- Review the main risk factors for coronary heart disease (CHD) (per NCEP)
- Review of the basics of lipoprotein metabolism and the major lipid disorders.
- Review the guidelines for non-pharmacologic and pharmacologic management of hyperlipidemia.
- Review the current pharmacologic options for the treatment of hyperlipidemia.
- Review the pharmacology of atorvastatin.
- Mechanism of action
- Side effects
- Drug interactions
- Discuss the latest clinical trials comparing
atorvastatin to other statins.
Coronary heart disease (CHD) is one the leading causes of disability and death in the US. Although the etiology of CHD is multifactorial, there is an impress amount of evidence from experimental, epidemiological, and clinical studies indicating a strong association between coronary artery atherosclerosis and hypercholesterolemia. Epidemiological investigations have established a direct relationship between TC & LDL and cardiovascular morbidity and mortality.
When the plasma cholesterol levels are > 200 mg/dL, there is a marked increase in the relative incidence of myocardial infarction. This is easily demonstrated in individuals with familial hyper-cholesterolemia. The 10-yr-death-rate doubles in this patient population as the total cholesterol rises from 200 to 250 mg/dL. The correation is even stronger when LDL cholesterol values are used in place of the total cholesterol. Elevated apoB is also considered a risk factor for CHD. Furthermore,
there is strong evidence that the risk of CHD is further magnified by the coexistence of hyper-triglyceridemia. Table1 below summarizes the main risk factors predisposing patients for the development of CHD:
Risk Factors For Coronary Heart Disease (CHD)
- Age: >45 for males and >55 for females
- Genetic factor: Family history of "premature" CHD
- Elevated LDL
- Low HDL (<35);
- Obesity and sedentary lifestyle
- Drug abuse (alcohol, anabolic steroids)
Studies also show that low HDL (<35 mg/dL) is associated with increased coronary atherosclerosis, whereas high levels of HDL (>55 mg/dL) appear to protect against heart disease.
Cholesterol is a steroid alcohol that is an essential component of cells membranes and myelin sheaths. It also serves as a precursor for steroid hormones and bile acids. Most body cholesterol is made by the liver from acetyl-CoA (as shown in figure1 below). A very variable amount (0 to 1000 mg/day) is absorbed from diet. Consumption of saturated fat (animal products such as red meat, sausages, cheese and milk fat) promotes hepatic cholesterol production and tends to increase plasma cholesterol level. Figure 2 shows the normal daily balance of cholesterol
The critical, rate-limiting step in the synthesis of cholesterol, the conversion HMG-CoA to mavalonate, is indicated by the solid yellow arrow. That is where the statins exert their cholesterol-lowering action.
Normal balance of cholesterol. Most of the cholesterol circulating in the body is made in the liver. Half of the amount taken in via the diet is excreted in the feces. Also, half of the bile acids secreted into the intestine is lost in the feces; the other half is recirculated.
Triglycerides (TGs; fat) are used by muscle cells for energy production or taken up and stored in adipose tissue. Excess food intake is converted to fat (excess calories Þ TGs) and deposited in adipose tissue to be mobilized when the need arises (i.e., when energy expenditure exceeds intake).
Because lipid molecules (cholesterol and TGs) are water insoluble, they must be packaged in special molecular complexes known as lipoproteins in order to be transported in plasma. Lipoproteins
may accumulate in the plasma due to overproduction and/or deficient removal Figures 3, 4, and 5 illustrate the structure and composition of lipoproteins. A lipoprotein is made up of a hydrophilic (water-friendly) shell and a lipid-filled core (see figure 3 below). The core of a lipoprotein consists mostly of TGs and cholesterol esters. The shell consists of proteins called apo-proteins (A, B100, B48, CI, CII, and E), cholesterol, and phospholipids (PLs). Specific apoproteins have specific functions; apoCII is necessary for the activation of lipoprotein lipases (LPL), and apoE may be necessary for certain lipoproteins (chylomicron remnants, IDL, and VLDL remnants) to engage the cell surface receptors which mediate their uptake into liver cells (by a process known as receptor-mediated endocytosis). Defective apoE can have a profound effect on lipid metabolism.
ApoB is the major structural apoprotein of the TG-rich lipoproteins secreted by the liver (called very law-density lipoproteins, VLDL; see below), but also serves as the ligand for the binding of low-density lipoproteins (LDL) to cellular LDL receptors.
