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Treatment of lipids (including

hypercholesterolemia) in secondary prevention
Author
Robert S Rosenson, MD

Section Editor
Mason W Freeman, MD

Deputy Editor
David M Rind, MD

Last literature review version 17.3: September 2009 | This topic last updated: April 21, 2009 (More)
INTRODUCTION Patients with known coronary heart disease (CHD) or coronary equivalents (as defined below) are at
high risk for cardiovascular events. Statins have been shown to reduce such events, and to reduce all-cause mortality. Trials
of other lipid-lowering agents have also shown reductions in cardiovascular events.
The major issues related to the treatment of different causes of hypercholesterolemia for secondary prevention of coronary
heart disease are reviewed here, as are the medications available for treatment.
The clinical trials upon which the recommendations are based are discussed in detail separately as is treatment in primary
prevention. (See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents"
and see "Treatment of lipids (including hypercholesterolemia) in primary prevention" ).
Also discussed separately is a discussion of the appropriate intensity of lipid lowering therapy in secondary prevention. ( See
"Intensity of lipid lowering therapy in secondary prevention of coronary heart disease" ).
IDENTIFICATION OF PATIENTS AT RISK We generally suggest following 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). The ATP III
recommendations for the treatment of hypercholesterolemia are discussed in detail separately. ( See "ATP III guidelines for
treatment of high blood cholesterol" ).
The vast majority of patients with known CHD or a CHD risk equivalent will require lipid lowering therapy to meet ATP III
goals. CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself,
include [1] :
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 using the ATP III modification of the Framingham
risk tables (show table 1A-1B).
In addition to the conditions identified by ATP III as CHD equivalents, we consider chronic renal insufficiency (defined by a
plasma creatinine concentration that exceeds 1.5 mg/dL [133 mol/L] or an estimated glomerular filtration rate that is less
than 60 mL/min per 1.73 m2) to be a CHD equivalent. ( See "Chronic kidney disease and coronary heart disease" , section on
Chronic kidney disease alone as risk factor for CHD).
EFFECTS OF THERAPY Cardiovascular benefits of cholesterol lowering with statin drugs have been demonstrated in
various groups including [2] :
Patients with CHD, with or without hyperlipidemia [ 3,4]
Men with hyperlipidemia but no known CHD [ 5]
Men with hypertension and multiple cardiac risk factors but without hyperlipidemia [ 6]
Men and women with average total and LDL-C levels and no known CHD [ 7]
The relative risk reduction in cardiovascular outcomes for each of these studies were similar. However, many more patients
need to be treated to achieve benefit for primary compared with secondary prevention [ 8] . As an example, the number
needed to treat for one year to prevent one fatal or nonfatal coronary event (not counting uncomplicated coronary
interventions) varies from 63 in 4S (patients with CHD and hyperlipidemia) and 71 in ASCOT-LLA (patients with hypertension
plus at least three other cardiac risk factors, but without hyperlipidemia) to 256 in AFCAPS/TexCAPS (patients without CHD or
hyperlipidemia). The number needed to treat was intermediate in WOSCOPS (217) and CARE (167), patients with
hyperlipidemia and no CHD, and patients with CHD and normal lipids, respectively.
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 ( see "Drug
therapy" below ).

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 have a risk of myocardial infarction 20 times
higher than those without CHD [ 9] .
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 noncardiovascular
deaths [10] . ( See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents"
and see "Cholesterol lowering after an acute coronary syndrome" ).
A meta-analysis of 25 trials using statins for cholesterol lowering in 69,511 patients with CHD found a 16 percent reduction in
the risk of all-cause mortality (relative risk 0.84, 95% CI 0.79-0.89) [ 11] .
Specific results from some of the trials of statins include:
The Scandinavian Simvastatin Survival Study (4S) of patients with hyperlipidemia (baseline plasma total cholesterol
levels between 212 and 309 mg/dL [5.5 and 8.0 mmol/L]) found that simvastatin therapy versus placebo for 5.4 years
resulted in statistically significant reductions in total mortality (8 versus 12 percent), major coronary events (19 versus
28 percent), CHD deaths (42 percent reduction), revascularization procedures (CABG or coronary angioplasty, 37
percent reduction), and fatal plus nonfatal cerebrovascular events (2.7 versus 4.3 percent) ( show figure 1 and show
figure 2) [ 3] .
The CARE trial treated patients with average cholesterol levels (mean serum total cholesterol concentration of 209
mg/dL [5.4 mmol/L]) with pravastatin (40 mg before sleep) or placebo [ 4] . At five years, benefits with pravastatin
compared with placebo included significant reductions in the combined incidence of coronary death and nonfatal MI
(10.2 versus 13.2 percent, p = 0.003, show figure 3), the need for revascularization (14.1 versus 18.8 percent,
p<0.001), and the frequency of stroke (2.6 versus 3.8 percent, p = 0.03). The benefits were more apparent among
women, older patients (above age 60), and pretreatment serum LDL-C above 125 mg/dL (3.2 mmol/L).
More recently, the Heart Protection Study randomly assigned 20,536 subjects to simvastatin (40 mg/day) or placebo:
33 percent had baseline LDL-C <116 mg/dL (<3 mmol/L), 25 percent had a level of 116 to 135 mg/dL (3 to 3.5
mmol/L), and 42 percent had levels >135 mg/dL (>3.5 mmol/L) [ 12] . Entry criteria included a history of
cardiovascular disease (coronary cerebrovascular or peripheral vascular disease), diabetes mellitus, or treated
hypertension. Thus, most patients were treated for secondary prevention. ( See "Clinical trials of cholesterol lowering in
patients with coronary heart disease or coronary risk equivalents" , section on Heart Protection Study).
After an average follow-up of 5.5 years, there were significant reductions in all-cause mortality (12.9 versus 14.7 percent;
relative risk reduction [RRR] 13 percent), deaths from heart disease or related blood vessel disease (7.6 versus 9.1 percent;
RRR 17 percent), and major cardiovascular events (19.8 versus 25.2 percent; RRR 24 percent) ( show figure 4). The percent
reduction in events was similar in the three tertiles of baseline LDL-C (the lowest being <116 mg/dL [<3 mmol/L]) and was
also similar in those with a baseline LDL-C below 100 mg/dL (2.6 mmol/L).
These subgroup observations suggest that if there is a threshold below which lowering LDL-C no longer reduces cardiovascular
risk in patients with cardiovascular disease, it is apparently at a much lower concentration than is typically seen in Western
populations. The benefit in patients with lower LDL-C concentrations may reflect actions of statins other than lipid lowering.
(See "Summary and recommendations" below and see "Mechanisms of benefit of lipid lowering drugs in patients with
coronary heart disease").
In addition to the reduction in clinical events, serial angiographic studies have shown that cholesterol lowering can retard the
progression, and in some cases, induce regression of coronary atherosclerosis (show table 2 ) [ 13] . This benefit is most
prominent when LDL-C levels are reduced below 100 mg/dL (2.6 mmol/L) or lower. In general, lipid-lowering drugs are
required, since dietary modification alone is relatively ineffective ( show table 5 ). ( See "Clinical trials of cholesterol lowering in
patients with coronary heart disease or coronary risk equivalents" for a complete review of these issues).
Secondary intervention trials have shown that, compared with men, women may have increased regression of coronary
lesions and a similar improvement in survival with intensive lipid lowering [ 14,15] . ( See "Determinants and management of
cardiovascular risk in women").
Taken together, these findings suggest that patients who already have CHD merit aggressive lipid management.
Timing of therapy We feel that 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 [ 16] . 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) [ 17] . The statin dose should be titrated every four to six
weeks to achieve the goal.
Patients with an acute myocardial infarction should be started on a statin during hospitalization [ 18,19] . ( See "Cholesterol

