Official reprint from UpToDate®

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Treatment of lipids (including hypercholesterolemia) in secondary prevention

Author Section Editor Deputy Editor

Robert S Rosenson, MD Mason W Freeman, MD David M Rind, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2013. | This topic last updated: may 24, 2013.

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 "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. Additionally, as
discussed below, we suggest that all such patients be treated with statin therapy when tolerated (see 'Summary and recommendations' below). CHD
equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, include [1]:

Many patients with diabetes mellitus (see 'Diabetes mellitus as a CHD equivalent' below)
Symptomatic carotid artery disease
Peripheral artery 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 (table 1A-B)

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 µmol/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 as an independent risk factor for CHD'.)

Diabetes mellitus as a CHD equivalent — Although ATP III considered diabetes mellitus (DM) to be a CHD risk equivalent (risk of CHD events
greater than 20 percent in 10 years) (see "ATP III guidelines for treatment of high blood cholesterol"), this actually averages events across patients with
widely differing risks of CHD [2,3]. Issues that may affect risk with DM include patient age, sex, other cardiovascular risk factors, duration of DM, and
whether the patient has type 1 or type 2 DM.

Given this, it would be preferable to calculate patient-specific risks rather than to simply consider all patients with DM to have a CHD risk equivalent,
particularly in patients who are under age 60 without multiple cardiovascular risk factors. A downloadable calculator for this purpose is available for
patients with type 2 DM from the UK Prospective Diabetes Study.

If a patient-specific risk calculator cannot be accessed, we suggest considering the following patients with diabetes mellitus (DM) to have a CHD risk
equivalent:

Men over age 40 with type 2 DM and any other CHD risk factor, or over age 50 with or without other CHD risk factors

Women over age 45 with type 2 DM and any other CHD risk factor, or over age 55 with or without other CHD risk factors

Men or women of any age who have had DM (type 1 or type 2) for more than 20 years if they have another risk factor or more than 25 years
without another risk factor

EFFECTS OF THERAPY — Cardiovascular benefits of cholesterol lowering with statin drugs have been demonstrated in various groups including [4]:

Patients with CHD, with or without hyperlipidemia [5,6]

Men with hyperlipidemia but no known CHD [7]
Men with hypertension and multiple cardiac risk factors but without hyperlipidemia [8]
Men and women with average total and LDL-C levels and no known CHD [9]
The relative risk reduction in cardiovascular outcomes for each of these studies was similar. However, many more patients need to be treated to achieve
benefit for primary compared with secondary prevention [10]. 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 [11].

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 [12]. (See "Clinical trials of cholesterol lowering in patients with
coronary heart disease or coronary risk equivalents" and "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) [13].

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) (figure 1 and figure
2) [5].

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 [6]. 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), (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) [14]. 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) (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
"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 (table 2) [15]. 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 (table 3). A complete review of
these issues is presented elsewhere. (See "Clinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents".)

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 [16,17]. (See "Determinants and management of cardiovascular risk in women".)

Taken together, these findings suggest that patients who already have CHD merit aggressive lipid management.

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 additional detail separately. We suggest the following management (see "Intensity of lipid lowering therapy in secondary prevention
of coronary heart disease"):

In patients with CHD or a CHD equivalent (table 4) who can tolerate statin therapy, we suggest treatment with at least a moderate dose of a
statin (eg, 40 mg of lovastatin, pravastatin, or simvastatin, 20 mg of atorvastatin, or 5 to 10 mg of rosuvastatin) independent of the baseline
LDL-C. That is, even if a patient’s baseline LDL-C is below goal or is close to goal such that a low dose of a statin would be expected to reduce
the LDL-C below the ATP-III goal, we would initiate a statin and choose a moderate dose of a statin. The below goal-based recommendations
 assume that patients with CHD or a CHD equivalent will be treated with at least a moderate dose of a statin.

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 (table 3) might also be expected to benefit from more
intensive lipid lowering therapy. We suggest that such patients be treated with a dose of a statin that reduces their LDL-C at least 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 suggest the addition of a
second lipid-lowering agent. Other experts, including other authors for UpToDate, would make differing recommendations regarding the need for a
second agent. (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 (table 3), patients with stable CHD or a CHD equivalent be treated with a dose of statin that reduces the LDL-C to less than
100 mg/dL (2.6 mmol/L). 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. (See "Intensity of lipid lowering
therapy in secondary prevention of coronary heart disease", section on 'Putting the evidence together'.)

