© 1997 American Heart Association, Inc.
Articles |
Efficacy and Safety of a New Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor, Atorvastatin, in Patients with Combined Hyperlipidemia: Comparison with Fenofibrate
From the Ottawa Civic Hospital, Ottawa, Ontario, Canada (T.C.O., A.S.); Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, Mich (T.H., L.S., D.M.B.); Lipid and Lipoprotein Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Okla (P.A.); Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Montreal, Quebec, Canada (J.D.); St. Michael's Health Center, Toronto, Ontario, Canada (L.L.); Centre Hospitalier de l'Universite Laval, Foy, Quebec, Canada (P.J.L.); Royal Victoria Hospital, Montreal, Quebec Canada (A.D.S.); Camp Hill Medical Centre, Halifax, Nova Scotia, Canada (M.H.T.); and Clinique des Lipides, Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada (G.T.).
Correspondence and reprint requests to Teik C. Ooi, MB, Ottawa Civic Hospital, 1053 Carling Ave., Ottawa, ON K1Y 4E9, Canada.
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Abstract |
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Abstract This 24-week, randomized, open-label multicenter study evaluated the efficacy and safety of atorvastatin compared with fenofibrate in the treatment of patients with combined hyperlipidemia (CHL). Following a 6-week baseline period, 84 patients with CHL were randomly assigned to either atorvastatin treatment, 10 mg QD for 12 weeks increasing to 20 mg QD for 12 weeks, or fenofibrate treatment, 100 mg TID for 24 weeks. Changes from baseline in lipid parameters were evaluated at weeks 12 and 24. At both 10- and 20-mg doses, atorvastatin treatment resulted in significantly greater reductions in LDL cholesterol, apolipoprotein (apo) B, total cholesterol, LDL-apoB, and lipoprotein-B compared to 300-mg fenofibrate treatment (P<.05). While atorvastatin also resulted in clinically significant reductions in triglyceride, VLDL cholesterol, apoB in VLDL, triglyceride in VLDL, and apoC-III and significant increases in HDL cholesterol and apoA-I levels, fenofibrate was more effective than atorvastatin in altering all these parameters. However, by significantly affecting both the cholesterol-rich and triglyceride-rich particles, atorvastatin holds promise as a lipid-regulator able to adequately treat a broad range of patients that includes those with CHL.
Key Words: atorvastatin • combined hyperlipidemia • hydroxy-methylglutaryl coenzyme A reductase inhibitor • fenofibrate
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Introduction |
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It is well recognized that high levels of serum total cholesterol (TC) and LDL cholesterol (LDL-C) are associated with an increased risk of coronary artery disease (CAD).1–3 There is also evidence that while elevated LDL-C is the strongest risk factor, triglycerides (TG) also increase risk more than previously appreciated.4–6 Individuals with combined elevation of cholesterol and TG (combined hyperlipidemia; CHL) may, in addition, have low HDL cholesterol (HDL-C) levels, which further heighten risk for CAD. According to population-based frequency studies, CHL is common, occurring in 36% to 48% of families with CAD.7
While common, CHL remains difficult to treat. Diet modifications and exercise are usually not sufficient, and pharmacotherapy is often required. Bile acid sequestering resins are effective against hypercholesterolemia but they have a tendency to increase serum TG levels. They are also associated with unpleasant side effects, making them not the ideal medications for CHL. Nicotinic acid can decrease serum LDL-C and TG levels, but it is not well tolerated. The European Atherosclerosis Society and the National Cholesterol Education Program (NCEP) consider fibric acid derivatives (fibrates) and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors to be effective therapy for CHL.8,9 Unfortunately, while fibrates effectively reduce TG levels, they do not consistently reduce LDL-C and TC levels. Conversely, existing HMG-CoA reductase inhibitors reduce LDL-C and TC levels but have limited TG-lowering effects. These two classes of agents have been used together with good results, but the safety of the combination has been a concern especially in relation to an increased risk of myositis and renal failure.10 The advantage of a single drug that is capable of safely lowering both cholesterol and TG effectively is evident.