lowering after an acute coronary syndrome" ).

Intensity of therapy The appropriate goal LDL-C in patients with CHD or CHD equivalents being treated for secondary
prevention is controversial and is discussed in detail separately. We suggest the following management ( see "Intensity of lipid
lowering therapy in secondary prevention of coronary heart disease" ):
Intensive statin therapy with atorvastatin 80 mg daily reduces mortality in patients with an acute coronary syndrome
and is recommended as initial therapy. Given that benefit occurs earlier than the first cholesterol measurement on
therapy would normally be obtained, we recommend that patients be started on atorvastatin 80 mg daily early in their
hospital course, rather than titrating the dose upward in the outpatient setting. (See "Cholesterol lowering after an
acute coronary syndrome" ).
Patients at very high risk for CHD events such as those in the proposed NCEP guidelines ( show table 5 ) 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 (1.8 mmol/L). If such patients cannot achieve an
LDL-C below 100 mg/dL (2.6 mmol/L) with a statin alone, we recommend the addition of a second lipid-lowering
agent.
While awaiting further studies, except in the highest risk patients ( show table 5 ), we suggest that patients with stable
CHD or a CHD equivalent be treated with the lowest dose of statin that reduces the LDL-C to less than 100 mg/dL (2.6
mmol/L). More intensive statin therapy in patients with stable CHD should generally only be used in those patients
who, after discussion of the risks and benefits, would prefer to reduce the risk of cardiovascular events even if the
added benefit on overall mortality is minimal or if noncardiac causes of death are increased such that there is no effect
on all-cause mortality.
In the absence of clear evidence, we suggest that patients with stable CHD who do not tolerate a statin be treated
with another lipid-lowering agent. Although the evidence also does not allow a clear answer on whether to add a
second agent in usual risk patients with stable CHD who are unable to achieve their goal LDL-C with a statin alone, we
suggest the use of a second agent in such patients.
Primary prevention Treatment of lipid disorders in primary prevention is discussed in detail separately. (See "Treatment
of lipids (including hypercholesterolemia) in primary prevention").
Cost-effectiveness of cholesterol-lowering therapy
evaluated for secondary prevention [ 14,20,21] .

The cost-effectiveness of cholesterol lowering has been

The 4S study estimated the cost savings derived from cholesterol lowering using a cost-minimization analysis [ 14,20] .
Cost minimization analyses approximate health costs in the two treated groups and attribute the difference in costs to
the alternate therapy [ 14] . Hospitalizations from acute cardiac events (myocardial infarction, angina pectoris,
congestive heart failure) were reduced by 32 percent and revascularization procedures by 26 percent in patients
treated with simvastatin. The mean length of stay for acute cardiovascular events and revascularization procedures
was also less in the simvastatin group (7.1 versus 7.9 days, p = 0.006). The estimated reduction in costs over 5.4
years with simvastatin therapy would be $3872 per patient. However, the cost of the medication used is higher in the
United States.
A second report from the 4S study analyzed the cost-effectiveness of simvastatin in relation to age, sex, and cholesterol level
using Swedish healthcare prices [20] . When the analysis included indirect costs associated with decreased morbidity from
CHD, treatment led to a savings among men and women aged 35; the cost per year of life gained ranged from $1,200 to
$13,300 in older patients (show figure 5).
Another cost-effectiveness analysis of secondary prevention was based upon the CARE trial in which patients had only
borderline elevations in serum cholesterol [21] . In this lower-risk group, pravastatin therapy was associated with an
incremental cost of $16,000 to $32,000 per quality-adjusted life-year gained; cost-effectiveness was greater for
patients more than 60 years of age or with pretreatment LDL-C above 125 mg/dL (3.2 mmol/L) [ 13] .
Safety of cholesterol lowering Some initial studies, such as the Helsinki Heart Study, suggested that cholesterol
lowering might be associated with an increased incidence of noncardiovascular deaths due to accidents, suicide, or violence
[22] . However, more recent larger trials (primarily conducted with an HMG CoA reductase inhibitor [statin]) have been
unable to confirm such a relationship [12,23-25] . A meta-analysis of 19 randomized trials of primary and secondary
prevention found no increase in noncardiovascular mortality associated with cholesterol-lowering therapy overall or with the
administration of a statin; there may be a modest increase in risk with nonstatin therapy (p = 0.06) [ 25] . There have been
case reports of patients developing severe irritability and aggression associated with the use of statins [ 26] . It is not known
whether the statin use caused these symptoms, but very rare idiosyncratic reactions of this sort could be missed in controlled
trials.
Specific groups

