BENJAMIN J. ANSELL, MD, Associate Clinical Professor of Medicine; and Co-Director of the Cholesterol, Hypertension, and Atherosclerosis Management
Program (CHAMP), Divisions of Cardiology and General Internal Medicine/Health Services Research, Department of Medicine, University
of California, Los Angeles, School of Medicine, Los Angeles.
The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) published its clinical guidelines (ATP III)
for the detection, evaluation, and treatment of high levels of blood cholesterol in 2001.1 These guidelines placed a strong emphasis on the results of large, randomized, controlled clinical trials. Since then, however,
a number of major trials of statin therapy have been published, providing more information on clinical cardiovascular end
points in persons with coronary heart disease (CHD) or with CHD risk equivalents, particularly those considered to be at high
or very high risk.2-5 As a result, the NCEP issued an updated document assessing the implications of these clinical trials on cholesterol management.6
This review summarizes the key points outlined in the latest NCEP recommendations on LDL-cholesterol (LDL-C) goals for moderately
high-risk, high-risk, and very-high-risk patients and discusses other important clinical trials that provide evidence for
intensified LDL-C-lowering therapy in both the acute and chronic settings. It also provides practical recommendations to assist
you in getting your patients to these new, more rigorous LDL-C goals.
ATP III TREATMENT ALGORITHM
The classification algorithm that was set forth in ATP III stratified patients into 3 risk categories:
- Established CHD or CHD risk equivalents (noncoronary atherosclerotic disease, diabetes mellitus, multiple [2+] CHD risk factors
with a 10-year CHD risk of greater than 20%)
- Multiple (2+) risk factors
- 0 to 1 risk factor.1,6
Estimate of 10-year CHD risk for men, women
|
For treatment purposes, all patients with CHD or CHD risk equivalents are considered high risk, and the LDL-C goal in this
group is less than 100 mg/dL. Beyond this, ATP III also recommended more aggressive LDL-C lowering in patients with multiple
(2+) risk factors (among hypertension, cigarette smoking, family history of premature CHD, HDL cholesterol [HDL-C] less than
40 mg/dL, and age greater than 45 for men or 55 for women), based on their 10-year Framingham CHD risk score.
Patients with 2+ risk factors and a 10-year CHD risk greater than 20% were considered to have a CHD risk equivalent, and they
were elevated to the high-risk category.1,6 Moderately high-risk patients have 2+ risk factors and a 10-year CHD risk of 10% to 20%, and moderate-risk patients have
2+ risk factors and a 10-year CHD risk of less than 10%. For both moderately high-risk patients and moderate-risk patients,
ATP III set an LDL-C goal of less than 130 mg/dL but provided different cut points at which drug therapy should be initiated
(130 mg/dL and above and 160 mg/dL and above, respectively).1,6
RATIONALE FOR INTENSIFIED LDL-C REDUCTION IN HIGH-RISK PATIENTS
Results of randomized clinical trials reported within the past 3 years suggest that aggressive LDL-C goals are warranted.
Accordingly, a recent update to the NCEP ATP III sets the optimal LDL-C goal for high-risk patients with CHD or risk equivalents
at less than 100 mg/dL, with the option of lowering LDL-C to less than 70 mg/dL.6
High-risk and very-high-risk patients
The Heart Protection Study (HPS) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study provided
evidence that intensified LDL-C lowering (ie, to levels below 70 mg/dL) may benefit high-risk patients who already have a
low LDL-C level at baseline.2,3 The HPS followed more than 20,000 adults at high CHD risk, based on the presence of coronary disease, other occlusive arterial
disease, or diabetes mellitus. After a mean follow-up of 5 years, all-cause mortality was significantly decreased in patients
treated with simvastatin, 40 mg, compared with placebo (12.9% versus 14.7%), owing primarily to a significant reduction in
CHD mortality (5.7% versus 6.9%).2 The benefits of statin therapy extended to subgroups with baseline LDL-C levels of less than 116 mg/dL (n=6793) and even
in those whose baseline levels were less than 100 mg/dL (n=3421).2
PROVE IT sought to define optimal LDL-C lowering in more than 4100 patients hospitalized for acute coronary syndrome (ACS)
within the preceding 10 days.3 Treatment with standard therapy (pravastatin, 40 mg/d) or intensive therapy (atorvastatin, 80 mg/d) reduced LDL-C levels
to a median of 95 mg/dL and 62 mg/dL, respectively (P<.001). A subsequent cardiovascular event (MI, unstable angina, revascularization, or stroke) occurred in 22.4% of atorvastatin-treated
patients and in 26.3% of pravastatin-treated patients, reflecting a 16% relative risk reduction in favor of intensive therapy.