Atorvastatin is a new HMG-CoA reductase inhibitor, which, in addition to being able to lower LDL-C levels by 40% to 60%, has greater TG-lowering effects than other currently available HMG-CoA reductase inhibitors.11 This TG lowering property of atorvastatin has been demonstrated in individuals with primary hypercholesterolemia, diabetes mellitus, and in those with primary hypertriglyceridemia.12–15 In this report, we present for the first time data on the effects of atorvastatin on lipid and lipoprotein parameters in CHL. The data include parameters that reflect all classes of lipoproteins. In addition, this is the first report of a direct comparison of the effects of atorvastatin with those of a fibrate, fenofibrate.
Apolipoprotein (apo) B, the major apolipoprotein in LDL and TG-rich VLDL and VLDL remnants, appears to be a more accurate clinical measure of atherogenic risk than either of these lipoproteins alone.16–20 Given this evidence, the effect of therapy on apoB levels as well as LDL cholesterol were of primary interest.
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Methods |
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Patients
Outpatients entered a 6-week dietary placebo-baseline phase at seven centers in Canada. Identical protocols were submitted to and approved by an institutional review board at each center, and written informed consent was obtained from each patient prior to their participation in the study. Eligible patients were 18 to 80 years old with a body mass index
32 kg/m2. Patients were
ineligible if they were pregnant or nursing, had active liver disease
or hepatic dysfunction; nephrotic syndrome or renal insufficiency;
uncontrolled hypertension, uncontrolled hypothyroidism, or uncontrolled
diabetes (defined by glycosylated hemoglobin >13%); were consuming
more than 10 alcoholic drinks per week, or had a history of drug abuse.
Patients with known CAD or peripheral vascular disease were
not excluded from the study; however, patients must not have had a
major cardiovascular insult resulting in
hospitalization during the 3 months preceding study entry. A total of
10 entered patients had a history of CAD; five randomized to
atorvastatin and five randomized to fenofibrate. Additional CAD risk
factor information was not collected. Patients were screened for Type
III dyslipidemia. The one patient found to have E2/E2
phenotype was excluded from the study. Patients with TC
>5.2 mmol/L (200 mg/dL) and <9.0
mmol/L (350 mg/dL), TG >2.3 mmol/L (200
mg/dL), and apoB levels >1.10g/L during the dietary
stabilization phase were entered into the treatment phase. Patients who
met the lipid entry criteria for the study were stratified into two
groups based on their baseline LDL-C levels. Patients with a mean LDL-C
3.49 mmol/L (135 mg/dL) and TG 2.3
mmol/L (200 mg/dL) were considered to have CHL. All other
patients were considered to have isolated
hypertriglyceridemia. Eighty-five percent
(84/99) of the patients had CHL by these criteria. Safety information
and efficacy results reported here represent data from only
those patients with CHL, because atorvastatin's effect in patients
with isolated hypertriglyceridemia has been
previously described.15
Baseline Phase
The baseline phase was designed to ensure that patients were
following a standard lipid-regulating diet prior to treatment. On entry
into the baseline phase, patients were counseled to follow the National
Institutes of Health (NIH) National Cholesterol Education
Program (NCEP) Step 1 diet, which limits dietary
cholesterol to <300 mg/d, saturated fats to <10%
of total calories, and total fats to <30% of total calories.
Compliance with the NCEP Step 1 diet was assessed by a food record
rating (FRR) 2 weeks before treatment was scheduled to
begin.21 A consecutive 3-day dietary diary was used, which
included 1 weekend day and 2 weekdays from the week prior to the
dietary visit. The record was scored at the site by personnel
trained in dietary assessments with a score of 15 or less considered in
compliance.