Treatment in diabetes Diabetes mellitus is considered a CHD equivalent and, as mentioned above, both the CARE
trial [27] and the Heart Protection Study [ 12,28] found significant improvement in outcomes with statin therapy even at
LDL-cholesterol (LDL-C) values below 116 mg/dL (3.0 mmol/L). The CARDS study found similar benefits of statin therapy in
patients with an LDL-C above or below 120 mg/dL (3.1 mmol/L) [ 29] . A meta-analysis of patients with diabetes in 14
randomized trials of statins (n = 18,686) also found that relative benefits appeared unrelated to the baseline LDL-C [ 30] .
Thus, the ATP-III goal LDL-C is similar to that in patients with CHD: less than 100 mg/dL (2.6 mmol/L). As discussed above,
even more aggressive target LDL-C goals of 70 to 80 mg/dL (1.8 to 2.1 mmol/L) may be appropriate ( see "Intensity of
therapy" above ).
Treatment in the elderly The decision whether to treat hypercholesterolemia in an elderly individual is highly
individualized, based upon both chronological and physiologic age. A patient with a limited life span from a concomitant illness
is probably not a candidate for drug therapy. On the other hand, an otherwise healthy elderly individual should not be denied
drug therapy simply on the basis of age alone [ 9] .
There appears to be ample evidence supporting the use of lipid-lowering therapy for secondary prevention in elderly patients
with established CHD who do not have life-limiting comorbid disease [ 31] . In the CARE trial, for example, approximately
one-half of patients were above age 60, and the benefit of cholesterol lowering in these patients was similar to that in
younger patients [4] . Similarly, the percent reduction in events in the Heart Protection Study was similar in patients above
and below age 65 [ 12] . ( See "Treatment of dyslipidemia in the elderly" ).
Treatment in patients with familial hypercholesterolemia The therapeutic approach to patients with either
homozygous or heterozygous familial hypercholesterolemia (FH) is discussed separately. ( See "Primary disorders of
LDL-cholesterol metabolism", section on Familial hypercholesterolemia and see "Diseases associated with atherosclerosis in
childhood", section on Familial hypercholesterolemia).
Patients with low HDL Therapy aimed at raising HDL-C levels into the normal range has been advocated by some
investigators in patients with overt CHD and those at high risk because of a strong family history [ 32,33] . In ATP III, low
HDL-C is defined as <40 mg/dL (1.03 mmol/L), a change from the level of 35 mg/dL (0.91 mmol/L) in ATP II [ 31] . The
details of medical therapy for patients with low HDL-C are discussed separately. ( See "HDL metabolism and approach to the
patient with abnormal HDL-cholesterol levels" ).
Patients with hypertriglyceridemia It may be beneficial to treat hypertriglyceridemia in patients who also have
hypercholesterolemia and/or hypoalphalipoproteinemia. Since triglyceride-rich lipoproteins also transport cholesterol,
hypercholesterolemia of varying severity often accompanies hypertriglyceridemia. The magnitude of the hypercholesterolemia
depends upon the number and composition of triglyceride-rich lipoproteins that are present. Thus, the presence of
hypertriglyceridemia should suggest that any increase in serum total cholesterol is due, at least in part, to increased
VLDL-cholesterol.
Possible indications for treatment of isolated hypertriglyceridemia include overt CHD, a strong family history of CHD, and
multiple coexisting cardiac risk factors. In addition, subjects with very high triglyceride levels (>500 mg/dL [5.6 mmol/L])
should be treated to avoid pancreatitis and, in patients with triglyceride levels above 1000 mg/dL (11.3 mmol/L), the
chylomicronemia syndrome. ( See "Approach to the patient with hypertriglyceridemia").
As mentioned above, 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]) [ 31] . The goal for non-HDL-C in this circumstance is a concentration that is
30 mg/dL (0.78 mmol/L) higher than that for LDL-C ( show table 6 ).
C-reactive protein Levels of C-reactive protein (CRP) appear to be associated with clinical outcomes. The possible
implications of this for identifying appropriate patients for lipid lowering therapy and for goals of therapy are discussed
separately. ( See "Screening for cardiovascular risk with C-reactive protein" and see "C-reactive protein in cardiovascular
disease" and see "Secondary prevention of cardiovascular disease: Risk factor reduction" ).
Heart failure Patients with heart failure do not appear to gain significant benefits from statins, even when they have
ischemic causes of heart failure. ( See "Statin therapy in patients with heart failure").
End-stage renal disease Patients on dialysis do not appear to gain significant benefits from statin therapy. ( See
"Secondary prevention of cardiovascular disease in end-stage renal disease (dialysis)" ). This does not change the
recommendation that people with chronic kidney disease who do not yet require dialysis be aggressively treated as having a
coronary risk equivalent when choosing statin therapy. ( See "Identification of patients at risk" above ).
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. The goals of cholesterol
lowering are described above in the sections on primary and secondary prevention. The following section will review how
these goals can be achieved. A number of issues arise when treating patients with specific primary and secondary disorders of
LDL metabolism. These issues are discussed in detail separately. ( See "Primary disorders of LDL-cholesterol metabolism" and
see "Secondary causes of dyslipidemia" ).
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 and saturated fat (show table 7 ), weight loss in overweight patients,

