1. The Pyramid of Recent Trials Relative Size of the Various Segments of the Population
Very high cholesterol with CHD or MI
Moderately high cholesterol in high risk CHD or MI
Normal cholesterol with CHD or MI
High cholesterol without CHD or MI
No history of CHD or MI 4S
LIPID
CARE
The pyramid of recent trials
The benefit of lipid-lowering therapy on preventing coronary artery disease (CAD) was not clearly established until the publication of major trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy that had morbidity and mortality as primary endpoints. The Scandinavian Simvastatin Survival Study (4S), published in 1994, may well be the most important clinical trial of the century, because it demonstrated that lipid-lowering statin therapy reduced total mortality in patients with CAD (history of myocardial infarction [MI] and/or angina) and severely elevated cholesterol. The Long-Term Intervention with Pravastatin in Ischaemic Disease trial (LIPID) and the Cholesterol and Recurrent Events trial (CARE) studied CAD patients with moderately elevated and average cholesterol levels, respectively. Patients without previous MI were studied in the West of Scotland Coronary Prevention Study (WOSCOPS), which examined patients with severe hypercholesterolemia, and the Air Force/Texas Coronary Prevention Study (AFCAPS/TexCAPS), which studied patients with average cholesterol. Together these 5 studies enrolled 30,000 patients; each study showed that lipid lowering with a statin prevents clinical events, and with each study, the pool of patients proven to benefit was expanded. These trials also demonstrated the safety of statin therapy; in the 15,000 patients randomized to statins, there were no cases of serious liver complications and only one serious muscle complication that resolved with discontinuation of therapy.
References:
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
WOSCOPS
AFCAPS/TexCAPS

2. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (1998)
Evaluated the effects of lovastatin on first acute major coronary event in 6605 men and women without any coronary or vascular disease and with
TC mg/dl
HDL-C 45 mg/dl in men and 47 mg/dl in women
LDL-C mg/dl, or
LDL-C mg/dl with TC/HDL-C ratio >6
Randomized to lovastatin 20 mg vs. placebo with titration to 40 mg with goal of LDL-C 110 mg/dl
Mean follow-up 5 years
AFCAPS/TexCAPS design
AFCAPS/TexCAPS was a landmark study because, by design, it examined relatively low-risk patients; patients with evidence of CAD were excluded, and low-density lipoprotein cholesterol (LDL-C) was only mildly to moderately elevated. Of this study population, 86% may not have been treated with a lipid-lowering drug by a conservative application of the National Cholesterol Education Program (NCEP) guidelines, using the cutpoints for initiation of drug therapy.
References:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:
Downs JR et al. JAMA 1998;279:

3. AFCAPS/TexCAPS Results
150
115
40%
37%
Risk Reduction with Rx
25% reduction
1st acute major coronary event
p<0.001
Fatal or nonfatal MI
p=0.002
AFCAPS/TexCAPS results
In AFCAPS/TexCAPS, lovastatin at a dosage of 20–40 mg/d reduced LDL-C by 25%, from a mean of 150 mg/dl at baseline to a mean of 115 mg/dl at 1-year follow-up. The primary endpoint—first acute major coronary event, defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death—was significantly reduced by 37%, and fatal or nonfatal MI was significantly reduced by 40%.
References:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
Downs JR et al. JAMA 1998;279:

4. AFCAPS/TexCAPS Tertiary Endpoint Analysis: Mortality
AFCAPS/TexCAPS tertiary endpoint analysis: mortality Because AFCAPS/TexCAPS was conducted in lower-risk patients, having neither CAD nor severely elevated LDL-C, fewer clinical events occurred even in the placebo group. Therefore, although the study answered the scientific question of whether these patients receive benefit from lipid-lowering therapy, it raises an economic question: whom should you not treat? Because the cost of extending treatment to everyone who might benefit would be prohibitively expensive, guidelines and algorithms for risk assessment are needed to determine who should be treated.
References:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
Pearson TA. Lipid-lowering therapy in low-risk patients [letter]. JAMA 1998;279:
*Too few for survival analyses

5. NCEP Adult Treatment Panel II Guidelines
In the NCEP guidelines, the highest-risk patients require the most aggressive therapy. At highest risk are patients with known CAD, but what about patients without CAD who have multiple risk factors with borderline LDL-C?
Reference:
National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:
National Cholesterol Education Program Circulation 1994;89:1329–1445.

6. CARE: Is There a Lower Threshold?
LDL-C <125 mg/dl
LDL-C 125–150 mg/dl
LDL-C >150 mg/dl 20 15 5 30 35 25 10 20 15 5 30 35 25 10 20 15 5 30 35 25 10
Placebo
Placebo
Placebo
Incidence (%)
Pravastatin
Pravastatin
Pravastatin 1 3 2 4 5 1 3 2 4 5 1 3 2 4 5
CARE: is there a lower threshold?
The NCEP guidelines focus on LDL-C, but because the statins have other properties in addition to lowering LDL-C, it may be argued that LDL-C is not important. If that were true, then benefit should be the same in patients with high and in patients with lower LDL-C. In CARE, patients in the highest LDL-C subgroup received the greatest benefit and patients in the lowest subgroup received the least benefit; however, these subgroups were not tertiles, and in quartile analysis of CARE, in which the lowest quartile had LDL-C <126 mg/dl, there was benefit in all quartiles. In LIPID (which had twice as many patients, with similar characteristics, as CARE), patients with lower LDL-C received benefit, albeit less than patients with higher LDL-C.
References:
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:
Years
Years
Years
Change in risk +3%
p=0.85
Change in risk –26%
p<0.001
Change in risk –35%
p=0.008
Sacks FM et al. N Engl J Med. 1996;335:
Copyright © 1996 Massachusetts Medical Society. All rights reserved.