Open-Label, Parallel-Arm Treatment Phase
All patients were randomized into one of two treatment groups:
atorvastatin, 10 mg QD, or fenofibrate, 100 mg TID, for the initial 12
weeks of the treatment phase (Period 1). During this period, patients,
investigators, and the sponsor were blinded to lipid values, although
they were not blinded to study medication. For the remaining 12 weeks
of the treatment phase (Period 2), patients who had received
atorvastatin, 10 mg, during Period 1 received 20 mg of atorvastatin,
while those patients initially receiving fenofibrate, 100 mg TID,
remained on this treatment through Period 2. During the course of the
study, patients were not allowed to concurrently take drugs known to
affect plasma lipid concentrations, or known to interact with study
medications (niacin, probucol, psyllium preparations, other fibric acid
derivatives, other HMG-CoA reductase inhibitors, fish oils,
immunosuppressive agents, steroids, isotretinoin,
cyclosporine, and erythromycin).
Laboratory Analyses
All lipid and apolipoprotein analyses were performed by
two central laboratories. The Core Laboratory for Clinical Studies of
the Lipid Research Center, Washington University, St. Louis, Mo,
performed analyses of TC, TG, VLDL-C, LDL-C, HDL-C, VLDL-TG,
LDL-TG, VLDL-apoB, LDL-apoB, apoA-I, and apoB. The Lipid and
Lipoprotein Laboratory, Oklahoma Medical Research Foundation, Oklahoma
City, OK, was responsible for measuring apoC-III and lipoprotein B
(Lp-B). Fasting (12-hour minimum) venous blood samples were drawn
between 6 and 18 hours after the previous dose of medicine. Alcohol
consumption was prohibited 72 hours prior to blood sampling. Lipid,
lipoprotein, and apolipoprotein evaluations were performed on screening
for study entry, 2 weeks and 1 week prior to randomization, at the time
of randomization, and at the end of treatment Periods 1 and 2. At the
screening visit, a lipid profile was performed.
Analyses of Lipids and Lipoprotein Cholesterol
Cholesterol and glycerol-blanked TG were measured
using commercial enzymatic kits (Bayer) on the Technicon AXON. TC, TG,
and HDL-C were determined in whole serum. LDL-C was calculated by the
Friedewald equation during the screening phase only.22 At
all visits where LDL-C was used in the efficacy analysis,
ß-quantification was performed on samples from all patients to
determine LDL-C according to a modification of the Lipids Research
Clinics method.23,24 Following removal of VLDL by
ultracentrifugation, the corresponding infranate was
treated by dextran sulfate (Mr
50 000)/Mg2+ in order to selectively remove the
apoB-containing LDL.25 TC and glycerol-blanked TG were
determined in the ultracentrifugal supernatants and infranates, whereas
HDL-C was measured in the infranate after precipitation of
apoB-containing lipoproteins as previously described.13
LDL-C and LDL-TG were calculated as infranatant lipids minus HDL
lipids. The levels of VLDL-C and VLDL-TG were determined as the
difference between these analytes in the whole serum and the
ultracentrifugal infranate. TC, TG, and HDL-C were standardized through
the Lipid Standardization Program of the Centers of Disease Control,
Atlanta, Ga.
Analyses of Apolipoproteins and Lipoprotein
Particles
Apolipoprotein B and apoA-I were measured in whole serum using
commercial immunochemical kits (Behringwerke) on the Behring
nephelometer. Apolipoprotein B, analyzed in the
ultracentrifugal infranate from ß-quantification, was termed
LDL-apoB; VLDL-apoB levels were determined as the difference between
apoB in the whole serum minus apoB in the ultracentrifugal infranate.
Apolipoprotein C-III was quantified by
electroimmunoassay.26 The quantitative determination of
cholesterol-rich Lp-B was performed by immunoaffinity
chromatography of whole plasma on an anti-apoC-III
immunosorber according to a previously described
procedure.27
Safety Evaluation
Prior to entering the baseline phase, patients received a
physical examination and clinical laboratory evaluation including
urinalysis. During active treatment 2, 6, 12, and 24 weeks after
therapy was initiated, full chemistry/hematology evaluations were
conducted. Patients whose alanine aminotransferase or aspartate
aminotransferase levels were consistently greater than three
times the upper limit of normal or with creatine phosphokinase levels
greater than 10 times the upper limit of normal were required to
discontinue study medication. At each visit, new or worsening adverse
events were noted.