aerobic exercise, and plant stanols/sterols. 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 [34] . Other diets can lower LDL-C by as much as 30 percent [ 35] . ( See "Lipid lowering
with diet or dietary supplements" ).
Another study randomly assigned 180 postmenopausal women and 197 men with low levels of HDL-C and moderately
elevated levels of LDL-C to aerobic exercise, diet, diet plus exercise, or no treatment [ 36] . Although there were no significant
changes in HDL-C in any group, there were significant reductions in LDL-C in both men and women (14.5 and 20 mg/dL [0.38
and 0.52 mmol/L], respectively) in the diet plus exercise group compared with control or diet alone and, in men, in the diet
plus exercise group compared with exercise alone.
The benefits of LDL-C lowering may be evident within 6 to 12 months [ 37,38] . The individual response to a
cholesterol-lowering diet depends upon many factors; some of the response is genetically determined, and increased body
mass index is associated with less response to dietary change [ 39] . 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 [ 40,41] . 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 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 a table ( show
table 8), and the range of expected changes in the lipid profile are listed in a table ( show table 9 ).
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 [ 42] . 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 noncardiac deaths. ( See "Clinical trials of cholesterol lowering for primary
prevention of coronary heart disease" ). A large trial of fenofibrate in patients with diabetes (some of whom had known
cardiovascular disease) found a nonsignificant increase in overall mortality [ 43] . A large trial of gemfibrozil in secondary
prevention also failed to show any improvement in overall mortality, although cardiac mortality was reduced [ 44] . ( See
"Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents" , sections on VA-HIT
trial and FIELD trial).
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. (See "Intensity of lipid lowering therapy in secondary prevention of
coronary heart disease", section on Use of medications other than statins).
The recommended goal LDL-C concentrations are described above. ( See "Effects of therapy" above ). If an additional agent is
needed, abnormalities in other lipoproteins may influence the choice of that agent. In patients with a pure elevation in LDL-C
who are being treated for secondary prevention, addition of ezetimibe or a bile acid sequestrant is a reasonable option.
In patients who do not tolerate a statin because of myopathy, it may be appropriate to try another statin such as pravastatin
that appears to have a lower risk of producing myopathy. ( See "Muscle injury associated with lipid lowering drugs" ).
In patients who do not tolerate any statin and are being treated for secondary prevention, reasonable options include the use
of ezetimibe, bile acid sequestrants, fenofibrate, and niacin. Referral to a lipid specialist is appropriate in such patients.
Statins 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 ( show table 10) [ 45-47] . Fluvastatin is
somewhat less potent, decreasing LDL-C levels by 20 to 25 percent at the maximum recommended dose [ 46,48] .
Atorvastatin and rosuvastatin are the most potent statins approved in the United States, reducing LDL levels by around 60
percent at doses of 80 and 40 mg/day, respectively ( show figure 6) [ 49] . An additional benefit of atorvastatin and
rosuvastatin is more effective triglyceride lowering in patients with hypercholesterolemia; triglyceride lowering with
atorvastatin, for instance, ranges from 14 to 33 percent [ 50,51] . Rosuvastatin is also more effective in raising HDL-C levels
than atorvastatin, simvastatin, or pravastatin [52] . ( See "Lipid lowering with statins").
The effects of statin therapy are additive to those of a controlled diet. As an example, one study randomized 120 men with
hypercholesterolemia to a usual diet or a modified Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and
dietary fibers; each group was further randomized to simvastatin (20 mg) or placebo and after 12 weeks crossed over to the
alternate therapy [ 53] . After 24 weeks, the reduction in LDL was greater with diet and drug (41 versus 30 and 11 percent for
drug and diet alone); a similar additive effect was seen on triglyceride, HDL-C, and apolipoprotein B and A1 levels.
Adverse reactions occur less frequently with the statins than with the other classes of lipid-lowering agents. Muscle injury is an
important concern, primarily in patients who are also treated with cyclosporine or a fibrate; the excess risk appears to be
eliminated by using pravastatin or fluvastatin, which are not metabolized by CYP3A4 ( show table 11). ( See "Muscle injury
associated with lipid lowering drugs").