There are at least six distinct lipoproteins differing in size, composition, density, and function. Figure 4 depicts four of the main liporoteins and table 2 describes thei essential features
In the cells of the small of intestine, dietary lipids are packaged into large lipoprotein complexes called chylomicrons, which have a high-TG, low-cholesterol content. Chylomicrons reach the circulation via lymph, and are subject to the action of lipoprotein lipases in the blood capillaries of muscle and adipose tissue, where TGs are hydrolyzed and taken up. The remaining cholesterol-rich structure, now call chylomicron remnant is taken up by the liver cells and broken down into its individual components. Some pts may have a lipoprotein lipase deficiency resulting in elevated chylomicron concentration (type I hyperlipidemia). There is no evidence that chylomicrons are pro-atherogenic; they are probably too large to penetrate the vascular endothelium.
The basic structure of a lipoprotein. The core contains mostly lipids and the shell has a composition similar to cell membranes (protein + phospholipids + cholesterol). The shell protein molecules (apo-proteins) serve to activate surface receptors and enzymes essential for the uptake and metabolism of lipoproteins.
Relative sizes and densities of the four major lipoproteins. Chylomicrons (density < 0.95) are not shown here because of their enormous size (about 100 x the size of VLDL).
Relative composition of the major lipoproteins (as % of total mass). The composition of IDL (not shown here) is intermediate between VLDL and LDL.
Table 2 |
The Main Lipids
w A steroid alcohol synthesized in the liver with variable amounts obtained from diet
w Average total body cholesterol = 150 g of which 90% as part of cell membrane structure.
w Necessary for the synthesis of steroid hormones.
w Saturated fat: red meat, dairy products, coconut oil and palm oil.
w Unsaturated fat: w-3: (fish oil, soybean, canola oil) w-6: vegetable oils (corn, sunflower)
w Monounsaturated fat: olive oil Tras-fatty acids: hydrogenated vegetable oils (margarine)
|VLDL (density <1)|
w Produced in the liver w Rich in TGs (>65%) and cholesterol (20%)
w Serves to transport endogenous lipids (particularly TGs) to extrahepatic sites.
w Hydrolyzed by LPL first to IDL and then to LDL
|LDL (density ~ 1)|
w Product of VLDL catabolism (catalyzed by LPL)
w Contains >60% cholesterol and accounts for >60% of the total plasma cholesterol.
w Taken up by hepatic and extrahepatic tissue through receptor-mediated endocytosis triggered by apoB100 - LDL receptor interaction.
w Has a high atherogenic potential. LDL activates monocytes (Þ macrophages). Oxidized LDL is a major source of cholesterol for macrophages in atheromatous plaques.
|IDL (density ~ 1.05)|
w Derived from both VLDL and HDL.
w IDL particles are either taken up by the liver, a process mediated by apoE or may be reduced to LDL (by losing apoE and more TGs).
|HDL (density ~ 1.15)|
w Produced by extrahepatic tissue and serves as a vehicle for the transfer of cholesterol from the peripheral tissues to the liver.
w HDL takes up the cholesterol liberated in the course of normal cell membrane turnover.
w Cholesterol esters are transferred form HDL to IDL which are then converted to LDL or take up by the liver directly.
In the liver, triglyceride (TG), cholesterol esters (CE), and apo B-100 are packaged and released into plasma as TG-rich lipoprotein called very low density lipoprotein (VLDL), whose primary
function is the endogenous transport of TGs made in the liver or released by adipose tissue. VLDL are hydrolyzed by LPL mainly in muscle capillaries releasing FFA, which are taken by muscle
cells. The atherogenic potential of VLDL is not clear because they may be too large to penetrate the endothelium and participate directly in the process of atherosclerosis. However, CHD risk correlates with hypertriglyceridemia almost as well as it does with hypercholesterolemia and most of the triglycerides in plasma are carried in VLDL.
Through enzymatic action, VLDL may be either reduced to a remnant (taken by the liver) or transformed into intermediate density lipoprotein (IDL). The latter is in turn either taken up
by the liver or is further modified to form the low density lipoprotein (LDL). Abnormal IDL metabolism may result from abnormal apoE, a condition designated as type III hyperlipidemia (or dys-beta-lipoproteinemia). This condition (which is characterized by high levels of IDL, LDL, TG, and TC) affects about 0.5% of the population and accounts for ~15% of MI survivors over the age if 60 yrs.