7. On-Treatment LDL Levels and Correlation with Major Coronary Events in 4S
Absolute difference in event rate:
2.3%
5.6%
On-treatment LDL levels and correlation with major coronary events in 4S
In a tertile analysis of on-treatment LDL-C in 4S, 19% of patients in the highest tertile had an event, compared with only 11% of patients in the lowest tertile. Accordingly, the absolute risk reduction decreases as LDL-C levels is reduced to near 100 mg/dl: compared with the highest tertile, the middle tertile had 5.6% fewer events, but compared with the middle tertile, the lowest tertile had only a 2.3% reduction in event rate.
Reference:
Pederson TR, Kjekshus, Olsson AG, Cook TJ. 4S results support AHA guidelines to reduce LDL-cholesterol to less than 100 mg/dl in patients with CHD [abstract]. Circulation 1997;96:I-717.
Circulation 1997;96:I-717

8. AVERT: Study Design 18 months
CAD ³1 lesion ³50% stenosis LDL-C ³115 mg/dL (³3.0 mmol/L) LVEF ³40% Bruce protocol treadmill test or 20-W/min bicycle exercise test ³4 min
Atorvastatin 80 mg/d + usual medical therapy n=164*
Angioplasty + usual care, including lipid lowering n=177†
18 months
AVERT: study design
In the Atorvastatin versus Revascularization Treatment study (AVERT), 341 patients with stable CAD were randomized to receive PTCA plus usual medical care (including lipid-lowering therapy) or aggressive lipid-lowering therapy with atorvastatin 80 mg/d. The primary endpoint was the proportion of patients who had an ischemic event during the 18-month follow-up.
Reference:
Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-76.
Occurrence of ischemic events (death from cardiac causes, resuscitation after cardiac arrest, nonfatal MI, CVA, CABG, angioplasty, worsening angina verified by objective evidence resulting in hospitalization)
Time to first ischemic event
Safety
*1 patient did not receive atorvastatin.
†11 patients did not have baseline revascularization.
Pitt B et al. N Engl J Med 1999;341:70-76.

9. Results - Intent to Treat5 10 15 20 25
Atorvastatin
Angioplasty/UC
% of patients
with an
ischemic event
13%
21%
36% difference*
(p = 0.048) 22 37
*p=0.048 vs an adjusted significance level of p=0.045.
AVERT: results—intent to treat
Analysis of the primary endpoint indicated a 36% reduction in the percent of patients with an ischemic event; because of adjustment for interim analyses, this difference was not statistically significant.
Reference:
Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-76.
Pitt B et al. N Engl J Med 1999;341:70-76.

10. Time to First Ischemic Event:Intent-to-Treat Analysis5 10 15 20 25
0.0
0.5
1.0
1.5
p=0.027
Risk reduction 36%
(95% CI: 5% to 67%)
Cumulative Incidence (%)
Atorvastatin
Angioplasty/UC
Time since randomization (yr)
AVERT: time to first ischemic event—intent-to-treat analysis
During the first 6 months, patients in the PTCA group might have been expected to have more events because of restenosis, but the greatest difference in cumulative incidence of events occurred after 6 months. The benefit in patients receiving atorvastatin is most likely due to plaque stabilization.
Reference:
Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-76.
Pitt B et al. N Engl J Med 1999;341:70-76.
Copyright © 1999 Massachusetts Medical Society. All rights reserved.

11. Summary of Lipid Parameters
250
31% *
Atorvastatin baseline
(6.5)
10%
Atorvastatin end of study
Angioplasty/UC baseline
200
11% *
Angioplasty/UC end of study
(5.2)
46% *
10%
18%
150
(3.9)
mg/dL
(mmol/L)
100
(2.6) 8%
11% 50
AVERT: summary of lipid parameters
At 18-month follow-up, LDL-C was reduced to 119 mg/dl in PTCA patients and to 77 mg/dl in atorvastatin patients. The incidence of ischemic events in the respective groups reaffirms the NCEP goal of reducing LDL-C to £100 mg/dl in patients with CAD. The results of AVERT also indicate that treatment of symptomatic lesions with PTCA may be effective in relieving angina but is insufficient to prevent events. Most clinical events are not caused by "critical" lesions of >70% stenosis but by lesions of <50% stenosis. Treating the symptoms without treating the underlying disease process is incomplete therapy.
Reference:
Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-76.
(1.3)
LDL-C TC TG †
HDL-C
*Significantly different from angioplasty/UC (p<0.05).
† To convert TG to mmol/L, multiply by
Note: 73% of angioplasty/UC-treated patients were on lipid-lowering medication.
Pitt B et al. N Engl J Med 1999;341:70-76.
Copyright © 1999 Massachusetts Medical Society. All rights reserved.