Data Analysis
The sample size for this study was chosen to detect a 10%
difference between treatments in percent change from baseline in apoB
and LDL-C based on a two-sided t test at a 5% level of
significance. Analysis of covariance was performed to
compare the effects of atorvastatin and fenofibrate in terms of percent
change from baseline in all parameters measured. The
baseline was defined as the mean of the two measurements taken 2 weeks
prior to and at the time of randomization. The analysis of
covariance model included the effects of treatment, center, and
the baseline as a covariate. All testing was two-sided and conducted at
a 5% significance level. Version 6.08 of SAS was used for
analysis and summarization.
Data from CHL patients who were randomized to treatment and who had both a baseline measurement and at least one open-label measurement taken within 3 days of the last day of treatment were included in the analysis. For patients who did not have data collected at one of the weeks under evaluation (week 12 or 24), their last open-label observation was carried forward, although measurements from the first 12-week period were not carried forward to week 24.
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Results |
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Patient Characteristics and Disposition
Eighty-four patients with CHL were randomly assigned to treatment with either atorvastatin (41 patients) or fenofibrate (43 patients). Of these patients, 74 completed the 24-week study (39 and 35, respectively). Most of the patients were white (96%) and middle-aged (54±1.2 years); 66% were male and 34% were female. For all patients, both lipid and nonlipid parameters were well balanced between the atorvastatin and fenofibrate treatment groups (Table 1
), although patients in the atorvastatin
group had higher mean values for TG and VLDL-TG (4.34 and 3.52
mmol/L, respectively) than patients in the fenofibrate group
(3.82 and 3.03 mmol/L, respectively).
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Dietary Analysis
Mean FRR scores prior to randomization for both treatment groups
were comparable. From pretreatment to the end of the study, mean FRR
scores for both treatment groups showed a trend toward increasing
values over time, indicating that patients may have become lax or
inconsistent with following the standard lipid-lowering diet,
despite continued dietary counseling. In the fenofibrate group, 31% of
patients had FRR scores >15 during the treatment period compared with
36% in the atorvastatin group. Mean FRR scores for both treatment
groups remained comparable throughout the study.
Efficacy Analysis
All of the changes for atorvastatin and fenofibrate in Period 1
were significantly different from baseline (P<.05).
However, the adjusted mean decreases of LDL-C, apoB, and TC from
baseline values were significantly greater in the atorvastatin group
(30%, 28%, and 27%) than in the fenofibrate group (7%, 18%, and
16%; Table 2). Additionally, subjects in
the atorvastatin group had significantly greater mean decreases of
LDL-TG, LDL-apoB, and cholesterol-rich Lp-B particles than
subjects in the fenofibrate group.
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The concentrations of TG, VLDL-C, VLDL-TG, VLDL-apoB, and apoC-III were decreased more significantly with fenofibrate (47%, 56%, 57%, 39%, and 35%) compared with atorvastatin 10 mg (25%, 35%, 27%, 19%, and 19%) in Period 1. Fenofibrate also had a better effect on HDL-C and apoA-I, increasing these levels to a significantly greater extent than atorvastatin (24% and 11% versus 11% and 6%). Differences in the nonHDL-C/HDL-C ratio and the apoB/HDL-C ratio were not significant between the treatment groups in Period 1.