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. 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'.)

Timing of therapy — As discussed in the prior section, we suggest initiation of moderate statin therapy in all patients with CHD or a CHD risk
equivalent. If, instead, a decision is made to target a particular LDL-C goal, 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 [18]. 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) [19]. 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 [20,21]. (See "Cholesterol lowering after an acute
coronary syndrome".)

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 — The cost-effectiveness of cholesterol lowering has been evaluated for secondary prevention
[16,22,23]. These studies, published between 1996 and 2001 at a time when these medications were not available as generics, show that treatment
with statins for secondary prevention was cost-effective for secondary prevention even in an era when they were much more expensive. Cost-
effectiveness will have improved as the cost of such therapy has come down. The cost-effectiveness of statins in primary prevention is discussed
separately. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Cost-effectiveness modeling'.)

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 [24]. However, more recent larger trials (primarily
conducted with an HMG CoA reductase inhibitor [statin]) have been unable to confirm such a relationship [14,25-27]. 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) [27]. There have been case reports of patients
developing severe irritability and aggression associated with the use of statins [28]. 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 — In many patients, diabetes mellitus is considered a CHD equivalent (table 4) and, as mentioned above, both the CARE
trial [29] and the Heart Protection Study [14,30] 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) [31]. 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 [32].

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 in some patients. (See 'Intensity of therapy' above.)

Treatment in older adults — The decision whether to treat hypercholesterolemia in an older 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 older individual should not be denied drug therapy simply on the basis of age alone [11].

There appears to be ample evidence supporting the use of lipid-lowering therapy for secondary prevention in older patients with established CHD who
do not have life-limiting comorbid disease [1]. 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 [6]. Similarly, the percent reduction in events in the Heart Protection Study
was similar in patients above and below age 65 [14]. (See "Treatment of dyslipidemia in the older adult".)
 Treatment in patients with familial hypercholesterolemia — The therapeutic approach to patients with either homozygous or heterozygous
familial hypercholesterolemia (FH) is discussed separately. (See "Inherited disorders of LDL-cholesterol metabolism", section on 'Familial
hypercholesterolemia' and "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 [33,34]. 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 [1]. 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 (>1000 mg/dL [11.3 mmol/L]) should be treated to avoid pancreatitis. (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]) [1]. 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 (table 5).

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 "C-reactive protein in cardiovascular disease" and "Secondary prevention of cardiovascular disease".)

Stroke — Lipid lowering therapy, at least with statins, is effective in patients with cerebrovascular disease. This is discussed in detail separately.
(See "Secondary prevention of stroke: Risk factor reduction", section on 'Dyslipidemia'.)

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.)

Women — Concerns have been raised that the evidence for a benefit for treating women for secondary prevention with statins is not as convincing
as the evidence in men [35]. A 2012 meta-analysis of randomized trials concluded that while statins prevent CV events in both men and women, they
are not beneficial in reducing stroke or all-cause mortality in women [36]. Others have raised objections to this and similar analyses [37]. A particular
concern is that, in general, the default assumption should be that relative effects across subgroups (such as men and women) are similar and an
absence of a statistically-significant effect in a particular subgroup should not be a reason to conclude that real differences exist [38].

In this 2012 meta-analysis, there was no statistically-significant difference between the relative effects of statins in men and women on the outcomes of
stroke or all-cause mortality [36]. We believe the best evidence suggests that statins are similarly effective, in terms of relative effect, for secondary
prevention of the same CV outcomes in both men and women. Men and women frequently have different baseline risks of specific CV outcomes, and
the expected absolute benefit of statin therapy depends on the baseline risk in an individual.

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 "Inherited disorders of LDL-
cholesterol metabolism" and "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 (table 6), weight loss in overweight patients, aerobic exercise, and eating a diet rich in fruits and
vegetables. 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 [39]. Other diets can lower LDL-C by as much as
30 percent [40]. (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 [41]. 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 six to 12 months [42,43]. 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 [44].
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 [45,46]. 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 (table 7), and the range of expected changes in the lipid profile are listed in a table (table 8).

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 [47]. 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 [48]. A large trial of gemfibrozil in secondary prevention also failed to show
any improvement in overall mortality, although cardiac mortality was reduced [49]. (See "Clinical trials of cholesterol lowering in patients with coronary
heart disease or coronary risk equivalents", section on 'VA-HIT trial' and "Clinical trials of cholesterol lowering in patients with coronary heart disease or
coronary risk equivalents", section on '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 "Statin myopathy".)