A drug interaction in which statin therapy interferes with the activation of clopidogrel was suggested in an initial study.
However, subgroup analyses of randomized trials have not demonstrated clinical significance of such an interaction, and thus
a change in practice is not recommended. ( See "Lipid lowering with statins", section on Drug interactions).
Fibrates The major effects of the fibrates are to lower plasma triglyceride and raise HDL-C levels [ 54,55] . They are
effective for the treatment of hypertriglyceridemia and combined hyperlipidemia with or without hypoalphalipoproteinemia
[54] . There is an increased risk of muscle toxicity in patients taking a fibrate and a statin. ( See "Muscle injury associated
with lipid lowering drugs").
Nicotinic acid Nicotinic acid is effective in patients with hypercholesterolemia and in combined hyperlipidemia
associated with normal and low levels of HDL-C (hypoalphalipoproteinemia) [ 56,57] . The HDL raising properties of nicotinic
acid occur with dosages as low as 1 to 1.5 g/day [ 57] . In contrast, while modest VLDL-C and LDL-C lowering effects can
occur at doses of 1.5 to 2.0 g/day, doses above this amount (3 g/day) often produce greater effects [ 47,56] . The use of
nicotinic acid is often limited by poor tolerability. (See "Lipid lowering with drugs other than statins and fibrates").
Ezetimibe Ezetimibe modestly lowers the LDL-C when used alone and may be helpful for avoiding high doses of
statins (and potentially increased susceptibility to muscle injury) in patients who do not meet cholesterol goals on low dose
statin therapy alone. However, the clinical benefits of either ezetimibe monotherapy or combining ezetimibe with statin
therapy remain to be proven. ( See "Lipid lowering with drugs other than statins and fibrates", section on Ezetimibe).
Bile acid sequestrants 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) can be achieved at maximal recommended doses (24 and 30 g/day, respectively). A similar
reduction in LDL cholesterol can be achieved with 1.5 to 4.5 g/day of colesevelam . 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 ( show
figure 7). The use of a bile acid sequestrant is often limited by side effects. ( See "Lipid lowering with drugs other than statins
and fibrates").
Success rate Despite awareness of the target LDL-C levels recommended by the National Cholesterol Education
Program, lipid management is not optimal. As an example, one study of 4888 dyslipidemic patients from five regions in the
United States found that, overall, only 38 percent achieved ATP II target LDL-C levels [ 58] . Success rates were 68 percent
among low-risk patients (no evidence of CHD and less than two risk factors), 37 percent in high-risk patients (no evidence of
CHD and two or more risk factors), and 18 percent among those with CHD.
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 [ 31] . Thereafter, measurement every 6 to 12 months is reasonable in patients adherent to lifestyle
modifications.
One analysis suggested that, given the gradual long-term increases in LDL-C with age and short-term variability in cholesterol
measurements, monitoring lipid levels every three to five years might be superior to more frequent monitoring in adherent
patients with well-controlled lipid levels [ 59] .
INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. ( See "Patient information:
High cholesterol and lipids (hyperlipidemia)"). We encourage you to print or e-mail this topic review, or to refer patients to
our public web site, www.uptodate.com/patients , which includes this and other topics.
SUMMARY AND RECOMMENDATIONS
Our recommendations for secondary prevention are based upon data subsequent to ATP-III and are more aggressive
than those of ATP-III, but less aggressive than some proposed modifications to ATP-III. ( See "Intensity of lipid lowering
therapy in secondary prevention of coronary heart disease" ).
We suggest that all patients with an LDL-C above goal undergo lifestyle modifications in an effort to reduce the serum
cholesterol (Grade 2C). These modifications include diet and exercise. ( See "Lipid lowering with diet or dietary
supplements").
In patients with CHD or a CHD equivalent (diabetes mellitus, symptomatic carotid artery disease, peripheral arterial
disease, abdominal aortic aneurysm, chronic kidney disease, or multiple risk factors that confer a 10-year risk of CHD
greater than 20 percent) who are significantly above the goal LDL-C, drug therapy should not be delayed while waiting
to see if lifestyle modifications are effective ( see "Timing of therapy" above ).
Patients who require drug therapy should almost always be treated with a statin ( see "Drug therapy" above ).
The appropriate goal LDL-C in patients with CHD or CHD equivalents being treated for secondary prevention is
controversial and is discussed in detail separately. (See "Intensity of lipid lowering therapy in secondary prevention of
coronary heart disease").
We recommend that patients with an acute coronary syndrome be treated with intensive statin therapy with

atorvastatin 80 mg daily ( Grade 1B). ( See "Cholesterol lowering after an acute coronary syndrome" ).
Patients at very high risk for CHD events such as those in the proposed NCEP guidelines ( show table 5 ) might also be
expected to benefit from more intensive lipid lowering therapy. We suggest that such patients be treated with the
lowest dose of a statin that reduces their LDL-C below 70 mg/dL (1.8 mmol/L) ( Grade 2B). If such patients cannot
achieve an LDL-C below 100 mg/dL (2.6 mmol/L) with a statin alone, we suggest the addition of a second
lipid-lowering agent ( Grade 2B). Other experts, including other authors for UpToDate, would make differing
recommendations. ( See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease" , section
on Use of medications other than statins).
Given the increased side effects with more intensive statin therapy, and the lack of benefit on all-cause mortality, we
suggest that, except in the highest risk patients ( show table 5 ), patients with stable CHD or a CHD equivalent be
treated with the lowest dose of statin that reduces the LDL-C to less than 100 mg/dL (2.6 mmol/L) ( Grade 2B).
However, more aggressive LDL-C lowering treatment to slightly reduce nonfatal cardiovascular events is a reasonable
option in patients for whom the additional therapy would not impose undue burdens from side effects or cost.
In the absence of clear evidence, we suggest that patients with stable CHD who do not tolerate a statin be treated
with another lipid-lowering agent ( Grade 2B). Although the evidence also does not allow a clear answer on whether to
add a second agent in usual risk patients with stable CHD who are unable to achieve their goal LDL-C with a statin
alone, we suggest the use of a second agent in such patients ( Grade 2B). Other experts, including other authors for
UpToDate, would make differing recommendations. ( See "Intensity of lipid lowering therapy in secondary prevention of
coronary heart disease", section on Use of medications other than statins).
Use of UpToDate is subject to the Subscription and License Agreement.
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GRAPHICS
Framingham/ATP III point scores in men
Age, years

Points

20 to 34

-9

35 to 39

-4

40 to 44

45 to 49

50 to 54

55 to 59

60 to 64

10

65 to 69

11

70 to 74

12

75 to 79

13

Total cholesterol mg/dL

(mmol/L)

Age 20 to 39

Age 40 to
49

Age 50 to 59

Age 60
to 69

Age 70
to 79

<160 (3.4)

160 to 199 (3.4 to 5.15)

200 to 239 (5.17 to 6.18)

240 to 279 (6.2 to 7.21)