All of the changes for atorvastatin and fenofibrate in Period 2 were
significantly different from baseline. The reductions in LDL-C, apoB,
TC, LDL-apoB, and Lp-B in the atorvastatin group remained significantly
greater than in the fenofibrate group (Table 3). With the increase in atorvastatin
dose to 20 mg QD, the LDL-C and TC reduction improved by 8% and 6%
respectively. The reductions in TG, VLDL-apoB, VLDC-C, and apoC-III
were not statistically different between treatment groups; however,
fenofibrate was still more effective than atorvastatin, 20 mg, in
decreasing VLDL-TG and increasing HDL-C and apoA-I. During this
treatment period, the non-HDL-C/HDL-C ratio and the apoB/HDL-C ratio
were now significantly lower in atorvastatin-treated patients than the
corresponding ratios in the fenofibrate treatment group (44% versus
33%; P<.05). Individual patient responses have been
plotted over time for LDL-C, TG, and apoB (Fig 1).
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Safety
An adverse event was defined as any noxious or unintended
change in the patient's profile involving function, structure, or
chemistry that occurred during the study, including any intercurrent
illness, toxicity, sensitivity, or sudden death. Based on the
investigators' assessment of drug attributability, the incidence of
adverse events considered associated with treatment was 12 (29%) in
the atorvastatin group compared to 18 (42%) in the fenofibrate group.
A greater percentage of patients were withdrawn due to adverse events
(either associated or not associated) in the fenofibrate group, 6
(14%), than in the atorvastatin group, 1 (2%). Atorvastatin treatment
was more often associated with headache, whereas fenofibrate treatment
was more often associated with dyspepsia, flatulence, myalgia, and
rash. No atorvastatin-treated patient experienced a clinically
important laboratory abnormality. No atorvastatin-treated patients and
two fenofibrate-treated patients were withdrawn due to increased liver
transaminase levels.
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Discussion |
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HMG-CoA reductase inhibitors such as lovastatin, pravastatin, simvastatin, and fluvastatin are the drugs of choice for lowering plasma cholesterol and cholesterol-rich lipoproteins.27–34 However, these drugs have a rather limited capacity for lowering TG-rich lipoproteins and only a moderate potential for increasing high-density lipoproteins.27,29–34 It has recently been shown that atorvastatin, a newly developed HMG-CoA reductase inhibitor, reduces plasma cholesterol up to 45% and LDL-C up to 60% in a dose-dependent manner when administered to subjects with primary hypercholesterolemia.12 In the same study, TG levels were decreased from baseline by 9% to 32% with no apparent dose trend. However, in a study evaluating patients with high TG levels a dose trend was evident with TG reductions of 27%, 32%, and 43% at 5, 20, and 80 mg, respectively.15
Fibrates including gemfibrozil, bezafibrate, and fenofibrate markedly reduce the levels of TG and TG-rich lipoproteins, but have a limited capacity for lowering cholesterol-rich lipoproteins.35–39 Because of these differential effects of HMG-CoA reductase inhibitors and fibrates on the concentrations of cholesterol-rich and TG-rich lipoproteins and because of the already documented substantial TG-lowering effect of atorvastatin, it was of considerable interest and importance to further test this newly developed HMG-CoA reductase inhibitor for its potential to uniquely decrease both cholesterol-rich and TG-rich lipoproteins. This testing was performed in subjects with CHL in a direct comparison with fenofibrate as a fibrate of choice.
Results of the present study have confirmed the characteristic "statin-like" capacity of atorvastatin to lower the concentrations of cholesterol-rich lipoprotein constituents (TC, LDL-C, LDL-TG, apoB, and LDL-apoB) in subjects with CHL to a similar extent as in subjects with primary hypercholesterolemia.12 Fenofibrate treatment also resulted in a significant reduction of these constituents; however, the percent decrease in all these variables was significantly greater with atorvastatin than fenofibrate. In contrast, subjects treated with fenofibrate had greater decreases in constituents of TG-rich lipoproteins (TG, VLDL-C, VLDL-TG, and VLDL-apoB) than subjects treated with atorvastatin at 10 mg QD. However, atorvastatin administered at a larger dose (20 mg/d during Period 2) resulted in further reductions in TG, VLDL-C, and VLDL-apoB, which were now not significantly different from reductions resulting from fenofibrate treatment (300 mg/d). Only the reduction in VLDL-TG remained significantly lower in the fenofibrate group. This trend was clearly reflected in the reducing effect on apoC-III, which was significantly higher in fenofibrate- than atorvastatin-treated subjects during Period 1; during Period 2, this advantage disappeared, resulting in very similar values for apoC-III reductions between these two treatment groups.