Thus, despite the fact that the ATP III LDL-C goal of less than 100 mg/dL was achieved in the majority of patients in the
standard-therapy group, further reductions in LDL-C in the intensive-therapy group resulted in additional benefit.3
Results of these trials led the ATP III committee to update their earlier guidelines to recommend a new, optional LDL-C goal
of less than 70 mg/dL for high-risk patients.6 The presence of certain clinical factors that place a patient in the category of very high risk—established atherosclerotic
cardio-vascular disease, plus multiple risk factors (especially diabetes), severe and poorly controlled risk factors (especially
continued cigarette smoking), metabolic syndrome, or ACS—support this more intensified LDL-C goal in this subset of patients.6 Patients with ACS, in particular, appear to derive benefit from more aggressive LDL-C lowering, as demonstrated by PROVE
IT. An earlier study, the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study,
showed the clinical benefits of high-dose atorvastatin therapy in reducing recurrent ischemic events in the first 16
weeks following ACS, providing additional support for the concept of intensified LDL-C lowering in the acute setting.7
A more recent study in high-risk patients has yielded data that support reducing LDL-C to well below 100 mg/dL. In the Treating
to New Targets (TNT) trial, 10,001 patients with stable, chronic CHD and LDL-C levels of less than 130 mg/dL were randomly
assigned to treatment with low- or high-dose atorvastatin (10 or 80 mg, respectively). Mean LDL-C at randomization was 98
mg/dL in the low-dose group and 97 mg/dL in the high-dose group, and on-therapy LDL-C levels were 101 mg/dL and 77 mg/dL,
respectively. After a median follow-up of 4.9 years, a cardiovascular event occurred in 8.7% of patients in the high-dose
group and 10.9% of patients in the low-dose group, a 22% relative risk reduction (P<.001).8
Moderately high-risk patients
Based on the Framingham risk score, ATP III considers 2+ risk factors (but without evidence of overt vascular disease) to
be moderately high risk if the patient has a 10-year risk between 10% and 20%.1 These patients are candidates for LDL-lowering drugs if their serum LDL-C level is 130 mg/dL or higher after lifestyle modification;
drug therapy is not recommended for those with levels lower than 130 mg/dL.1
Data from 2 trials, however—the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) and the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)—support a more aggressive treatment threshold for
moderately high-risk patients.4,5 In ASCOT, hypertensive patients with at least 3 other CHD risk factors and nonfasting total cholesterol level of 251 mg/dL
or lower were randomly assigned to treatment with atorvastatin, 10 mg, or placebo. The incidence of fatal and nonfatal MI
was significantly reduced (36%; P=.0005) in the atorvastatin group, in which the on-treatment LDL-C level was 90 mg/dL, compared with placebo. Statins were
also associated with a 27% reduction in fatal and nonfatal stroke.4
ALLHAT evaluated patients who were, for the most part, at moderately high risk (55 years or older, hypertensive, moderately
hypercholesterolemic, and with 1 additional CHD risk factor).5 Although there were no differences between the group taking pravastatin, 40 mg/d, and usual-care groups in the primary end
point of all-cause mortality over 8 years of follow-up—likely a result of the small differences in achieved cholesterol levels
between groups—CHD events were significantly lower in the African American subgroup treated with pravastatin versus usual
care.5 Findings from these 2 studies led the ATP III committee to alter the recommendation in moderately high-risk patients to
include the option of drug therapy in those with LDL-C values between 100 and 120 mg/dL, in order to achieve an LDL-C level
of less than 100 mg/dL.6
ACHIEVING LDL-C GOALS
The large body of evidence from secondary prevention trials indicates that little more than 50% of patients treated with the
doses of statins typically used in these studies will achieve an LDL-C level of less than 100 mg/dL.6 Given the importance of intensive LDL-C reduction in lowering risk for major CHD events, optimal modification of lipids