In patients who do not tolerate any statin and are being treated for secondary prevention, reasonable options include the use of bile acid sequestrants,
fenofibrate, niacin, and ezetimibe. 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 (table 9) [50-52]. Fluvastatin is somewhat less potent, decreasing LDL-C levels by 20 to 25
percent at the maximum recommended dose [51,53]. Atorvastatin and rosuvastatin are the most potent statins approved in the United States, reducing
LDL-C levels by around 60 percent at doses of 80 and 40 mg/day, respectively (figure 5) [54]. 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 [55,56]. Rosuvastatin is also more effective in raising HDL-C levels than atorvastatin, simvastatin, or pravastatin [57]. (See "Statins: Actions,
side effects, and administration".)

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 [58]. 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 some 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 (table 10). (See "Statin myopathy".)

Fibrates — The major effects of the fibrates are to lower plasma triglyceride and raise HDL-C levels [59,60]. They are effective for the treatment of
hypertriglyceridemia and combined hyperlipidemia with or without hypoalphalipoproteinemia [59]. There is an increased risk of muscle toxicity in
patients taking some fibrates and a statin. (See "Statin myopathy".)

Nicotinic acid — Nicotinic acid is effective in patients with hypercholesterolemia and in combined hyperlipidemia associated with normal and low
levels of HDL-C (hypoalphalipoproteinemia) [61,62]. The HDL raising properties of nicotinic acid occur with dosages as low as 1 to 1.5 g/day [62]. 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 [52,61]. 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 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 (figure 6). 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 [63]. 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 [1]. Thereafter, measurement every 6 to 12
months is reasonable in patients adherent to lifestyle modifications.

With statins in particular, lipids levels stabilize within several weeks (with some variation with particular statins) after a change in dose, and so checking
lipid levels six weeks after a dosage change should provide a reliable result. As discussed elsewhere, however, the beneficial effects of statins appear to
occur sooner than can be explained by changes in LDL-C, and with discontinuation may reverse more quickly as well [64]. (See "Mechanisms of benefit
of lipid-lowering drugs in patients with coronary heart disease", section on 'Timing and mechanisms of benefit' and "Clinical trials of cholesterol lowering
in patients with coronary heart disease or coronary risk equivalents", section on 'PROVE IT-TIMI 22 trial'.)

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 [65].

A meta-analysis of individual patient data from the treatment arms of trials of statin therapy found an association between achieved lipid values
(including LDL-C, non-HDL-C, and apolipoprotein B) and risk of major CV events [66]. While it is not surprising that these achieved lipid parameters
correlate with CV risk, the clinical application of the information from this analysis is limited as the data come from multiple trials with differing doses of
statins, inclusion criteria, and baseline characteristics. When to modify therapy based on lipid response is controversial and is discussed in detail
separately. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease", section on 'Putting the evidence together'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient information: High cholesterol treatment options (Beyond the Basics)" and "Patient information: High
cholesterol and lipids (hyperlipidemia) (Beyond the Basics)")

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".)

Patients who are given drug therapy should almost always be treated with a statin. (See 'Drug therapy' above.)

In patients with CHD or a CHD equivalent (table 4) who can tolerate statin therapy, we suggest treatment with at least a moderate dose of a
statin (eg, 40 mg of lovastatin, pravastatin, or simvastatin, 20 mg of atorvastatin, or 5 to 10 mg of rosuvastatin) independent of the baseline
LDL-C (Grade 2B). That is, even if a patient’s baseline LDL-C is below goal or is close to goal such that a low dose of a statin would be
expected to reduce the LDL-C below the ATP-III goal, we would initiate a statin and choose a moderate dose of a statin. (See "Intensity of lipid
lowering therapy in secondary prevention of coronary heart disease", section on 'Putting the evidence together'.)

The appropriate goal LDL-C in patients with CHD or CHD equivalents being treated for secondary prevention is controversial and is discussed in
additional detail separately. The below goal-based recommendations assume that, as discussed above, patients with CHD or a CHD equivalent
will be treated with at least a moderate dose of a statin. (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 (table 3) might also be expected to benefit from more
intensive lipid-lowering therapy. We suggest that such patients be treated with a dose of a statin that reduces their LDL-C at least 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 regarding the need for a second agent. (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 (table 3), patients with stable CHD or a CHD equivalent be treated with a 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. (See "Intensity of lipid
lowering therapy in secondary prevention of coronary heart disease", section on 'Putting the evidence together'.)