In the present study, the differences in the lipoprotein response to atorvastatin and fenofibrate were also monitored and determined by measuring cholesterol-rich Lp-B. Although the Lp-B particles occur mainly within the LDL density range, this apoB-containing lipoprotein family may be found to varying degrees throughout the entire low density spectrum (d=0.94 to 1.063 g/mL).40,41 The results of this study demonstrate that atorvastatin, even when administered at a low dose, effectively reduces the potentially atherogenic Lp-B particles more effectively than does fenofibrate.
HDL-C and apoA-I levels have been inversely associated with risk for CAD.42 Fenofibrate had a more pronounced effect in raising the levels of HDL-C and apoA-I than atorvastatin does at either the 10- or 20-mg dose. Atorvastatin administration seemed to result in a statistically significant difference in Lp-A-I and Lp-A-I:A-II particles, but the qualitative and/or quantitative changes have not been adequately documented.15 The effect of both fenofibrate and atorvastatin on apoA-containing lipoproteins remains to be investigated in further studies.
In conclusion, even when administered at relatively low doses, atorvastatin effectively lowered constituents of cholesterol-rich lipoproteins particles. Furthermore, atorvastatin also reduced constituents of TG-rich lipoproteins to a similar extent as fenofibrate. By affecting significantly both the cholesterol-rich and TG-rich apoB-containing lipoprotein particles, atorvastatin holds promise as the first HMG-CoA reductase inhibitor to treat a broad range of patients that include both hypercholesterolemia and CHL. Additionally, the atorvastatin safety profile may increase patient compliance to long-term therapy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, Ann Arbor, Mich. The authors would like to thank David Blank, MD, and Mark Sherman, MD (Royal Victoria Hospital, Montreal, Quebec), Robert G. Josse, MD (St. Michael's Health Center, Toronto, Ontario), and Martine Montigny, MD (Clinical Research Institute of Montreal, Montreal, Quebec). The authors also would like to thank R. E. Laskey, PhD, for assistance in preparing this manuscript.
Received November 1, 1996; accepted January 3, 1997.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Consensus Conference. Lowering blood cholesterol to prevent heart disease. JAMA. 1985;253:2080–2086.
2.
Anderson KM, Castelli WP, Levy D.
Cholesterol and mortality: 30 years of follow-up from the
Framingham Study. JAMA. 1987;257:2176–2180.
3. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]
4.
Hokanson JE, Austin MA, Zambon A, Brunzell JD. Plasma
triglyceride and LDL heterogeneity in
familial combined hyperlipidemia. Arterioscler
Thromb. 1993;13:427–434.
5.
Austin MA. Plasma triglyceride and
coronary heart disease. Arterioscler Thromb. 1991;11:2–14.
6.
Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG,
Sacks FM, Hennekens CH. A prospective study of triglyceride
level, low-density lipoprotein particle diameter and risk of myocardial
infarction. JAMA. 1996;276:882–888.
7.
Williams RR, Hopkins PN, Hunt SC, Wu LL, Hasstedt SJ,
Lalouel JM, Ash KO, Stults BM, Kuida H. Population-based frequency of
dyslipidemia syndromes in coronary-prone families
in Utah. Arch Intern Med. 1990;150:582–588.
8. Guidelines of the European Atherosclerosis Society, A Desktop Guide to the Management of Risk Factors for Coronary Heart Disease, 1993.
9.
Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults. Summary of the Second
Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel II).
JAMA. 1993;269:3015–3023.