in more high-risk patients remains a key challenge. As noted in the update to ATP III, newer and more potent statins have
increased the likelihood of achieving such robust reductions.6 Standard doses of the more potent statins can usually provide a 30% to 40% reduction in LDL-C levels, which will ultimately
impart a similar reduction in CHD risk over 5 years.6
Evidence from recent trials
Starting at the appropriate dose of one of the more potent statins is an important strategy to achieve these goals. The clinical
utility of this strategy has been borne out by studies such as PROVE IT, TNT, and the A to Z trial, which compared early intensive
versus delayed conservative treatment with simvastatin.3,8,9 Most experts now agree that initial use of less potent statins is no longer justified.6
Comparative efficacy studies with currently available statins appear to support that position. The CURVES Study, published
in 1998, was the first trial to compare the lipid-lowering efficacy of all the statins marketed at that time—atorvastatin
(Lipitor), simvastatin (Zocor), pravastatin (Pravachol), lovastatin (Mevacor), and fluvastatin (Lescol)—across their dose
ranges.10 In this open-label study, 534 hypercholesterolemic patients were randomized to 1 of the 5 statins at low, medium, or high
doses. Efficacy end points were mean percent change in lipid concentrations. After 8 weeks, atorvastatin, 10, 20, and 40 mg,
produced greater reductions in LDL-C and total cholesterol levels than milligram-equivalent doses of the other statins. At
the 10-mg dose, atorvastatin produced reductions in LDL-C comparable to or greater than the comparator statins at 10 to 40
mg. Further, the atorvastatin 40-mg dose produced greater reductions in triglyceride levels than did the 40-mg doses of the
other statins.10
The same 5 statins were compared for their ability to get patients to LDL-C targets, both at initial doses and after titration,
in the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS).11 More than 3900 hypercholesterolemic patients with or without CHD were randomized to starting doses of one of the statins.
The dosages were titrated at 6-week intervals in patients who did not reach NCEP goals. After 54 weeks, atorvastatin-treated
patients were more likely than those treated with other statins to achieve and maintain their target LDL-C levels. The percent
reduction in the LDL-C level that was achieved at the initial dose correlated strongly with the proportion of patients who
maintained their goals at 54 weeks. The investigators concluded that the further LDL-C levels are lowered below NCEP target
levels, the greater the likelihood of maintaining goal levels over the long term.11
The Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) also compared the ability of
different statins to achieve intensified lipid goals. In STELLAR, more than 2400 patients with elevated LDL-C and triglyceride
levels were randomly assigned to treatment with rosuvastatin, atorvastatin, simvastatin, or pravastatin, following 6 weeks
of the NCEP step 1 diet.12
Rosuvastatin reduced LDL-C significantly more than atorvastatin, pravastatin, or simvastatin across all doses, and the proportion
of patients achieving the ATP III LDL-C goal of less than 100 mg/dL was significantly greater for rosuvastatin (53%-80%) than
for equivalent doses of atorvastatin (18%-70%), and equivalent or higher doses of simvastatin (8%-53%) or pravastatin (1%-8%).12,13 Results were similar in the large subgroup of 665 patients classified as high risk according to the ATP III guidelines.13
Treating other lipid abnormalities
A further clinical consideration for high-risk patients in the update to ATP III is the need to control lifestyle-related
risk factors. In addition, high-risk patients with high triglyceride levels and low levels of HDL-C should be targeted for
therapy regardless of their LDL-C level.6 In this respect, non-HDL-C may be even more reliable than LDL-C as an important predictor of CHD risk. According to the
ATP III, when triglyceride levels are 200 mg/dL or higher, non-HDL-C becomes a secondary target.