12. Clinical Event Rates by LDL-C Achieved in Statin Trials
2° prevention placebo
2° prevention statin
1° prevention placebo
1° prevention statin
AFCAPS
WOSCOPS
CARE
LIPID 4S
Event Rate (%)
Clinical event rates by LDL-C achieved in statin trials
In the statin trials with morbidity and mortality endpoints, clinical event rates paralleled the LDL-C level achieved on treatment during the trial. Although this correlation underscores the importance of LDL-C in determining CAD risk, in each trial patients with CAD had higher event rates than patients without CAD, even in CARE in which LDL-C was reduced to <100 mg/dl. It is important to consider not only LDL-C but also the overall risk of the patient; because of their increased risk, patients with CAD merit aggressive interventions to reduce risk.
References:
Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:
Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.
Reprinted with permission from Excerpta Medica Inc.

13. How Low Should You Go?
SEARCH: Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine
Simvastatin 20 mg vs. 80 mg
TNT: Treating to New Targets
Atorvastatin 10 mg vs. 80 mg
How low should you go?
On-going studies are examining how low LDL-C should be decreased for optimal risk reduction by comparing lower with higher dosages of the more potent statins.

14. Clinical Judgment
The NCEP ATP II guidelines recommend the use of clinical judgment in deciding whether to initiate drug therapy in
Patients with CHD and LDL-C 100–129 mg/dl
Patients without CHD who have 2 risk factors and LDL-C 130–159 mg/dl
Middle-aged and older patients without CHD who have <2 risk factors and LDL-C 160–189 mg/dl
Clinical judgment
In patients whose LDL-C is above target yet below the cutpoints for initiation of drug therapy, the NCEP guidelines specify that clinical judgment should be used to determining whether to initiate drug therapy. Since the guidelines were written in 1993, abundant clinical trial evidence has become available on which to base clinical judgment. These data strongly support treatment in many of these patients.
Reference:
National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:
National Cholesterol Education Program Circulation 1994;89:1329–1445.

15. NHANES III Adult Population Estimates by ATP II Risk Category
<2 RF
2 RF
CHD
Number of US Adults (millions)
107.1
38.5
9.4
NHANES III adult population estimates by ATP II risk category
Estimates based on updated National Health and Nutrition Examination Survey III (NHANES III) data from 1988–1994 indicate that 38.5 million Americans without CAD may be at high risk for developing CAD because of the presence of 2 or more risk factors in the NCEP algorithm for primary prevention.
Reference:
Jacobson TA, Griffiths GG, Varas C, Gause D, Sung JC, Ballantyne CM. Impact of evidence-based "clinical judgment" on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. National Health and Nutrition Examination Survey. Arch Intern Med May 8;160(9):
Jacobson TA, Griffiths GG, Varas C, Schein JR, Ballantyne CM. Impact of clinical judgment on number of patients requiring lipid-lowering therapy based on Adult Treatment Panel II guidelines and new National Health and Nutrition Examination Survey III data [abstract]. J Am Coll Cardiol 1999;33:296A.
Jacobson TA et al. Arch Intern Med. 2000;160(9):

16. LDL-C Distribution in U.S. Adults Data from NHANES III, 1988–1994
without CHD and with 2 RF
Number of US Adults (millions)
with CHD
LDL-C distribution in US adults: data from NHANES III, 1988–1994
A comparison of LDL-C distribution based on NHANES III data shows that most patients with CAD have LDL-C <160 mg/dl. If treatment of patients without CAD who have ³2 risk factors is restricted to patients with >160 mg/dl (the cutpoint for initiation of drug therapy in the NCEP guidelines), the majority of first events will not be prevented. To be successful in primary prevention, not only LDL-C but also other risk factors must be considered. Because the number of patients with multiple risk factors who have not yet developed CAD is much greater than the number of CAD patients, it is essential to identify high-risk patients and target them for more aggressive therapy.
Reference:
Jacobson TA, Griffiths GG, Varas C, Gause D, Sung JC, Ballantyne CM. Impact of evidence-based "clinical judgment" on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. National Health and Nutrition Examination Survey. Arch Intern Med May 8;160(9):
Jacobson TA, Griffiths GG, Varas C, Schein JR, Ballantyne CM. Impact of clinical judgment on number of patients requiring lipid-lowering therapy based on Adult Treatment Panel II guidelines and new National Health and Nutrition Examination Survey III data [abstract]. J Am Coll Cardiol 1999;33:296A.
<60
60–69
70–79
80–89
90–99
100–109
110–119
120–129
130–139
140–149
150–159
160–169
170–179
180–189
190–199
200–209
210–219
220–229
230–239
240–249
250–259
260–269
270–279
280–289
290–299
300–309
310–319
320–329
330–339
340–349
350
LDL-C (mg/dl)
Jacobson TA et al. Arch Intern Med. 2000;160(9):