LDL is either taken up and broken down by the liver or is taken up by extrahepatic tissue and transformed into the high density lipoprotein (HDL), which is further modified by an enzyme called lecithin cholesterol acyl transferase (LCAT) to form IDL. An elevated HDL level (>55 mg/dL) is considered a negative risk factor (here negative is good !!). It is believed that HDL protects against atherosclerosis by facilitating reverse cholesterol transport, i.e. the ability of HDL to accept excess cholesterol.
Figure 6 illustrates the dynamics of cholesterol transport through the exogenous (gut « liver) and the endogenous pathways (hepatic « extrahepatic tissue).
The uptake of LDL is mediated by special receptors (LDLRs) whose number is influenced by genetic as well as regulatory factors. A low intracellular cholesterol concentration tends to promote
the production of LDLRs so that their number on the cell surface increases. Patients (0.2% of population) with inherited deficiency in LDLR suffer from familial primary hyper-cholesterolemia (type IIa), characterized by elevated LDL and TC levels. These pts may develop CHD very early in their lives.
Atherosclerosis is a disease process in which cholesterol and other fatty material are deposited within the wall of the medium and large diameter arteries.The initial trigger in this process is not well defined, but it is thought to damage the endothelial lining of the blood vessel, causing platelet aggregation and adhesion to the injured surface.The platelets then release a number of substances (factors) which increase the permeability of the endothelium and stimulate the proliferation of the vascular smooth muscle cells, leading to the thickening of the vascular wall in the injured area. An adequate supply of cholesterol (LDL) is necessary for cell proliferation. In the presence of high LDL levels, monocytes are stimulated to penetrate the endothelial wall and become macrophages. LDL also penetrates the endothelium, is oxidized and taken up by macrophages, which become foam cells or lipophages. The complex process of plaque (atheroma) formation and growth begins as newly formed smooth muscle cells filled with cholesterol build up and protrude into the vessel lumen. The surface of the plaque is covered with abnormal endothelial cells that have fatty streaks containing collagen, fibrin, elastin, proteoglycans, and foam cells. In addtion to the hardening of the vessel wall and the narrowing of the vessel lumen (Þ ñ vascular resistance), a stable plaque may also provide a rough surface for thrombus formation. Unstable plaques may rupture leading to the formation of thrombi, the occlusion of the arteries, and tissue infarction. The atherosclerotic process may also deform the vessel wall and weaken it to the point that it forms aneurysm
LDL is the most atherogenic of all lipoproteins and its level is used as a guide in the management of hypercholesterolemia. The LDL level may be estimated indirectly from the values for total cholesterol (TC), HDL, and TGs using this equation:
There is no fixed "normal range" for the plasma levels of total cholesterol (TC) or the lipoproteins. However, for each variable there are desirable levels and upper limits
whose values depend on the patient's risk assessment (table 3 below). For pts without CHD and less than 2 risk factors, the upper limits are 200 for TC and 160 mg/dL for LDL. In a similar patient that has
> 2 risk factors, the LDL limit is only 130 mg/dL, and if this same pt develops CHD or some atherosclerotic disease, the LDL limit falls to 100 mg/dL.
Lipid disorders are not limited to genetically based, primary hyper-lipoproteinemias (summarized in table 4). Probably more common are lipid disorders secondary to other diseases such as diabetes, renal disease, alcoholism, and hypothyroidism. About 50% of pts newly diagnosed with NIDDM are found to have CHD, and 75% of all hospital admissions for diabetics are attributed to some cardiovascular complication related to atherosclerosis. Lipid disorders can also be caused by drug therapy; thiazide diuretics, cyclosporine, ß-blockers, glucocorticoids, and anabolic steroids are examples of drugs that can alter lipid metabolism. Secondary causes of hyperlipidemia are summarized in table 5
| Table 3|
Desired Levels and Upper Limits for TC and LDL
|Risk Status||Desirable LDL||Upper limit
|Desirable TC||Upper Limit|
|No CHD and <2 RFs ||<130
|No CHD, but|
with 2 or more RFs
||130|| || |
|Pts with CHD||<100
||100|| || |
During the past 10 years dramatic progress has made in the field of lipid-lowering drugs and the management of hyperlipidemia. LDL and triglyceride "action thresholds" established by the NCEP expert panel have provided guidelines for defining and treating hypercholesterolemia and hypertriglyceridemia.
|Table 4 |
Classes of Primary Hyperlipidemias
|LP Lipase def.
||ñChylos; ñTGs; Pancreatitis, DM|
|LDL receptor def.