Although most statins also lower triglyceride levels and modestly increase HDL-C levels, some are more effective. In ACCESS,
at weeks 6 and 24, 10 mg of atorvastatin produced greater mean reductions in triglyceride levels than 10 mg of simvastatin,
10 mg of pravastatin, 20 mg of lovastatin, or 20 mg of fluvastatin. Both simvastatin and lovastatin produced significantly
greater reductions in triglyceride levels than fluvastatin or pravastatin (P<.05 for all comparisons).11 In the STELLAR trial, atorvastatin and rosuvastatin reduced triglyceride levels to a similar extent and significantly more
than either simvastatin or pravastatin. Rosuvastatin was associated with the largest increases in HDL-C (7.7%-9.6%) compared
with the other statin treatment groups (2.1%-6.8%).12
Treatment strategies
When patients who are receiving statin monotherapy fail to attain their lipid goals, you have 3 treatment options. You can
try increasing the dose, initiating combination therapy, or switching the statin (see "Case study: Now what?").
Consider titrating the statin
Doubling the dose of a statin produces about a 5% additional reduction in total cholesterol values and about a 7% additional
reduction in LDL-C levels.14 With the less potent statins, such titrations may worry or discourage your patients but are unlikely to help them reach
goal. Moreover, although adverse events with statins are rare, the potential increases at the highest doses.15 Other methods of getting to goal may thus be preferable.
Combine a statin with another lipid-lowering agent
In many situations, statin monotherapy is preferable. However, if dyslipidemia persists despite increased statin dosing,
combination therapy is usually safer than the underlying lipid abnormality.
Other available drugs act by mechanisms different from those of the statins to reduce LDL-C (bile acid sequestrants, ezetimibe
[Zetia]) and/or increase HDL-C and reduce triglyceride levels (niacin [Niacor, Niaspan], fenofibrate [Tricor]). Consider adding
one of these agents to a statin for those patients not achieving the LDL-C goal with aggressive statin monotherapy or for
those whose triglyceride or non-HDL-C levels remain elevated once the LDL-C goal is reached.
In one study, the cholesterol-absorption inhibitor ezetimibe, when added to atorvastatin, 10 to 40 mg, reduced the values
for LDL-C an additional 12%, triglycerides, 8%, and high-sensitivity C-reactive protein, 10%, and raised HDL-C an additional
3%.16 A larger study with more than 1500 patients showed that more patients achieved LDL-C levels of less than 100 mg/dL on combination
therapy with simvastatin plus ezetimibe than with simvastatin alone (P<.001). Other lipid parameters and C-reactive protein were also improved with combination treatment.17 Fenofibrate is preferable to gemfibrozil (Lopid) in combination with a statin, since it is far less likely to increase plasma
statin levels and the risk of rhabdomyolysis.18
Switch statins
Although few data are available to guide clinicians in switching from one statin to another, a recent study found that
this approach can lead to significant improvements in achieving LDL-C goals.19 In an open-label, multicenter trial of more than 3100 high-risk patients, a significantly greater proportion of patients
who were switched to rosuvastatin, 10 mg, achieved their LDL-C goal, compared with patients remaining on atorvastatin, 10
mg; simvastatin, 20 mg; or pravastatin, 40 mg.19
This article was contributed by Dr Ansell and edited by Peter D'Epiro, PhD.
Dr Ansell discloses that he has an equity position with Bruin Pharma and that he is a paid consultant for, or has an ongoing
relationship with, Pfizer, AstraZeneca, Merck/Schering-Plough, and Kos.