17. US Adults Requiring Drug Therapy Assuming 10% LDL-C Reduction with Diet
28.4
17.5
Number of US Adults (millions)
6.8
US adults requiring drug therapy assuming 10% LDL-C reduction with diet
Even assuming a 10% reduction in LDL-C with diet therapy, extending treatment to all patients for whom the guidelines recommend the use of clinical judgment in determining whether to initiate drug therapy would require treating an enormous number of patients. The largest increase is in the number of individuals without CAD who have multiple risk factors; in contrast to 5.5 million who would be considered for drug therapy by a strict application of the NCEP cutpoints, 17.5 million would be considered by a broader application of clinical judgment (i.e., the inclusion of patients with LDL-C of 130–160 mg/dl) as recommended in the guidelines. The magnitude of this increase in potential patients raises the issue of cost-effectiveness, to ensure that appropriate treatment is extended to as many high-risk patients as possible.
Reference:
Jacobson TA, Griffiths GG, Varas C, Gause D, Sung JC, Ballantyne CM. Impact of evidence-based "clinical judgment" on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. National Health and Nutrition Examination Survey. Arch Intern Med May 8;160(9):
Jacobson TA, Griffiths GG, Varas C, Schein JR, Ballantyne CM. Impact of clinical judgment on number of patients requiring lipid-lowering therapy based on Adult Treatment Panel II guidelines and new National Health and Nutrition Examination Survey III data [abstract]. J Am Coll Cardiol 1999;33:296A.
4.1
10.4
5.5
1.6
3.3
<2 RF
2 RF
CHD
Total
Jacobson TA et al. Arch Intern Med. 2000;160(9):

18. Effect of Statin Therapy on CHD: Clinical Events Trials
Although all the statin trials with clinical event endpoints reported substantial relative risk reductions (RRR), absolute risk reduction (ARR) and consequently the number needed to treat (NNT) varies greatly with the patient population. Because of the high event rates in 4S patients, who had CAD and severely elevated LDL-C, only 12 patients needed to be treated to prevent 1 event. However, as treatment is extended to lower-risk patients, increasingly larger numbers of patients must be treated to prevent 1 event. In the relatively low-risk patients in AFCAPS/TexCAPS, who did not have CAD and whose LDL-C was only mildly to moderately elevated, 56 patients needed to be treated to prevent 1 event. Yet, despite the range of mean baseline LDL-C levels in these trials, all demonstrated benefit with treatment, suggesting that factors besides LDL-C are important contributors to CAD risk.
References:
Jacobson TA, Schein JR, Williamson A, Ballantyne CM. Maximizing the cost-effectiveness of lipid-lowering therapy. Arch Intern Med 1998;158:
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
*Nonfatal MI or CHD death in WOSCOPS, CARE, LIPID; nonfatal or fatal MI, unstable angina, or sudden cardiac death as first event in AFCAPS; nonfatal MI, coronary death, or resuscitated cardiac arrest in 4S.
†vs. placebo
Jacobson TA et al. Arch Intern Med 1998;158:1977–1989.

19. LDL and HDL Impact on CHD Risk A Compounded Rather Than Additive Impact
400
1000 (in 6 years)
Incidence per
300
>195
200
LDL and HDL impact on CHD risk
A major influence on CAD risk is high-density lipoprotein cholesterol (HDL-C). Risk stratification is improved by evaluating both LDL-C and HDL-C levels. At a given LDL-C level, risk is increased dramatically with low HDL-C.
Reference:
Assmann G, Schulte H, von Eckardstein A, Huang Y. High‑density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124:S11‑20.
100
LDL-cholesterol (mg/dL)
<135
<35
35-55
>55
HDL-cholesterol (mg/dL)
Assmann G, et al. Atherosclerosis 1996;124(suppl):S11-S20.
Reprinted with permission from Elsevier Science.

20. HDL is a major factor in predicting CAD20 40 60 80
100
120
<35
>55
HDL-cholesterol (mg/dL)
Incidence of CHD (per 1000 in 6 years)
n=4,407
HDL is a major factor in predicting CAD
In epidemiological studies, HDL-C has consistently been shown to be an important marker for CAD risk. Univariate analysis of data from the Prospective Cardiovascular Münster (PROCAM) study indicated a significant association between CAD incidence and HDL-C (p <0.001), which remained after adjustment for other risk factors.
Reference:
Assmann G, Schulte H, von Eckardstein A, Huang Y. High‑density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 1996;124:S11‑20.
Assmann G, et al. Atherosclerosis 1996;124(suppl):S11-S20.
Reprinted with permission from Elsevier Science.

21. HDL-C Distribution in US Adults
Number of US Adults (millions)
HDL-C (mg/dl)
HDL-C distribution in US adults
Many American adults without CAD but who have multiple risk factors have low HDL-C as one of their risk factors. Approximately 14 million individuals in this category have HDL-C <35 mg/dl, which is defined as low in the NCEP guidelines, and another 14 million have HDL-C _35 mg/dl but <45 mg/dl, which many experts would consider low.
Data from NHANES III, 1988–1994.

22. HDL-C in Clinical Practice
Risk assessment
Routinely measured in all adult patients
HDL-C <35 mg/dL is a major positive risk factor
HDL-C 60 mg/dL is a negative risk factor; subtract 1 risk factor from total
Risk reduction
Nonpharmacologic therapy (exercise, weight loss, smoking cessation)
Pharmacologic therapy
Clinical trial data show decreased CAD progression and decreased CAD events with increased HDL-C
HDL-C in clinical practice
The NCEP guidelines provide for routine measurement of HDL-C in all adults and include HDL-C level in the treatment algorithm for primary prevention. The primary therapy for low HDL-C is lifestyle modification. In patients requiring drug therapy to lower LDL-C, the guidelines recommend selecting an agent that will also increase HDL-C, and in CAD patients with low HDL-C, the guidelines suggest the initiation of niacin even if LDL-C is not elevated. Recently, clinical trial data have shown benefits on CAD progression and events when HDL-C is increased.
Reference:
National Cholesterol Education Program: Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:

23. Reduction in CAD Progression with Fluvastatin in Low vs
Reduction in CAD Progression with Fluvastatin in Low vs. High HDL-C Patients
Progression (MLD decrease), mm
HDL-C <35 mg/dl
(p=0.0004)
n=43
n=25
HDL-C 35 mg/dl
(p=0.09)
n=128
n=143
0.065
0.274
0.036
0.083
p=0.01
LCAS: reduction in CAD progression with fluvastatin in low– vs. high–HDL-C patients
In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), which enrolled CAD patients with mildly to moderately elevated LDL-C, patients with low HDL-C randomized to placebo had the most CAD progression at 2.5-year follow-up angiography. Low–HDL-C patients also had the greatest benefit with fluvastatin therapy, although the primary effect of fluvastatin, like the other statins, is to reduce LDL-C.
Reference:
Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:
Ballantyne CM et al. Circulation 1999;99:

24. Reduced CAD Events with Fluvastatin in Low HDL-C Patients
1.00
0.75
0.50
0.25
0.00
Fluvastatin
Placebo
HDL-C <35 mg/dl
p=0.002
Probability of event-free survival 1 2
2.5
1.00
0.75
0.50
0.25
0.00
Placebo
Fluvastatin
HDL-C 35 mg/dl
p=0.232
LCAS: reduced CAD events with fluvastatin in low–HDL-C patients
Although LCAS was an angiographic trial, a post hoc analysis indicated a significant improvement in event-free survival with fluvastatin treatment in low–HDL-C patients. Not only did low–HDL-C patients have the most events without therapy, but they also received the most benefit with statin therapy.
Reference:
Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99: 1 2
2.5
Years
Ballantyne CM et al. Circulation 1999;99:

25. Angiographic Trials in Low–HDL-C Patients
Baseline (mg/dl) %
MLDPL –MLDDR (mm)
Trial
Drug
LDL-C
HDL-C
LCAS
fluvastatin 40 mg/d
146 43
–25 +9
0.07
LCAS HDL-C <35 mg/dl
143 32
+16
0.21
BECAIT
bezafibrate 600 mg/d
180 34
–3.5
0.11
LOCAT
gemfibrozil 1200 mg/d
138 31
–4.5
+21
0.04
Angiographic trials in low–HDL-C patients Statins generally increase HDL-C by up to 10%, but greater increases are usually seen with fibrates. In a comparison of LCAS with angiographic trials of fibrate therapy conducted in patients with low HDL-C, statin therapy produced at least as much benefit on CAD progression in low–HDL-C patients as fibrate therapy. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) used bezafibrate in young men with previous MI, and the Lopid Coronary Angiography Trial (LOCAT) used gemfibrozil in men with previous CABG.
References:
Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:
Ericsson C-G, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347:
Syvänne M, Nieminen MS, Frick MH, Kauma H, Majahalme S, Virtanen V, Kesäniemi YA, Pasternack A, Ehnholm C, Taskinen M-R, for the Lopid Coronary Angiography Trial (LOCAT) Study Group. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:
Ballantyne CM et al. Circulation 1999;99:

26. Atherosclerosis Progression and Baseline HDL-C: Results from Post-CABG
Progression rate (%)
HDL-C (mg/dl)
Moderate therapy (LDL-C 134)
Aggressive therapy (LDL-C 95)
Relative risk
95% CI
<35 47 30
0.48
0.35–0.67
35–39 40 28
0.58
0.39–0.85
40–44 37 25
0.56
0.35–0.89
45 27
0.87
0.57–1.33
Post-CABG: atherosclerosis progression and baseline HDL-C
A post hoc analysis of the Post Coronary Artery Bypass Graft study (Post-CABG) examined the influence of HDL-C level on the progression of atherosclerosis in saphenous vein grafts. Similar to the results in LCAS in native coronary arteries, patients in Post-CABG with low HDL-C had a greater percentage of grafts with ³0.6 mm progression. These patients also had the greatest benefit on progression with aggressive lovastatin therapy (40–80 mg/d) compared with moderate lovastatin therapy (2.5–5.0 mg/d).
Reference:
Hunninghake D, Knatterud G, Campeau L, White CW, Domanski MJ, Forrester JS, Gobel F, Geller N, Herd JA, Hoogwerf B, Rosenberg Y. Baseline HDL-cholesterol and triglycerides as predictors of progression of atherosclerosis in saphenous vein grafts: NHLBI Post-CABG clinical trial [abstract]. Circulation. 1997;96:I-413.
Hunninghake D et al. Circulation 1997;96:I-413.