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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cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012; 307:1302.

Topic 4550 Version 31.0

GRAPHICS

Framingham/ATP III point scores in men

Age, years Points

20 to 34 -9

35 to 39 -4

40 to 44 0

45 to 49 3

50 to 54 6

55 to 59 8

60 to 64 10

65 to 69 11

70 to 74 12

75 to 79 13

Total cholesterol mg/dL Age 40 to Age 60 to Age 70 to

Age 20 to 39 Age 50 to 59
(mmol/L) 49 69 79
<160 (3.4) 0 0 0 0 0

160 to 199 (3.4 to 5.15) 4 3 2 1 0

200 to 239 (5.17 to 6.18) 7 5 3 1 0

240 to 279 (6.2 to 7.21) 9 6 4 2 1

≥280 (7.24) 11 8 5 3 1

Age 40 to Age 60 to Age 70 to

Age 20 to 39 Age 50 to 59
49 69 79
Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

HDL cholesterol mg/dL

Points
(mmol/L)
≥60 (1.55) -1

50 to 59 (1.29 to 1.53) 0

40 to 49 (1.03 to 1.27) 1

<40 (1.03) 2

Systolic blood pressure,

Untreated Treated
mmHg
<120 0 0

120 to 129 0 1

130 to 139 1 2

140 to 159 1 2

≥160 2 3

10-year risk, Point 10-year risk,

Point total
percent total percent
0 1 9 5

1 1 10 6

2 1 11 8

3 1 12 10

4 1 13 12

5 2 14 16
 6 2 15 20

7 3 16 25

8 4 ≥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 0

45 to 49 3

50 to 54 6

55 to 59 8

60 to 64 10

65 to 69 12

70 to 74 14

75 to 79 16

Total cholesterol mg/dL Age 40 to Age 60 to Age 70 to

Age 20 to 39 Age 50 to 59
(mmol/L) 49 69 79
<160 (3.4) 0 0 0 0 0

160 to 199 (3.4 to 5.15) 4 3 2 1 1

200 to 239 (5.17 to 6.18) 8 6 4 2 1

240 to 279 (6.2 to 7.21) 11 8 5 3 2

≥280 (7.24) 13 10 7 4 2

Age 40 to Age 60 to Age 70 to

Age 20 to 39 Age 50 to 59
49 69 79
Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

HDL cholesterol mg/dL

Points
(mmol/L)
≥60 (1.55) -1

50 to 59 (1.29 to 1.53) 0

40 to 49 (1.03 to 1.27) 1

<40 (1.03) 2

Systolic blood pressure,

Untreated Treated
mmHg
<120 0 0

120 to 129 1 3

130 to 139 2 4

140 to 159 3 5

≥160 4 6

10-year risk, Point 10-year risk,

Point total
percent total percent
<9 <1 17 5

9 1 18 6

10 1 19 8

11 1 20 11

12 1 21 14

13 2 22 17
 14 2 23 22

15 3 24 27

16 4 ≥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 (MI) 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

LDL, HDL, Regression, Progression,

Trial Intervention
percent percent percent percent

NHLBI Diet -5 NC 7 49

Cholestyramine -26 +8 7 32

CLAS I Diet -5 +2 2 61

Colestipol + NA -43 +37 16 39

FATS Diet + Colestipol -7 +5 11 46

Lovastatin + Colestipol -46 +15 32 21

NA + Colestipol -32 +43 39 25

UCSF- Diet -11 NC 12 41

SCOR Cholestyramine + NA ± -38 +26 32 20
Lovastatin

MARS Diet NC NC 12 41

Lovastatin -38 +10 23 29

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.
Coronary heart disease (CHD) risk equivalents

Diabetes mellitus
• It is preferable to calculate patient-specific risks rather than to simply consider all patients with DM to have a CHD risk
equivalent. A downloadable calculator for this purpose is available for patients with type 2 DM from the UK Prospective
Diabetes Study.

• If a patient-specific risk calculator cannot be accessed, we suggest considering the following patients with DM to have a
CHD risk equivalent:

- Men over age 40 with type 2 DM and any other CHD risk factor, or over age 50 with or without other CHD risk factors.

- Women over age 45 with type 2 DM and any other CHD risk factor, or over age 55 with or without other CHD risk
factors.