REFERENCES
1. The Expert Panel. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation. 2002;106:3143-3421.
2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in
20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
3. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis
in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
N Engl J Med. 2004;350:1495-1504.
4. Sever PS, Dahlf, Poulter NR, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin
in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac
Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.
5. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic,
hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998-3007.
6. Grundy SM, Cleeman JI, Bairey-Merz CN, et al, for the Coordinating Committee of the National Cholesterol Education Program.
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
Circulation. 2004;110:227-239.
7. Schwartz GG, Olsson AG, Ezekowitz MD, et al, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
(MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The
MIRACL Study: a randomized controlled trial. JAMA. 2001;285:1711-1718.
8. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
9. de Lemos JA, Blazing MA, Wiviott SD, et al, for the A to Z Investigators. Early intensive vs a delayed conservative simvastatin
strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004; 292:1307-1316.
10. Jones P, Kafonek S, Laurora I, et al, for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus
simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol. 1998;81:582-587.
11. Andrews TC, Ballantyne CM, Hsia JA, et al. Achieving and maintaining National Cholesterol Education Program low-density
lipoprotein cholesterol goals with five statins. Am JMed. 2001;111:185-191.
12. Jones PH, Davidson MH, Stein EA, et al, for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin
versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92:152-160.
13. McKenney JM, Jones PH, Adamczyk MA, et al, for the STELLAR Study Group. Comparison of the efficacy of rosuvastatin versus
atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial. Curr MedRes Opin. 2003;19:689-698.
14. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol. 1997;80:106-107.
15. Evans M, Rees A. Effects of MHG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf. 2002;25:649-663.
16. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin in 628 patients
with primary hypercholesterolemia: a prospective, randomized, double-blind-trial. Circulation. 2003;107:2409-2415.
17. Bays HE, Ose L, Fraser N, et al, for the Ezetimibe Study Group. A multicenter, randomized, double-blind, placebo-controlled,
factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared
with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther. 2004; 26:1758-1773.
18. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering
drugs. JAMA. 2004;292:2585-2590.
19. Schuster H, Barter PJ, Stender S, et al, for the MERCURY I Study Group. Effects of switching statins on achievement of
lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J. 2004;147:705-712.
Case study: Now what?
Victor L. is a 65-year-old man with hypertension, which was diagnosed 10 years ago. His BP is being controlled with a beta-blocker
and an ACE inhibitor. He also has documented carotid atherosclerosis. At 5 ft 8 inches tall, he weighs 180 lb and has a waist
circumference of 41 inches. His on-treatment BP is 122/76 mm Hg. Victor has smoked for more than 40 years, has tried many
times to quit smoking, and has cut down to a half-pack of cigarettes a day. Recently his sister, who is also hypertensive,
had a stroke. His last lipid profile revealed a mildly elevated cholesterol level. His current cholesterol levels reveal a
worsened dyslipidemia.
This patient's laboratory test values are- Total cholesterol (TC): 230 mg/dL
- LDL cholesterol (LDL-C; calculated): 164 mg/dL
- Triglycerides (TG): 175 mg/dL
- HDL cholesterol (HDL-C): 31 mg/dL
- Glucose: 120 mg/dL
- Serum urea nitrogen, creatinine, liver function tests, thyrotropin: All results within the reference range.
Treatment recommendations
According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines, Mr L's carotid
atherosclerosis makes him a coronary heart disease (CHD) risk equivalent; therefore, his LDL-C goal is less than 100 mg/dL.
He also has metabolic syndrome, a clustering of at least 3 of the following abnormalities: abdominal obesity (waist circumference
40 inches or more in men), elevated TG (over 150 mg/dL), low HDL-C (below 40 mg/dL in men), and impaired fasting glucose (110-126
mg/dL). Metabolic syndrome increases the risk for cardiovascular disease.