27. Event Reduction with Statin Therapy in Patients with Low vs. High HDL-C
WOSCOPS
AFCAPS
Coronary Events (%)
40
34
52
38
 43
<43
LIPID
 39
<39
Event reduction with statin therapy in low– vs. high–HDL-C patients
Similar to the results for CAD progression in angiographic statin trials, statin trials with morbidity and mortality endpoints reported the highest event rates in placebo patients with low HDL-C and the greatest benefit on clinical events with statin therapy in low–HDL-C patients. In each of the trials that compared patients with lower vs. higher HDL-C, low–HDL-C patients treated with a statin had about the same event rate as high–HDL-C patients on placebo. Statin therapy in effect eliminated much of the additional risk for a coronary event conferred by low HDL-C.
References:
Ballantyne CM, Herd JA, Ferlic LL, Dunn JK, Farmer JA, Jones PH, Schein JR, Gotto AM Jr. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999;99:
Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995;345:
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:
Adapted from Ballantyne CM et al. Circulation 1999;99:

28. Bezafibrate Infarction Prevention (BIP) Study Results
LDL-C
HDL-C TG
Change, %
Combined 1° endpoint:
fatal or nonfatal MI
and sudden death (NS)
Relative risk reduction, %
BIP study results
The Bezafibrate Infarction Prevention (BIP) Study investigated the effects of bezafibrate on 5-year coronary morbidity and mortality in 3122 men and women with prior MI (77.5%) and/or evidence of ischemia. Mean baseline lipids were LDL-C 148 mg/dl, HDL-C 35 mg/dl, and triglyceride 149 mg/dl. Lipid changes with bezafibrate 400 mg/d were –5%, +12%, and –22%, respectively. In contrast to studies of statins in patients with mildly to moderately elevated LDL-C (BIP entry criteria limited LDL-C to £180 mg/dl in all patients and £160 mg/dl in patients aged <50 years), no significant benefit in the combined primary endpoint was obtained with bezafibrate.
References:
Goldbourt U, Behar S, Reicher-Reiss H, Agmon J, Kaplinsky E, Graff E, Kishon Y, Caspi A, Weisbort J, Mandelzweig L, Abinader E, Aharon L, Braun S, David D, Flich M, Friedman Y, Kristal N, Leil N, Markiewicz W, Marmor A, Palant A, Pelled B, Rabinowitz B, Reisin L, Roguin N, Rosenfeld T, Schlesinger Z, Sclarovsky S, Sherf L, Tzivoni D, Zahavi I, Zion M, Brunner D, for the Bezafibrate Infarction Prevention Study Group. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention trial). Am J Cardiol 1993;71:
Goldbourt U, Brunner D, Behar S, Reicher-Reiss H, for the BIP Study Group. Baseline characteristics of patients participating in the Bezafibrate Infarction Prevention (BIP) study. Eur Heart J 1998;19:H42-H47.
Kaplinsky E et al. Presented at ESC, 1998

29. VA-HIT Design
Hypothesis: Gemfibrozil treatment of "isolated" low HDL-C in CHD patients will decrease CHD events
Subjects:
2531 male veterans aged 74 years (mean 64)
2° prevention (MI, revascularization, angina, angio)
Mean baseline HDL-C 32 mg/dl, LDL-C 111 mg/dl, TG 161 mg/dl
Treatment: gemfibrozil
Endpoints: nonfatal MI, CHD death
Follow-up: 5.1 years
VA-HIT design
The Veterans Affairs HDL Intervention Trial (VA-HIT) also examined the effect of fibrate therapy on clinical events in patients with CAD. Although the triglyceride criterion was the same as in the BIP study (£300 mg/dl), mean triglyceride in VA-HIT was higher than in the BIP study.
Reference:
Rubins HB, Robins SJ, Iwane MK, Boden WE, Elam MB, Fye CL, Gordon DJ, Schaefer EJ, Schectman G, Wittes JT. Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol. Am J Cardiol 1993;71:45-52.
Rubins HB et al. Am J Cardiol 1993;71:45-52.

30. VA-HIT Results Change from baseline, % Relative risk reduction, %
HDL-C TG
LDL-C
Nonfatal MI or CHD death
(p=.006)
Stroke
(NS)
Total death (NS)
CHD death (NS)
VA-HIT results
From baseline, HDL-C was increased by 6% and triglyceride was decreased by 29% with gemfibrozil at 1-year follow-up; LDL-C was not significantly different between treatment groups. Analysis of the primary endpoint indicated significant benefit with gemfibrozil. Other clinical events were also reduced with treatment but the differences were not statistically significant.
Reference:
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:
Rubins HB et al. N Engl J Med 1999;341:

31. Nonpharmacologic Treatment of Low HDL-C
Physical activity
Smoking cessation
Weight loss
Nonpharmacologic treatment of low HDL-C
The initial treatment of low HDL-C is lifestyle modification. Unfortunately, many patients are not willing to make these changes, and other patients with severely depressed levels of HDL-C do not receive sufficient elevations with lifestyle modification alone.
Reference: Belalcazar LM, Ballantyne CM. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol. Prog Cardiovasc Dis 1998;41:

32. Effects of Drugs on HDL-C Levels
Nicotinic acid  15–35%
Fibrates  10–15%
Estrogens  10–15%
Statins  5–10%
-blockers  10–20%
Alcohol  10%
Effects of drugs on HDL-C levels
A number of pharmacologic agents will also increase low HDL-C. Niacin provides the greatest increase in HDL-C.
Reference:
Belalcazar LM, Ballantyne CM. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol. Prog Cardiovasc Dis 1998;41:
Belalcazar LM et al. Progress in Cardiovascular
Disease 1998;41:

