Effects of Simvastatin (40 and80 mg/day) in Patients With

Mixed HyperlipidemiaEvan Stein, MD, PhD, Diane Plotkin, PhD, Harold Bays, MD, Michael Davidson, MD,

Carlos Dujovne, MD, Stanley Korenman, MD, Michael Stepanavage, BS, andMichele Mercuri, MD, PhD

Mixed hyperlipidemia is characterized by both elevatedtotal cholesterol and triglycerides. It is estimated to ac-count for 10% to 20% of patients with dyslipidemia. Thisstudy assessed the lipid-altering efficacy and tolerabilityof simvastatin 40 and 80 mg/day as monotherapy. Onehundred thirty patients (62 women [48%], 24 [16%] withtype 2 diabetes mellitus, mean age 53 years) with mixedhyperlipidemia (baseline low-density lipoprotein [LDL]cholesterol 156 mg/dl [mean], and triglycerides 391mg/dl [median) were randomized in a multicenter, dou-ble-masked, placebo-controlled, 3-period, 22-week,balanced crossover study, and received placebo, andsimvastatin 40 and 80 mg/day each for 6 weeks. Com-pared with placebo, simvastatin produced significant (p<0.01) and dose-dependent changes in all lipid andlipoprotein parameters (LDL cholesterol 2.1%, 228.9%,and 235.5%; triglycerides 23.5%, 227.8%, and

233.0%; high-density lipoprotein cholesterol 3.3%,13.1%, and 15.7%; apolipoprotein B 3.8%, 223.1%,and 230.6%; and apolipoprotein A-I 4.0%, 8.2%, and10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in pa-tients with diabetes mellitus. One patient taking simva-statin 80 mg/day had an asymptomatic and reversibleincrease in hepatic transaminases 3 times above theupper limit of normal. Simvastatin 40 and 80 mg/day iseffective in patients with mixed hyperlipidemia acrossthe entire lipid and lipoprotein profile. The reductions inLDL cholesterol and triglycerides are large, significant,and dose dependent. The increase in high-density li-poprotein cholesterol was greater than that observed inpatients with hypercholesterolemia, and appears dosedependent. Q2000 by Excerpta Medica, Inc.

(Am J Cardiol 2000;86:406–411)

M ixed hyperlipidemia is characterized by bothelevated total cholesterol and triglycerides due

to the accumulation of low-density lipoprotein (LDL)and very low density lipoprotein (VLDL) lipoproteins.Mixed hyperlipidemia is traditionally referred to asFredrickson type IIb dyslipidemia,1 and represents aconstellation of metabolic disorders that produces asimilar lipoprotein profile with variable and differentexpressions of LDL cholesterol and triglyceride ele-vations. Mixed hyperlipidemia accounts for 10% to20% of patients with dyslipidemia,2 whereas familialcombined hyperlipidemia is among the most commonphenotypic disorders in humans (0.5% to 1%) and isfrequently observed in adult survivors of myocardialinfarction.3 The lipoprotein profile of mixed hyperlip-idemia is highly atherogenic, and mixed hyperlipid-emia is often found in patients with obesity, renaldisease, or type 2 diabetes.4,5 In most hyperlipidemicpatients, lifestyle changes, weight loss, and dietary

counseling improve the plasma levels of all lipopro-tein fractions, but are unsuccessful in optimizing ormaintaining desirable levels of cholesterol and triglyc-eride over time. In patients with primary elevations ofLDL cholesterol, hydroxymethylglutaryl coenzyme A(HMG-CoA) reductase inhibitors reduce triglyceridesby approximately 10% to 15%, and increase high-density lipoprotein (HDL) cholesterol by 5% to 7%.Most previous studies of mixed hyperlipidemia in-cluded subjects with relatively low triglycerides andhave also focused on comparing the efficacy of lowerdoses of HMG-CoA reductase inhibitors with fibricacid derivatives. Furthermore, these studies havelacked a placebo control group.6–9 The present studydetermines in a large, placebo-controlled randomizedtrial the efficacy of simvastatin, 40 and 80 mg/day, onthe lipid and lipoprotein profile of patients with onlymixed hyperlipidemia.

METHODSPatients: Institutional review board approvals were

obtained for all centers, and all patients signed awritten informed consent. Eligible patients (aged 21 to70 years) were men, postmenopausal women, andpremenopausal women highly unlikely to conceive.Patients taking a lipid-lowering diet but not lipid-lowering medication for at least 6 weeks (8 weeks forfibric acid derivatives) with LDL cholesterol levels$130 mg/dl (3.4 mmol/L), and triglyceride levelsbetween 300 and 700 mg/dl (3.9 and 7.9 mmol/L) on

From the Medical Research Laboratory, Highland Heights, Kentucky;Endocrinology and Metabolism, and Biostatistics, Merck ResearchLaboratories, Rahway, New Jersey; Louisville Metabolic & Atheroscle-rosis Research Center, Louisville, Kentucky; Chicago Center for Clini-cal Research, Chicago, Illinois; Kansas Foundation for Clinical Phar-macology-Radiant Research, Kansas City, Kansas; and University ofCalifornia at Los Angeles, Los Angeles, California. Manuscript re-ceived October 5, 1999; revised manuscript received and acceptedMarch 1, 2000.

Address for reprints: Diane Plotkin, PhD, Endocrinology and Me-tabolism, Merck Research Laboratories, 126 Lincoln Avenue, Rahway,New Jersey, 06065–0900.