11

Age 20 to 39

Age 40 to
49

Age 50 to 59

Age 60
to 69

Age 70
to 79

Nonsmoker

Smoker

HDL cholesterol mg/dL

(mmol/L)

Points

280 (7.24)

60 (1.55)

-1

50 to 59 (1.29 to 1.53)

40 to 49 (1.03 to 1.27)

<40 (1.03)

Systolic blood pressure,

mmHg

Untreated

Treated

<120

120 to 129

130 to 139

140 to 159

Point total

10-year risk,
percent

Point
total

10-year risk,
percent

10

11

12

10

13

12

14

16

15

20

16

25

160

17

30

NOTE: These risk estimates for the development of coronary heart disease do not account for all important cardiovascular
risk factors. Not included are diabetes mellitus (which is considered a CHD equivalent), family history of CHD, alcohol
intake, and the serum C-reactive protein concentration. Adapted from Adult Treatment Panel III at
http://www.nhlbi.nih.gov/ The point total is determined in each category and the 10-year risk determined in the bottom
row.

Framingham/ATP III point scores in women

Age, years

Points

20 to 34

-7

35 to 39

-3

40 to 44

45 to 49

50 to 54

55 to 59

60 to 64

10

65 to 69

12

70 to 74

14

75 to 79

16

Total cholesterol mg/dL

(mmol/L)

Age 20 to 39

Age 40 to
49

Age 50 to 59

Age 60
to 69

Age 70
to 79

<160 (3.4)

160 to 199 (3.4 to 5.15)

200 to 239 (5.17 to 6.18)

240 to 279 (6.2 to 7.21)

11

13

10

Age 20 to 39

Age 40 to
49

Age 50 to 59

Age 60
to 69

Age 70
to 79

Nonsmoker

Smoker

HDL cholesterol mg/dL

(mmol/L)

Points

280 (7.24)

60 (1.55)

-1

50 to 59 (1.29 to 1.53)

40 to 49 (1.03 to 1.27)

<40 (1.03)

Systolic blood pressure,

mmHg

Untreated

Treated

<120

120 to 129

130 to 139

140 to 159

Point total

10-year risk,
percent

Point
total

10-year risk,
percent

<9

<1

17

18

10

19

11

20

11

12

21

14

13

22

17

14

23

22

15

24

27

16

160

25

30

NOTE: These risk estimates for the development of coronary heart disease do not account for all important cardiovascular
risk factors. Not included are diabetes mellitus (which is considered a CHD equivalent), family history of CHD, alcohol
intake, and the serum C-reactive protein concentration. The point total is determined in each category and the 10-year
risk determined in the bottom row. Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/.

Reduction in cholesterol with simvastatin reduces major

coronary events

Based upon a 5.4 year follow-up from the 4S trial, there is a direct
relationship between major coronary event (MCE) risk reduction at one
year and the percent reduction (right panel) and the absolute reduction
in serum LDL-cholesterol (right panel). The red lines indicate the 95
percent confidence intervals. Data from Pedersen, TR, Olsson, AG,
Faeryeman, O, et al, for the Scandinavian Simvastatin Survival Study
Group, Circulation 1998; 97:1453.

Simvastatin improves survival in hypercholesterolemic

patients

Overall survival in 4444 subjects with established coronary heart disease

and a plasma cholesterol concentration between 212 and 309 mg/dL (5.5
to 8.0 mmol/L) who were treated with simvastatin or placebo.
Simvastatin led to a significant improvement in patient survival
(p<0.003). Data from Pedersen, TR, and the Scandinavian Simvastatin
Survival Study Group, Lancet 1994; 344:1383.

Benefit of pravastatin post-MI in the CARE trial

Kaplan-Meier analysis of the incidence of coronary death or nonfatal

myocardial infarction in post-MI patients who had average levels of
cholesterol and were randomized to therapy with pravastatin or placebo.
The incidence of these endpoints was significantly reduced by therapy
with pravastatin (p = 0.003). A similar percent benefit was seen in the
subgroup of patients with near normal levels of LDL-cholesterol (125 to
150 mg/dL [3.2 to 3.9 mmol/L]). Redrawn from Sacks, FM, Pfeffer, MA,
Move, LA, et al for the Cholesterol and Recurrent Events Trial
Investigators, N Engl J Med 1996; 335:1001.

Benefit of simvastatin in heart protection study

Life-table plot of the benefit of simvastatin, mostly for secondary

prevention, in the 20,536 participants in the Heart Protection Study. Among
the patients who were allocated to simvastatin therapy, there was already a
nonsignificant trend towards fewer vascular events in the first year of
follow-up. During each subsequent year of follow-up there were highly
significant reductions in event rates even though, by the end of year three,
about one-sixth of patients taking placebo had started taking simvastatin.
Data from MRC/BHF Heart Protection Study of cholesterol lowering with
simvastatin in 20536 high-risk individuals: a randomised placebo-controlled
trial. Lancet 2002; 360:7.

Regression of coronary atherosclerosis with lipid lowering

Trial

NHLBI

CLAS I

FATS

LDL,

HDL,

Regression,

Progression,

Intervention

percent

percent

percent

percent

Diet

-5

NC

49

Cholestyramine

-26

+8

32

Diet

-5

+2

61

Colestipol + NA

-43

+37

16

39

Diet + Colestipol

-7

+5

11

46

Lovastatin + Colestipol

-46

+15

32

21

NA + Colestipol

-32

+43

39

25

Diet

-11

NC

12

41

-38

+26

32

20

Diet

NC

NC

12

41

Lovastatin

-38

+10

23

29

UCSF-SCOR Cholestyramine + NA
Lovastatin

MARS

NA: nicotinic acid.