33. Simvastatin Combined Hyperlipidemia Study Design and Patient Population
Double blind, randomized, placebo-controlled, 3-period, crossover study
130 men (52%) and women, aged years (mean 53) Type 2 diabetes: 18% - Type III hyperlipidemia (apo E2/2): 5%
Lipid entry criteria: - LDL-C > 130 mg/dL (mean 156) - Triglycerides mg/dL (median 389)
Treatment: placebo, simvastatin 40 and 80 mg/day (6 weeks each)
Main endpoints: - TC, TG, apo B, LDL-C, VLDL-C, apo A-I, HDL-C
Simvastatin Combined Hyperlipidemia Study: design and patient population
The Simvastatin Combined Hyperlipidemia Study examined the efficacy and safety of simvastatin dosed at 40 mg/d and 80 mg/d compared with placebo in patients with mixed hyperlipidemia.
Reference:
Hunninghake DB, Plotkin D, Stepanavage M, Bays H, Davidson MH, Dujovne CA, Keilson LM, Korenman SG, Robertson DG, Stein EA, Weiss SR, Mercuri M. Large, dose dependent effects of simvastatin 40 and 80 mg/day in combined hyperlipidemia [abstract]. J Am Coll Cardiol 1999;33:244A.
Hunninghake DB et al. J Am Coll Cardiol 1999;33:244A

34. Changes in Lipids Mean % Change p<0.001 -29 -28 13 -36 -33 16 -40
-30
-20
-10 10 20
Simvastatin 40 mg/d
Simvastatin 80 mg/d
LDL-C TG
Mean % Change
HDL-C
p<0.001
Simvastatin Combined Hyperlipidemia Study: changes in lipids
Simvastatin provided significant improvements in LDL-C, triglyceride, and HDL-C, with greater improvements obtained at the higher dosage. At high dosages, statin therapy can substantially decrease triglyceride and increase HDL-C, particularly in patients with elevated triglyceride and low HDL-C.
Reference:
Hunninghake DB, Plotkin D, Stepanavage M, Bays H, Davidson MH, Dujovne CA, Keilson LM, Korenman SG, Robertson DG, Stein EA, Weiss SR, Mercuri M. Large, dose dependent effects of simvastatin 40 and 80 mg/day in combined hyperlipidemia [abstract]. J Am Coll Cardiol 1999;33:244A.
Hunninghake DB et al. J Am Coll Cardiol 1999;33:244A

35. Comparison of Simvastatin and Atorvastatin
Study Objective:
To compare relative efficacy of simvastatin and atorvastatin
Study Design:
12-week, open-label, randomized, parallel-group, multicenter study
842 patients, men and women, ages 21-70
Following a 4-week diet run-in period, patients were randomized into 4 treatment groups (simvastatin 40 mg, simvastatin 80 mg, atorvastatin 20 mg, atorvastatin 40 mg) for 12 weeks
Comparison of simvastatin and atorvastatin
Simvastatin and atorvastatin provide the greatest reductions in LDL-C. The effects of simvastatin and atorvastatin at two dosages were compared in patients with high cholesterol.
Reference:
Crouse JR III, Frohlich J, Ose L, Kush D. Wu M, Mercuri M. Simvastatin and atorvastatin have different effects on HDL cholesterol and apolipoprotein A-I [abstract]. J Am Coll Cardiol 1999;33:244A.
Crouse JR III et al. Am J Cardiol 1999;83:

36. Lipid Changes Mean % Change p<0.01 p<0.01 p<0.001 +7 +4 +7 +310
LDL-C TG +7 +4 +7 +3 +6 +5 +6
-10
HDL-C
apo A-I
-20
Mean % Change
-23
-23
-30
-25
-30
Simvastatin 40 mg/d
-40
Simvastatin 80 mg/d
-43
Lipid changes: simvastatin vs. atorvastatin
At corresponding dosages, LDL-C and triglyceride reductions were similar with simvastatin and atorvastatin. However, simvastatin provided greater increases in HDL-C and the HDL-associated apolipoprotein (apo) A-I than did atorvastatin, and higher-dose atorvastatin provided smaller increases in both parameters than did lower-dose atorvastatin.
Reference:
Crouse JR III, Frohlich J, Ose L, Kush D. Wu M, Mercuri M. Simvastatin and atorvastatin have different effects on HDL cholesterol and apolipoprotein A-I [abstract]. J Am Coll Cardiol 1999;33:244A.
-45
p<0.05
-50
Atorvastatin 20 mg/d
-49
-51
Atorvastatin 40 mg/d
-60
p<0.05
p<0.05
Crouse JR III et al. Am J Cardiol 1999;83:

37. Subgroup Analysis for HDL-C above or below 35 mg/dl17 13 12
Mean % change in HDL-C
p<0.05 7 6 5
Subgroup analysis for HDL-C above or below 35 mg/dl: simvastatin vs. atorvastatin
The differential effects on HDL-C was even greater in patients with low HDL-C, with simvastatin providing increased benefit, particularly at the higher dosage, than atorvastatin, which increased HDL-C by only about half as much at the higher dosage compared with the lower dosage.
Reference:
Crouse JR III, Frohlich J, Ose L, Kush D. Wu M, Mercuri M. Simvastatin and atorvastatin have different effects on HDL cholesterol and apolipoprotein A-I [abstract]. J Am Coll Cardiol 1999;33:244A. 3 3
Crouse JR III et al. Am J Cardiol 1999;83:
Reprinted with permission from Excerpta Medica, Inc.