10. East C, Bilheimer DW, Grundy SM. Combination drug therapy for familial combined hyperlipidemia. Ann Intern Med. 1988;109:25–32.
11. Black D. Atorvastatin. A Step Ahead for HMG-CoA Reductase Inhibitors. In: Woodford FP, Davignon J, Sniderman A, eds. Atherosclerosis X. New York: Elsevier Science; 1995:307–310.
12.
Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL,
Schwartz SL, Lupien PJ, Jones PH, Haber HE, Black DM. Reduction of LDL
cholesterol by 25% to 60% in patients with primary
hypercholesterolemia by atorvastatin, a new
HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc
Biol. 1995;15:678–682.
13. Heinonen TM, Schrott H, McKenney JM, Sniderman AD, Broyles FE, Zavoral JH, Kivel F, Black DM. Atorvastatin, a new HMG-CoA reductase inhibitor as mono-therapy and combined with colestipol. J Cardiovasc Pharmacol Therapeut. 1996;1:117–122.
14. Best JD, Nicholson GC, O'Neal DN, Kotowicz M, Sanders K. Atorvastatin and simvastatin reduce elevated cholesterol in non-insulin dependent diabetes. Diab Nutr Metab. 1996;9:74–80.
15.
Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon
J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske
LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase
inhibitor, atorvastatin, in patients with
hypertriglyceridemia. JAMA. 1996;275:128–133.
16.
Durrington PN, Hunt L, Ishoha M, Kane J, Stephens WP.
Serum apolipoproteins AI & B and lipoproteins in middle-aged men with
and without previous myocardial infarction. Br Heart J. 1986;56:206–212.
17. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Després JP. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study. Circulation. 1996;94:237–278.
18.
Sniderman AD, Cianflone K. Measurement of apoproteins:
Time to improve the diagnosis and treatment of the atherogenic
dyslipoproteinemias [editorial; comment]. Clin Chem. 1996;42:489–491.
19. Wald NJ, Law M, Watt HC, Wu T, Bailey A, Johnson AM, Craig WY, Ledue TB, Haddow JE. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet. 1994;343:75–79.[Medline] [Order article via Infotrieve]
20. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, Zhao X-Q, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–1298.[Abstract]
21. Remmell PS, Gorder DD, Hall Y, Tillotson JL. Assessing dietary adherence in the Multiple Risk Factor Intervention Trial (MRFIT). I. Use of a dietary monitoring tool. J Am Diet Assoc. 1980;76:351–356.[Medline] [Order article via Infotrieve]
22. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
23. Cole TG, Ferguson CA, Gibson DW. High-throughput B-quantification methods. Atherosclerosis. 1994;108(suppl):S191.
24. Lipid Research Clinics Program. Manual of Laboratory Operations, Vol. 1. Lipid and Lipoprotein Analysis. DHEW Publication No. (NIH) 75–628 Washington, DC: U. S. Government Printing Office, 1974.
25. Warnick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+ Precipitation Procedure for Quantitation of High Density Lipoprotein Cholesterol. In: Cooper GR, ed. Selected Methods of Clinical Chemistry, Vol. 10. Washington, DC: American Association of Clinical Chemistry; 1983:91–99.
26. Curry MD, McConathy WJ, Fesmire JD, Alaupovic P. Quantitative determination of human apolipoprotein C-III by electroimmunoassay. Biochim Biophys Acta. 1980;617:505–513.
27.
Alaupovic P, Hodis HN, Knight-Gibson C, Mack WJ, LaBree
L, Cashin-Hemphill L, Corder CN, Kramsch DM, Blankenhorn DH. Effects of
lovastatin on apoA- and apoB-containing lipoproteins.
Families in a subpopulation of patients participating in the Monitored
Atherosclerosis Regression Study (MARS).
Arterioscler Thromb. 1994;14:1906–1914.
28. Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res. 1992;33:1569–1582.[Medline] [Order article via Infotrieve]
29.