Summary of the results of five different trials in patients with hypercholesterolemia comparing the results of moderate
dietary modification with pharmacologic intervention on the course of coronary atherosclerosis at two to five years. Drug
therapy was associated with a greater reduction in LDL-cholesterol, a modest increase in HDL-cholesterol, a greater
likelihood of coronary regression, and less frequent coronary progression than seen with diet alone.
Data from Rosenson, RS, The Physician and Sportsmedicine 1994; 22:59.

Definition of "very high risk" in NCEP guidelines

Established coronary heart disease
PLUS
Multiple major risk factors (especially diabetes)
OR
Severe and poorly controlled risk factors (especially continued smoking)
OR
Multple risk factors of the metabolic syndrome (especially triglycerides

200 plus non-HDL-C

130 plus

HDL-C <40)
OR
Acute coronary syndrome
Adapted from Grundy, SM, Cleeman, JI, Merz, NB, et al. Circulation 2004; 110:227.

Cost per year of life gained in patients with coronary heart disease who received simvastatin
treatment for five years
Age 35
Total cholesterol before treatment , mg/dl*

Men

Women

Age 59

Age 70

Men

Men

Women

Women

Analysis of direct costs, dollars

213

11,400

27,400

7,000

16,400

6,200

13,300

261

8,800

18,800

5,500

10,300

4,700

8,500

309

6,700

13,200

4,200

7,100

3,800

6,200

Analysis of direct and indirect costs, dollars

213

Savings

Savings

2,100

8,600

6,200

13,300

261

Savings

Savings

1,600

4,900

4,700

8,500

309

Savings

Savings

1,200

3,200

3,800

6,200

The cost per year of life gained with simvastatin treatment of patients with coronary heart disease is related to the
baseline total cholesterol level and the age of the patient. Direct costs are those for health care resulting from a cardiac
event, while indirect costs are lost productivity related to a cardiac event.
* To convert values for cholesterol to millimoles per liter, multiply by 0.02586.
Adapted from Johannesson, M, Jonsson, B, Kjekshus, J, et al, for the Scandinavian Simvastatin Survival Study Group. N
Engl J Med 1997; 336:332.

Non-HDL-cholesterol goals

Risk category

Non-HDL-cholesterol goal, mg/dL

(mmol/L)

Coronary heart disease (CHD) or equivalent (10- year risk of CHD

>20 percent)
Two or more CHD risk factors and 10-year risk of CHD

20 percent

0 to 1 CHD risk factor

<130 (3.36)
<160 (4.13)
<190 (4.91)

Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/.

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

* Trans fatty acids are another LDL-raising fat that should be kept at low intake.
Carbohydrates should be derived predominantly from foods rich in complex carbohydrates including grains, especially
whole grains, fruits, and vegetables.
Daily energy expenditure should include at least moderate physical activity (contributing approximately 200 kcal/day).
Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/.

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)

Lovastatin

Pravastatin
Simvastatin

20-80
mg/day
10-80
mg/day

Take with evening

meal. BID if dose >20
mg/day.
Take at bedtime.

hepatocellular enzymes and alkaline phosphatase.

5-80 mg/day

Myositis and rhabdomyolysis, primarily when given with

20-80

severe renal insufficiency (CrCl <30 mL/min). Lovastatin,

mg/day
Fluvastatin
80 mg

gemfibrozil or cyclosporine; myositis is also seen with

BID if dose >40
mg/day.

SR/day
Atorvastatin
Rosuvastatin
Gemfibrozil

Headache; nausea; sleep disturbance; elevations in

atorvastatin, rosuvastatin, and simvastatin potentiate

effect of warfarin and all but rosuvastatin raise digoxin
levels; these interactions not seen with pravastatin or
fluvastatin.

10-80
mg/day
5-40 mg/day
600 mg BID

30 to 60 min before

Potentiates warfarin action. Absorption of gemfibrozil

meals.

diminished by bile acid sequestrants.

Nanocrystal
145 mg/day
Fenofibrate

Micronized
160-200
mg/day

Micronized taken with

Skin rash, gastrointestinal (nausea, bloating, cramping)

meals. Use lower doses

myalgia; lowers blood cyclosporine levels; potentially

with renal insufficiency.

nephrotoxic in cyclosporine treated patients.

Given with meals. Start

with 100 mg BID and
titrate to 500 mg TID.
Nicotinic acid

1-12 g/day

After 6 weeks, check

lipids, glucose, liver
function, and uric acid.
Increase dose as

Prostaglandin-mediated cutaneous flushing, headache,

warm sensation, and pruritus; hyperpigmentation
(particularly in intertriginous regions); acanthosis
nigricans; dry skin; nausea; vomiting; diarrhea; and
myositis.

needed.
Bile acid sequestrants
Cholestyramine

4-24 g/day

Colestipol

5-30 g/day

Colesevelam

3.75 g/day

Take within 30 min of a

Nausea, bloating, cramping, and constipation; elevations

meal. A double dose

in hepatic transminases and alkaline phophatase.

with dinner produces

Impaired absorption of fat soluble vitamins, digoxin,

same lipid-lowering

warfarin, thiazides,

effect as BID dosing.

phenobarbital.

Take with meals QD or

divided BID

-blockers, thyroxine, and

Similar

Cholesterol absorption inhibitors

Ezetimibe

10 mg/day

Increased transaminases in combination with statins

Neomycin

1 g BID

Ototoxicity; nephrotoxicity

Probucol

500 mg BID

Loose stools; eosinophilia; QT prolongation;

angioneurotic edema.

BID: twice daily; QD: daily; TID: three times daily; SR: sustained release; CrCl: creatinine clearance.