38. Combination Therapy: Statin + Nicotinic Acid
Simvastatin 10 mg/day + nicotinic acid titrated up to 1.5 g/day1
LDL-C by 29%
HDL-C by 31%
TG by 31%
Fluvastatin 20 mg/day + nicotinic acid titrated up to 3 g/day2
LDL-C by 40%
HDL-C by 28%
TG by 30%
Combination therapy: statin + nicotinic acid Because of the beneficial effects of statins on HDL-C and on clinical events in patients with low HDL-C, even greater benefit might be expected by combining a statin with an agent that provides a greater increase in HDL-C. The combination of niacin with simvastatin or fluvastatin increased HDL-C by approximately 30%. Combining a statin with niacin may increase risk for myopathy and hepatitis, but studies that have used careful patient selection have reported few adverse effects.
References:
Stein EA, Davidson MH, Dujovne CA, Hunninghake DB, Goldberg RB, Illingworth DR, Knopp RH, Miller VT, Frost P, Isaacsohn JL, Mitchel YB, Melino MR, Shapiro D, Tobert JA. Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J Cardiovasc Pharmacol Therapeut 1996;1:
Jacobson TA, Chin MM, Fromell GJ, Jokubaitis LA, Amorosa LF. Fluvastatin with and without niacin for hypercholesterolemia. Am J Cardiol 1994;74:149‑154.
Jacobson TA, Amorosa LF. Combination therapy with fluvastatin and niacin in hypercholesterolemia: a preliminary report on safety. Am J Cardiol 1994;73:25D‑29D.
Gardner SF, Schneider EF, Granberry MC, Carter IR. Combination therapy with low-dose lovastatin and niacin is as effective as higher-dose lovastatin. Pharmacotherapy 1996;16:
1Stein EA et al. J Cardiovasc Pharmacol Ther 1996;1:
2Jacobson TA et al. Am J Cardiol 1994;74:

39. Combination Therapy: Statin + Fibrate
Lovastatin 20–40 mg/day + gemfibrozil 1200 mg/day1
LDL-C by 26%
HDL-C by 3%
TG by 35%
Pravastatin 40 mg/day + gemfibrozil 1200 mg/day2
LDL-C by 37%
HDL-C by 17%
TG by 42%
Combination therapy: statin + fibrate
Combining a statin with a fibrate can also increase HDL-C and can substantially reduce LDL-C and triglyceride. This combination may increase risk for myopathy, but few adverse effects were reported in these studies.
Reference:
Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. Am J Cardiol 1992;70:1-9.
Wiklund O, Angelin B, Bergman M, Berglund L, Bondjers G, Carlsson A, Lindén T, Miettinen T, Ödman B, Olofsson S-O, Saarinen I, Sipilä R, Sjöström P, Kron B, Vanhanen H, Wright I. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med 1993;94:13-20.
1Glueck CJ et al. Am J Cardiol 1992;70:1-9
2Wiklund O et al. Am J Med 1993;94:13-20

40. Combination Therapy: Pros and Cons
LDL-C, TG, HDL-C
May Lp(a) (niacin)
LDL particle size
Fibrinogen (fibrate)
Angiographic data
Increased adverse effects (rhabdomyolysis)
Drug interactions
Increased costs
Lack of outcome studies
Combination therapy: pros and cons
In determining whether to initiate combination therapy in a patient with dyslipidemia, the advantages must be weighed against potential disadvantages. Although clinical trial evidence of the effects of combination therapy on morbidity and mortality is lacking, a composite analysis of angiographic trials demonstrated that combination therapy decreased per-patient diameter stenosis by 1–2% (net regression), whereas monotherapy slowed progression but did not induce regression. However, there are still no large prospective clinical event trials to show that the combination of a statin with either a fibrate or niacin provides greater event reduction than a statin alone. Combination therapy is more expensive and is associated with increased adverse events such as rhabdomyolysis. In addition, the package labeling of all statins carries a warning about using a statin in combination with a fibrate.
References:
Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q.
Brown BG, Zhao X-Q, Bardsley J, Albers JJ. Secondary prevention of heart disease amongst patients with lipid abnormalities: practice and trends in the United States. J Intern Med 1997;241:

41. Summary
Recent clinical trials have shown a consistent benefit on reducing CHD in both primary and secondary prevention, in patients with LDL-C elevations ranging from mild to severe.
Patients with low HDL-C are at increased risk for CHD events.
Statins have been effective in patients with low HDL-C for slowing CAD progression and reducing CAD events.
Summary
In summary, abundant clinical trial data have established the benefit of lowering LDL-C with statin therapy in both primary and secondary prevention, in patients whose LDL-C elevations are either mild to moderate or severe. The emerging data on patients with low HDL-C will enable improved treatment of these high-risk patients. In general, a statin should be initiated as first-line therapy in most patients with elevated LDL-C. Although statins primarily lower LDL-C, enhanced benefit has been demonstrated in patients with low HDL-C.

42. Summary (continued)
Some but not all trials with fibrates have shown benefit for patients with low HDL-C.
Combination therapy with statins and other agents is very effective for comprehensive modification of the lipid profile, but drug side effects may be increased.
Summary (continued)
In contrast to the consistent benefit seen with statins, some but not all trials with fibrates have shown benefit for patients with low HDL-C. Although the addition of a second agent to a statin will provide more comprehensive improvement of the lipid profile, the long-term benefit, risk, and cost-effectiveness of combination therapy are unknown.