Fam. Combined Hyperlipidemia.
|High Apo B synthesis + defective Apo E
||ñVLDL, ñLDL, ñTC, ñTG.|
|Abnor. IDL metabolism
||ñIDL, ñTC, ñTGs|
|Abnor. VLDL metabolism
||ññ TGs + ñTC|
Fam. mixed Hypertriglyceridemia;
|Abnor. VLDL & Chylom metabolism
||ññTGs + ñ TC. ñVLDL, ñchylom; ó LDL.|
|Table 5 |
|Endocrine / Metabolic disorders
Diabetes Mellitus; Hypothyroidism; Cushing's
Uremia, nephrotic syndrome.
Primary biliary cirrhosis, acute hepatitis, etc.
|Thiazides; CSA ð ñ LDL & TC|
Glucocorticoids ð ñ VLDL, LDL, TC,
ß-Blockers ð ñ TG and òHDL
Anabolic S.ð ñ TC and òHDL
Management of Hyperlipidemia
Dietary and lifestyle modifications are extremely important in the managemnet of hyperlipidemic patients. These non-pharmacologic interventions include reduced intake of saturated fat and cholesterol, weight control, increased physical activity. An adequate trial of lifestyle intervention lasts usually 3-6 months. Pharmacologic interventions become necessary when lifestyle changes alone prove inadequate. However, it is important that lifestyle changes be continued after the initiation of drug therapy to maximize the effectiveness of the pharmacologic intervention.
In patients with CHD due to severe hyperlipidemia that is not likely to be corrected by diet alone, pharmacological intervention may be initiated before completing the initial period of lifestyle
Of the estimated 56 million Americans suffering from hypercholesterolemia, 26 millions would qualify for drug therapy, but only about 6 millions are actually receiving such therapy. Therefore, it is not surprising, given the strong correlation between LDL level and CHD, that about 15 millions have a history of CHD and about ~1.5 million have a heart attack every year. About half a million die within the first year after experiencing a major cardiac event.
The major drugs used for the treatment of dyslipidemia are summarized in the table 6:
|Drugs||Mechanism Of Action ||Effects On|
|Major Side Effects|
Cholestyramine (e.g, 4 g bid with meals) and Colistipol (4 or 5 g bid)
[NCEP 1st line drugs]
|Þñ bile excretion
Þñ # of LDLRs
Þñ LDL clearance.
Create a "sink" for cholesterol
| GI problems (bloating, constip, abd. pain)|
òabsorption of ADEK vitamins
(Nicotinic Acid; vit B3)
(dose titrated over a 10-wk period up to 2 g bid or tid).
[NCEP 1st line drugs]
The SR formulation may be less effective and more toxic (to liver and GI) than the immediate release.
|Þò VLDL prod
òVLDL = òTG level
ò LDL (25%)
ñ HDL (20%)
|Flushing of face & neck; pruritus; Stomach upset.|
(contraindicated in pts with DM or PUD)
|Fibric Acid deriv.|
Gemfibrosil (600 bid)
[NCEP 1st line drug for isolated hypertriglyceridemia]
Helsinki Heart Study
( Þò34% in CHD events)
|Þñcatabolism of VLDL and IDL
Þòhepatic FFA extraction and òVLDL production
|ò TG (45%)
|Headache & fatigue;|
GI upset; hepatotoxicity;
glucose intolerance; gallstones; myositis
May Þñ LDL;
Þñ free warfarin
|HMG-CoA Reductase Inhibitors ("the statins")
(atorva-, fluva-, lova-, prava-, simva-)
All are fungal derivatives except atorva and fluva
Lova and simva are prodrugs
|Þ ò conversion of HMG-CoA to mevalonate Þ ò hepatic cholesterol production Þ ò intracellular [cholest] Þ ñ synthesis of LDLRs Þ ñ hepatic LDL uptake and catabolism.
||All statins significantly ò LDL & TC
Effect depends on the dose and the statin used;
Atorvastatin Þ greatest reductions.
Þ ñHDL (8%)
Also, atorvastatin is the only statin that lowers TGs (20%)
|Generally well tolerated.|
GI problems (nausea; bloating, constip or diarrhea; abd. pain); headache; rash.
May Þ myopathy
Rarely Þ hepatotoxicity
Monitor Liver values and CPK regularly
Drug interactions: CSA, tacrolimus, Ca-channel blockers (CCBs) , erythromicin, azole antifungls, niacin, gemfibrozil., and warfarin.
The combination of a statin + CSA (or tacro) + a CCB may Þ rhabdomyolysis Þ ARF
More about: atorvastatin