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

Drug class

Serum LDL cholesterol

Serum HDL cholesterol

Serum triglycerides
No change*

Bile acid sequestrants

15 to 30 percent

0 to slight increase

Nicotinic acid

10 to 25 percent

15 to 35 percent

25 to 30 percent

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

Neomycin

20 to 25 percent

No change

No change

Omega 3 fatty acids

4 to 49 percent

5 to 9 percent

: Increase; : Decrease.
* Serum triglyceride levels may increase in patients with preexisting hypertriglyceridemia.
Lovaza 4 grams daily or 12 to 15 grams of less purified form of omega 3 fatty acids.

Properties of statins

23 to 45 percent

Variable

Atorvastatin

Fluvastatin

Lovastatin

Pravastatin

Rosuvastatin

Simvastatin

17-33

29-48

percent

percent

19-40 percent

52-63 percent

28-48 percent

(10-40)

(10-40)

(20-80)

(20-80)

(10-80)

15-30

0.5-2.3

2.9

1.3-2.8

19

2-3

12

19-29

18

20

80-90

>99

>95

43-55

88

94-98

Lipophilic

Lipophilic

Lipophilic

Hydrophilic

Hydrophilic

Lipophilic

3A4

2C9

3A4

Limited 2C9

3A4, 3A5

Yes

No

Yes

No

No

Yes

None

Negligible

Increased

Decreased

absorption

absorption

None

None

Evening

Bedtime

Bedtime

Anytime

Evening

20

10

13

LDL cholesterol
reductions

38-54 percent

(dose range,

(10-80)

mg)
Elimination
half-life, hours
Bioavailability,
percent
Protein
binding,
percent
Solubility
Cytochrome
450
metabolism
and lsozyme
Active
metabolites
Effect of food
on absorption
of drug
Optimal time
of

With meals

administration

(morning and
evening)

Renal
excretion of
absorbed
dose, percent

<6

10

Comparison of the efficacy of statin drugs

Comparison of the percent reduction in serum low density lipoprotein (LDL)-cholesterol

with various statin drugs.

Inhibitors of CYP3A4
Strong inhibitors

Moderate inhibitors

Atazanavir

Amiodarone

Clarithromycin

Amprenavir

Conivaptan

Aprepitant

Imatinib

Cyclosporine

Indinavir

Darunavir

Isoniazid

Delviridine

Itraconazole

Diltiazem

Ketoconazole

Erythromycin

Nefazodone

Fluconazole

Posaconazole

Fosamprenavir

Ritonavir

Grapefruit juice

Saquinavir

Verapamil

Telithromycin
Voriconazole
Data reproduced with permission from: Drug Interactions with Simvastatin. The Medical Letter 2008; 50(1297):83.
Copyright 2008 The Medical Letter, Inc.

The combination of a statin and a bile acid binding resin is

more effective than either alone

The reduction in low-density lipoprotein (LDL) cholesterol concentration

and the increase in high-density lipoprotein (HDL) concentration is
greater with the combination of a statin and a bile acid binding resin,
given as cholestyramine, when compared with therapy with either drug
alone. The effects of both drugs decline exponentially with increasing
doses. Data from The Prevastatin Multicenter Study Group II, Arch Intern
Med 1993; 153:1321.

Grade 2C recommendation
A Grade 2C recommendation is a very weak recommendation; other alternatives may be equally
reasonable.
Explanation:
A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but you may want to think
about it." It is unlikely that you should follow the suggested approach in all your patients, and you might reasonably
choose an alternative approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the
benefits and risks may be uncertain. In deciding whether to follow a Grade 2 recommendation in an individual patient,
you may want to think about your patient's values and preferences or about your patient's risk aversion.
Grade C means the evidence comes from observational studies, unsystematic clinical experience, or from randomized,
controlled trials with serious flaws. Any estimate of effect is uncertain.
Recommendation grades
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain
Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some
other form

C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials
with serious flaws
For a complete description of our grading system, please see the UpToDate editorial policy which can be found by clicking
"About UpToDate" and then selecting "Policies".

Grade 1B recommendation
A Grade 1B recommendation is a strong recommendation, and applies to most patients. Clinicians
should follow a strong recommendation unless a clear and compelling rationale for an alternative
approach is present.
Explanation:
A Grade 1 recommendation is a strong recommendation. It means that we believe that if you follow the
recommendation, you will be doing more good than harm for most, if not all of your patients.
Grade B means that the best estimates of the critical benefits and risks come from randomized, controlled trials with
important limitations (eg, inconsistent results, methodologic flaws, imprecise results, extrapolation from a different
population or setting) or very strong evidence of some other form. Further research (if performed) is likely to have an
impact on our confidence in the estimates of benefit and risk, and may change the estimates.
Recommendation grades
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain
Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some
other form
C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials
with serious flaws
For a complete description of our grading system, please see the UpToDate editorial policy which can be found by clicking
"About UpToDate" and then selecting "Policies".

Grade 2B recommendation
A Grade 2B recommendation is a weak recommendation; alternative approaches may be better
for some patients under some circumstances.
Explanation:
A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but you may want to think
about it." It is unlikely that you should follow the suggested approach in all your patients, and you might reasonably
choose an alternative approach. For Grade 2 recommendations, benefits and risks may be finely balanced, or the
benefits and risks may be uncertain. In deciding whether to follow a Grade 2 recommendation in an individual patient,
you may want to think about your patient's values and preferences or about your patient's risk aversion.
Grade B means that the best estimates of the critical benefits and risks come from randomized, controlled trials with
important limitations (eg, inconsistent results, methodologic flaws, imprecise results, extrapolation from a different
population or setting) or very strong evidence of some other form. Further research (if performed) is likely to have an
impact on our confidence in the estimates of benefit and risk, and may change the estimates.
Recommendation grades
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain
Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some
other form

C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials
with serious flaws
For a complete description of our grading system, please see the UpToDate editorial policy which can be found by clicking
"About UpToDate" and then selecting "Policies".

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