- Men or women of any age who have had DM (type 1 or type 2) for more than 20 years if they have another risk factor
or more than 25 years without another risk factor.

Symptomatic carotid artery disease

Peripheral arterial disease
Abdominal aortic aneurysm
Multiple risk factors that confer a 10-year risk of CHD >20 percent

Chronic kidney disease with creatinine >1.5 mg/dL [133 µmol/L] or estimated GFR <60 mL/min per 1.73 m2*

* Statin doses may require adjustment in patients with CKD.

Non-HDL-cholesterol goals

Non-HDL-cholesterol goal, mg/dL

Risk category
(mmol/L)
Coronary heart disease (CHD) or equivalent (10- year risk of CHD >20 <130 (3.36)
percent)

Two or more CHD risk factors and 10-year risk of CHD ≤20 percent <160 (4.13)

0 to 1 CHD risk factor <190 (4.91)

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 percent of total calories

Polyunsaturated fat Up to 10 percent of total calories

Monounsaturated fat Up to 20 percent of total calories

Total fat 25 to 35 percent of total calories

Carbohydrate• 50 to 60 percent of total calories

Fiber 20 to 30 g/day

Protein Approximately 15 percent of total calories

Cholesterol <200 mg/day

Total caloriesΔ 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.
Δ 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/.
Adult dosing, 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 20-80 IR take with evening Headache; nausea; sleep disturbance; elevations in hepatocellular
mg/day meal. BID with enzymes and alkaline phosphatase. Myositis and rhabdomyolysis,
meals if dose >20 primarily when given with gemfibrozil or cyclosporine; myositis is
mg/day. XR take any also seen with severe renal insufficiency (CrCl <30 mL/min).
time. Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate
effect of warfarin; this interaction is not seen with pravastatin,
Pravastatin 10-80 fluvastatin, or pitavastatin. Most statins can also affect digoxin
mg/day metabolism and levels.

Simvastatin 5-40 Take in the evening

mg/day

Fluvastatin 20-80 IR take in the

mg/day evening; if dose >40
mg/day take morning
80 mg and evening. XR take
XR/day any time.

Atorvastatin 10-80
mg/day

Rosuvastatin 5-40
mg/day

Pitavastatin 1-4 mg/day

Gemfibrozil 600 mg BID 30 to 60 min before Potentiates warfarin action. Absorption of gemfibrozil diminished by
meals bile acid sequestrants.

Fenofibrate Micronized taken Skin rash, gastrointestinal (nausea, bloating, cramping) myalgia;
Nanocrystal with meals. Use lowers blood cyclosporine levels; potentially nephrotoxic in
145 lower doses with cyclosporine treated patients. Avoid in patients with CrCl <30
mg/day renal insufficiency. mL/min.
Micronized
160-200
mg/day

Nicotinic acid 1-12 g/day Given with meals. Prostaglandin-mediated cutaneous flushing, headache, warm
Start with 100 mg sensation, and pruritus; hyperpigmentation (particularly in
BID and titrate to intertriginous regions); acanthosis nigricans; dry skin; nausea;
500 mg TID. After six vomiting; diarrhea; and myositis
weeks, check lipids,
glucose, liver
function, and uric
acid. Increase dose
as needed.

Bile acid sequestrants

Cholestyramine 4-24 g/day Take within 30 min of Nausea, bloating, cramping, and constipation; elevations in hepatic
a meal. A double transaminases and alkaline phosphatase. Impaired absorption of
Colestipol 5-30 g/day dose with dinner fat soluble vitamins, digoxin, warfarin, thiazides, β-blockers,
produces same lipid- thyroxine, and phenobarbital.
lowering effect as
BID dosing.

Colesevelam 3.75 g/day Take with meals QD Similar

or divided BID

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; IR: immediate release; XR: extended 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
Bile acid sequestrants ↓ 15 to 30 percent 0 to slight increase No change*

Nicotinic acid ↓ 10 to 25 percent ↑ 15 to 35 percent ↓ 25 to 30 percent

HMG CoA reductase inhibitors ↓ 20 to 60 percent ↑ 5 to 10 percent ↓ 10 to 33 percent

Gemfibrozil ↓ 10 to 15 percent ↑ 5 to 20 percent• ↓ 35 to 50 percent

Fenofibrate (micronized form) ↓ 6 to 20 percent ↑ 5 to 20 percent• ↓ 41 to 53 percent

