High Cholesterol Therapy

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.



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 (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. (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.




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 - (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 - 1 and 2.


- 1

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

* 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.


- 2

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

* 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 - 3.

- 3

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


A more detailed description of the nutrient content of the therapeutic lifelstyle changes diet is provided in - 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 - 4.

- 4

Non-HDL-C goals [2]

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 - 5, weight loss in overweight patients, aerobic exercise, and plant stanols/sterols.

- 5

Nutrient composition of the therapeutic lifestyle changes diet

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 - 6.

- 6

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

*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 - 7.

- 7

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

↑: 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 accep- LDL-C target as described in - 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 -ts 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 - 8.

- 8

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


Subsequently, there has been emergent clinical trial evidence to support a more intensive LDL-C lowering with statin agents in s- 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 S- 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 uns- 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 s- 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 - 7. Further in patients with s- 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 - 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.


High Cholesterol
High Cholesterol