Bradford RH, Shear CL, Chremos AN, Dujovne CA, Downton
M, Franklin FA, Gould AL, Hesney M, Higgins H, Hurley DP,
Langendorfer A, Nash DT, Pool JL, Schnaper H. Expanded Clinical
Evaluation of Lovastatin (EXCEL) study results. 1. Efficacy
in modifying plasma lipoproteins and adverse event profile in 8245
patients with moderate hypercholesterolemia.
Arch Intern Med. 1991;151:43–49.
30.
Rubenfire M, Maciejko JJ, Blevins RD, Orringer C,
Kobylak L, Rosman H, and the Southeastern Michigan Collaborative Group.
The effect of pravastatin on plasma lipoprotein and
apolipoprotein levels in primary
hypercholesterolemia. Arch Intern
Med. 1991;151:2234–2240.
31. Walker JF, Shapiro DR. Hydroxymethylglutaryl coenzyme-A reductase inhibitors as monotherapy in the treatment of hypercholesterolemia. Am J Cardiol. 1990;65:19F–22F.[Medline] [Order article via Infotrieve]
32.
Insull W Jr, Black D, Dujovne C, Hosking JD,
Hunninghake D, Keilson L, Knopp R, McKenney J, Stein E, Troendle AJ,
Wright T Jr. Efficacy and safety of once-daily vs twice-daily dosing
with fluvastatin, a synthetic reductase
inhibitor, in primary
hypercholesterolemia. Arch Intern
Med. 1994;154:2449–2455.
33.
Shepherd J. Statins. Is there a need for alternative or
adjunctive therapy? Br Heart J. 1995;74:13.
34. Davignon J, Montigny M, Dufour R. HMG-CoA reductase inhibitors: a look back and a look ahead. Can J Cardiol. 1992;8:843–864.[Medline] [Order article via Infotrieve]
35. Grundy SM, and Vega GL. Fibric acids: Effects on lipid and lipoprotein metabolism. Am J Med. 1987;83(suppl 5B):9–20.
36. Stohler R, Keller U, Riesen WF. Effects of simvastatin and fenofibrate on serum lipoproteins and apolipoproteins in primary hypercholesterolaemia [published erratum appears in Eur J Clin Pharmacol. 1989;37:623]. Eur J Clin Pharmacol. 1989;37:199–203.
37. Schulzeck P, Bojanovski M, Jochim A, Canzler H, Bojanovski D. Comparison between simvastatin and bezafibrate in effect on plasma lipoproteins and apolipoproteins in primary hypercholesterolaemia. Lancet. 1988;1:611–613.[Medline] [Order article via Infotrieve]
38. Tikkanen MJ, Bocanegra TS, Walker JF, Cook T. Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol—a multicenter study. Am J Med. 1989;87:47S–53S.
39. Betteridge DJ, Durrington PN, Fairhurst, Jackson G, McEwan MS, McInnes GT, Miller JP, Mir MA, Reckless JPD, Rees-Jones DI, Scarpello JHB, Bard JM, Fruchart JC, Jewitt-Harris J, Agnew AR, Peters TK, Pfister P. Comparison of lipid-lowering effects of low-dose fluvastatin and conventional-dose gemfibrozil in patients with primary hypercholesterolemia. Am J Med. 1994;96(suppl 6A):45S–54S.
40. Alaupovic P. The significance of apolipoproteins for structure, function and classification of plasma lipoproteins. Methods Enzymol. 1996; 32–60.
41. Alaupovic P, McConathy WJ, Fesmire J, Tavella M, Bard JM. Profiles of apolipoproteins and apolipoprotein B-containing lipoprotein particles in dyslipoproteinemias. Clin Chem. 1988;34:B13–B27.
42.
Gordon T, Kannel WB, Castelli WP, Dawber TR.
Lipoproteins, cardiovascular disease, and death. The
Framingham study. Arch Intern Med. 1981;141:1128–1131.
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