Cholesterol absorption inhibitors ↓ 17 percent ↑ 1 percent ↓ 7 to 8 percent

Neomycin ↓ 20 to 25 percent No change No change

Omega 3 fatty acidsΔ ↑ 4 to 49 percent ↑ 5 to 9 percent ↓ 23 to 45 percent

↑: increase; ↓: decrease.
* Serum triglyceride levels may increase in patients with pre-existing hypertriglyceridemia.
• Increases of 20 percent are seen in patients with very high triglycerides; increases of 5 percent are more typical with fibrate
monotherapy in patients with lower triglycerides.
Δ Lovaza 4 grams daily or 12 to 15 grams of less purified form of omega 3 fatty acids.
Properties of statins

Variable Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin

LDL 38 to 54 17 to 33 29 to 48 31 to 41 19 to 40 52 to 63 28 to 41
cholesterol percent (10 to percent (20 percent (20 percent (1 to percent (10 to percent (10 to percent (10 to
reductions 80) to 80) to 80) 4) 40) 40) 40)
(dose range,
mg)

Elimination 15 to 30 0.5 to 2.3 2.9 12 1.3 to 2.8 19 2 to 3

half-life, hours

Bioavailability, 12 19 to 29 5 51 18 20 5
percent

Protein 80 to 90 >99 >95 99 43 to 55 88 94 to 98

binding,
percent

Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic Lipophilic

Cytochrome 3A4 2C9 3A4 Limited 2C9, - Limited 2C9 3A4, 3A5
450 2C8
metabolism
and lsozyme

Active Yes No Yes Yes No No Yes

metabolites

Effect of food None Negligible Increased Decreases Decreased None None

on absorption absorption absorption
of drug

Optimal time Anytime Anytime Anytime Anytime Evening

of IR: evening IR: with
administration (or morning evening
and evening meal (or with
if taken twice morning and
daily) evening
meal if taken
XR: anytime twice daily)

XR: anytime

Renal 2 <6 10 15 20 10 13
excretion of
absorbed
dose, percent

IR: immediate release; XR: extended release.

Comparison of the efficacy of statin drugs

Comparison of the percent reduction in serum low density lipoprotein

(LDL)-cholesterol with various statin drugs.
Inhibitors and inducers of cytochrome P450 3A4 (CYP3A4)

Strong inhibitors Moderate inhibitors Strong inducers

Atazanavir Abiraterone Aminoglutethimide

Boceprevir Amiodarone Armodafinil*

Chloramphenicol Aprepitant Bexarotene*

Clarithromycin Bicalutamide Bosentan

Cobicistat containing coformulations Cimetidine Carbamazepine

Conivaptan Ciprofloxacin* Deferasirox*

Darunavir Clotrimazole Dexamethasone

Delavirdine Crizotinib Efavirenz

Fosamprenavir Cyclosporine Enzalutamide

Indinavir Desipramine Etravirine

Isoniazid* Diltiazem Fosphenytoin

Itraconazole Danazol* Griseofulvin*

Ketoconazole Dasatinib* Mitotane*

Lopinavir Dronedarone Modafinil*

Nefazodone Efavirenz Nafcillin

Nelfinavir Erythromycin Nevirapine

Nicardipine Fluconazole Oxcarbazepine

Posaconazole Fosaprepitant Pentobarbital

Ritonavir and ritonavir containing Grapefruit juice Phenobarbital

coformulations
Haloperidol Phenytoin
Saquinavir
Iloperidone Primidone
Telaprevir
Imatinib Rifabutin
Telithromycin
Lapatinib Rifampin (rifampicin)
Voriconazole
Lomitapide Rifapentine

Metronidazole Rufinamide*

Miconazole St. John's wort*

Mifepristone* Vemurafenib*

Norfloxacin

Quinupristin-dalfopristin*

Sertraline

Sitaxsentan

Tamoxifen*

Tetracycline

Verapamil

Zafirlukast*

Notes: Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose and method of
administration. Specific drug interactions and management suggestions may be determined by using Lexi-Interact,
the drug interactions program included with UpToDate.
* Less potent effect on CYP3A4 reported in some references.
Data from:
1. Lexicomp Online. Copyright © 1978-2013 Lexicomp, Inc. All Rights Reserved
2. Hansten PD, Horn JR. Top 100 drug interactions: guide to patient management, 13th ed, H&H Publications, 2013.
3. Inhibitors and inducers of CYP enzymes and P-glycoprotein; The Medical Letter 2013;55(1417):44.
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.