Based on his age, cholesterol levels, BP, and smoking status, Mr L's 10-year Framingham risk score is 25%. He is obviously
a very-high-risk patient. Mr L is started on a low dosage (10 mg/d) of atorvastatin (Lipitor), which will lower his LDL-C
by between 30% and 40%, approximately the degree of LDL-lowering needed to reach his goal of less than 100 mg/dL. He is also
advised to adhere to a strict regimen of diet and exercise to reduce his weight and waist size, and he is referred to a program
to help him quit smoking. After 8 weeks of atorvastatin therapy, repeat laboratory tests show the following values:
- TC: 160 mg/dL
- LDL-C: 110 mg/dL
- TG: 145 mg/dL
- HDL-C: 35 mg/dL
The starting dosage of atorvastatin has, as expected, lowered Mr L's TC, LDL-C, and TG levels, and slightly raised his HDL-C
level, but he has not yet reached the LDL-C target. As a very-high-risk patient, Mr L needs more aggressive LDL-C lowering
and would benefit from a greater increase in HDL-C. Should combination treatment be considered?
Discussion
According to the recent update to the NCEP ATP III guidelines, an LDL-C goal of less 70 mg/dL is a treatment option in very-high-risk
patients. Factors that favor a decision to reduce LDL-C levels to less than 70 mg/dL include continued cigarette smoking and
the multiple risk factors of metabolic syndrome, in addition to established cardiovascular disease, acute coronary syndromes,
and multiple major risk factors. This remains an optional recommendation at this time. However, the Heart Protection Study
proved that reducing LDL-C to levels less than 100 mg/dL can potentially lower the relative risk for CHD by an additional
20% to 30%, and the Treating to New Targets trial showed the additional benefit produced by lowering LDL-C to very low levels.1,2
Several options may be considered to further decrease Mr L's LDL-C: The atorvastatin dosage could be titrated up; he could
be switched to a more potent statin, such as rosuvastatin (Crestor), which might reduce his LDL-C to less than 70 mg/dL at
a 10- or 20-mg dose, as well as have a more favorable effect on HDL-C levels. Alternatively, in view of his low HDL-C levels,
his statin could be combined with niacin (Niacor, Niaspan) or ezetimibe (Zetia). A statin plus niacin has been shown to raise
HDL-C levels an additional 26% while maintaining effective reductions in LDL-C and vascular events.3 Another trial showed incremental improvement in carotid plaque progression when extended-release niacin was added to statin
therapy.4 However, many patients do not tolerate niacin, even when aspirin is given to prevent flushing. Ezetimibe can lower LDL-C
by up to an additional 20% with relatively few additional side effects.5,6 The second-generation bile acid sequestrant colesevelam (WelChol) is yet another option but requires 3 to 6 additional pills
per day to produce another 12% to 15% LDL-C reduction.7 Of course, as with any patient with metabolic syndrome, continued focus on therapeutic lifestyle changes is crucial to address
the breadth of physiologic abnormalities.
1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in
20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
2. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
3. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention
of coronary disease. N Engl J Med. 2001;345:1583-1592.
4. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing
Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression
in secondary prevention patients treated with statins. Circulation. 2004;110:3512-3517.
5. Vytorin: a combination of ezetimibe and simvastatin. Med Lett Drug Ther. 2004;46:73-74.
6. Fux R, Mrike K, Gundel U-F, et al. Ezetimibe and statin-associated myopathy [letter]. Ann Intern Med. 2004;140:671.
7. Ansell BJ. Colesevelam. Am J Cardiovasc Drugs. 2001;1:147-148.
Drugs mentioned in this article
Atorvastatin (Lipitor)
Colesevelam (WelChol)
Ezetimibe (Zetia)
Fenofibrate (Tricor)
Fluvastatin (Lescol)
Gemfibrozil (Lopid)
Lovastatin (Mevacor)
Niacin (Niacor, Niaspan)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
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