patients with CHD, with or without hyperlipidemia
• Men with hyperlipidemia but no known CHD
• Men with hypertension and multiple cardiac risk factors but without hyperlipidemia
• Men and women with average total and LDL-C levels and no known CHD

The statins are the only class of drugs to demonstrate clear reductions in overall mortality in primary (patients with risk factors, but no clinical manifestations of cardiovascular disease) and secondary prevention (patients with clinical manifest of cardiovascular disease or anatomical evidence of atherosclerotic vascular disease). Long-term follow-up from a clinical trial of niacin suggested some mortality benefits in secondary prevention.

Secondary prevention — Current ATP guidelines for LDL-C lowering in patients with existing CHD are more aggressive than those issued previously. This reflects a better understanding of both the high risk conferred by the presence of CHD and the impact of cholesterol lowering in these patients. Men and women with CHD patients have a risk of myocardial infarction that is 20 times higher than those without CHD [figure 2].

Figure 2 [11]
Rate of Myocardial Infarction Among Patients With and Without CHD Stratified by Total Cholesterol Concentration

Large trials have demonstrated that lipid lowering is beneficial in patients with CHD. A meta-analysis of 34 trials that looked at the use of statins and other therapies to reduce cholesterol levels in approximately 25,000 subjects with CHD found that cholesterol-lowering therapy was associated with a 13 percent reduction in mortality risk but no change in non-cardiovascular deaths [12].

Lipid lowering therapy reduced coronary revascularization events by 24 percent (Figure 3), stroke events were reduced by 19 percent [13] (Figure 4).

Figure 3
Association Between Reductions in LDL-C and CHD Events

Figure 4
Association Between Reductions in LDL-C and Stroke

Timing of therapy — Drug therapy should not be postponed if the target for LDL-C lowering is unlikely to be achieved in the near term by nonpharmaceutical approaches [2]. A proposal from the Coordinating Committee of the National Cholesterol Education Program (NCEP) makes a similar recommendation to initiate drug therapy at the same time as lifestyle changes whenever the LDL-C is ≥100 mg/dL (2.6 mmol/L) [6]. The statin dose should be adjusted every four to six weeks to achieve the goal.

Patients with an acute myocardial infarction should be started on a statin during hospitalization [14].

Intensity of therapy — The appropriate goal LDL-C in patients with CHD or CHD equivalents being treated for secondary prevention has been debated and the recommendations were made for more aggressive LDL-C target for certain subsets of very high risk patients as shown in Table 8.

Table 8
Definition of "very high risk" in NCEP guidelines [6]

Established coronary heart disease

PLUS

Multiple major risk factors (especially diabetes)

OR

Severe and poorly controlled risk factors (especially continued smoking)

OR

Multiple risk factors of the metabolic syndrome (especially triglycerides 200 plus non-HDL-C 130 plus HDL-C <40)

OR

Acute coronary syndrome

Subsequently, there has been emergent clinical trial evidence to support a more intensive LDL-C lowering with statin agents in stable CHD patients with the metabolic syndrome and type 2 diabetes as shown in figure 5 [15]. The metabolic syndrome is a constellation of risk markers that are associated with high future risk of type 2 diabetes and cardiovascular disease. The diagnosis of the metabolic syndrome requires the presence of at least 3 of the the following 5 risk markers: central obesity (waist circumference ≥40 inches(104 cm) in men or ≥35 inches (90 cm) in women; elevated fasting triglyceride ≥150 mg/dL (1.69 mmol/L); low HDL cholesterol (<35 mg/dL in men or <40 mg/dL in women); elevated blood pressure (systolic blood pressure ≥135 and/or diastolic blood pressure ≥85 mm Hg or treatment with blood pressure lowering medications); elevated fasting blood glucose ≥100 mg/dL (5.55 mmol/L). [16] The recommendation for more intensive LDL-C lowering in smokers cannot be supported by available randomized clinical trials.

Figure 5
Prevalence of Patients with Major Cardiovascular Events in Stable CHD Patients Stratified by Metabolic Syndrome and Diabetes Status [14]

Intensive statin therapy with atorvastatin 80 mg daily reduces mortality in patients with an acute coronary syndrome and is recommended as initial therapy. Given the early benefits, patients should be started on atorvastatin 80 mg daily early in their hospital course (Figure 6) [17].

The American Heart Association/American College of Cardiology guidelines for management of patients with unstable angina/non-ST-elevation myocardial infarction recommends diet modification and statin therapy in all patients, including post revascularization, regardless of baseline LDL-C [18].

Figure 6
All-Cause Death or Major CV Events in All Randomized Subjects [18]

Patients at very high risk for CHD events such as those in the proposed NCEP guidelines might also be expected to benefit from more intensive lipid lowering therapy. We recommend that such patients be treated with the lowest dose of a statin that reduces their LDL-C below 70 mg/dL (2.5 mmol/L). If such patients cannot achieve an LDL-C below 100 mg/dL (2.6 mmol/L) with a statin alone, the addition of a second lipid-lowering agent is conventionally implemented. Clinical trial evidence that provides support for the use of two lipid lowering agents to lower LDL-C below 100 mg/dL (2.6mmol/L) despite high-dose statin therapy is under investigation.

Among patients with stable CHD who do not tolerate a statin at the lowest available dosage, treatment with another class of lipid-lowering agents should be instituted even in the absence of clinical trial data. Side effects of statins that would prompt selection of a different class of lipid lowering therapy include muscle aches, weakness or damage or a more than 3 fold elevation in liver enzymes verified on repeat testing. Other common side effects of statins are described in Table 7. Further in patients with stable CHD who have not been able to adhere to their goal LDL-C with a statin alone, the use of a second agent in such patients is recommended.

The serum LDL-C concentration and risk factor status determine the suggested approach under ATP-III guidelines. Cardiovascular risk assessment is an essential requirement for the judicious use of cholesterol-lowering therapies in primary prevention of CHD. As mentioned above, diabetes mellitus is considered a CHD equivalent and therefore patients with diabetes do not fall within the category of primary prevention as described in Tables 1 and 2.

Limitations of applying controlled trials to clinical practice — An important question that must be addressed is the applicability of these observations to the primary care setting. There are two main issues: patient selection in the clinical trials and patient compliance with lipid-lowering therapy.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients at www.americanheart.org, www.nhlbi.nih.gov/chd, www.nlm.nih.gov/medlineplus/healthtopics.html, www.framingham.com/heart/, or www.patients.uptodate.com.

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