406 ©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matterThe American Journal of Cardiology Vol. 86 August 15, 2000 PII S0002-9149(00)00955-3

repeat measurement were eligible for inclusion. Pa-tients were classified as having type 2 diabetes melli-tus if they either had a clinical diagnosis of type 2diabetes at study entry, or they had fasting serumglucose levels$126 mg/dl on at least 2 occasionsbefore randomization, and hemoglobin A1C levels,10%.10 Patients with types I or V hyperlipidemia orhomozygous familial hypercholesterolemia were ex-cluded. Patients with serum creatinine.1.8 mg/dl,and patients with type 2 diabetes.1.4 mg/dl, livertransaminases.15% above the upper limit of normal,active liver disease, or unexplained creatine kinase.50% over the upper limit of normal were also ex-cluded.

Study design: This was a multicenter, randomized,double-masked, placebo-controlled, 3-period, com-plete block, balanced, crossover study with a 4-weekdiet/placebo run-in period before randomization. Onehundred thirty eligible patients were randomized to 1of 6 unique treatment sequences (three 6-week treat-ment periods) of placebo and simvastatin 40 and 80mg/day (Zocor, Merck & Co., Inc., Whitehouse Sta-tion, New Jersey) given in different orders. Therewere no washout periods between treatment periods.

From week24 through study end, patients were in-structed to consume a lipid-lowering diet (caloriesderived from 50% carbohydrate, 20% protein, and30% fat; a polyunsaturated:saturated fatty acid ratio of1; and cholesterol content,300 mg/day), and to re-strain their alcohol consumption not to exceed 7drinks/week.

Study end points: The primary efficacy end pointwas the percent change in LDL cholesterol relative tobaseline. Secondary end points included percentchange in total cholesterol, VLDL cholesterol, HDLcholesterol, triglycerides, non-HDL cholesterol, apo-lipoprotein B, apolipoprotein A-I, LDL apolipoproteinB, LDL cholesterol/HDL cholesterol, total cholester-ol/HDL cholesterol, lipoprotein A-I only particles,lipoprotein A-I:A-II, and lipoprotein(a), all relative tobaseline values.

Safety and tolerability were evaluated by assessingclinical and laboratory adverse event reports and lab-oratory determinations. Alanine aminotransferase oraspartate aminotransferase elevations$3 times, orcreatine kinase$10 times the upper limit of normalwere considered clinically relevant, and persistent el-evations resulted in patient withdrawal from the study.

Laboratory assessment: All blood samples were ob-tained in the fasting state (10 to 12 hours), air-freighted overnight at 4°C, to the central laboratory(Medical Research Laboratories, Highland Heights,Kentucky) for analysis. Throughout the study, thelaboratory participated in and remained certified bythe National Heart, Lung, and Blood Institute, Centersfor Disease Control Part III program.11 All lipid, li-poprotein, and apolipoprotein fractions were analyzedon ethylenediaminetetraacetic acid–treated plasma aspreviously described.12,13LDL and VLDL cholesterollevels were determined by ultracentrifugation.14 LDLcholesterol was obtained by subtracting HDL choles-terol from the density$1.006 g/ml fraction choles-terol. VLDL cholesterol levels were obtained by sub-tracting the density.1.006 g/ml cholesterol from thetotal cholesterol. A single laboratory measurementwas obtained at the end of each 6-week treatmentperiod.

Statistical analyses: For efficacy end points, thepercent change from baseline was analyzed. Between-group comparisons were performed using a linearmodel analysis of variance, with factors for treatment,center, patient (center), and period. Carryover effectwas tested and removed from the analysis of variancemodel due to nonsignificance (p.0.050). Because ofthe relatively small number of patients with type 2diabetes and observed variability, robust nonparamet-ric summary statistics were used in the efficacy anal-yses. The study was designed based on a minimum of96 evaluable patients completing the study. This sam-ple size corresponded to a detectable difference be-tween treatments of 4.9% in LDL cholesterol percentchange from baseline (90% power,a 5 0.050, 2-sidedtest). All statistical tests were 2-tailed withI 5 0.05.The p values were rounded to 3 decimal places, withp #0.05 considered statistically significant.

TABLE I Patient Baseline Demographic and ClinicalCharacteristics

Patients (n 5 130)

Mean age (years 6 SD) 53 6 10.3#40 years 13 (10.0)$60 years 21 (16.2)

Men 68 (52.3)Women 62 (47.7)White 121 (93.1)Non-white 9 (6.9)Cardiovascular disease† 53 (40.8)Systemic hypertension 34 (26.2)Type 2 diabetes mellitus* 24 (18.5)

*Defined as history of type 2 diabetes mellitus or at least 2 fasting serumglucose values $126 mg/dl.

†Defined as a history of angina, myocardial infarction, coronary arterybypass graft, angioplasty.

TABLE II Baseline Lipid Parameters of Randomized Patients(mg/dl, except for ratios)

Lipid Parameters Mean Median SD

LDL cholesterol 156 149 32Total cholesterol 281 277 43VLDL cholesterol 86 77 42Non-HDL cholesterol 242 233 43Apolipoprotein B 169 167 30LDL apolipoprotein B 142 143 31Triglyceride 407 391 130HDL cholesterol 39 38 8.8Apolipoprotein A-I 143 138 27.0LDL cholesterol/HDL cholesterol* 4.2 4.0 1.1Total cholesterol/HDL cholesterol* 7.6 7.3 1.9Lipoprotein A-I 42 40 12Lipoprotein A-I:A-II 101 99 18Lipoprotein(a) 24 8.0 33

*n 5 130 patients.

PREVENTIVE CARDIOLOGY/SIMVASTATIN IN MIXED HYPERLIPIDEMIA 407

RESULTSPatients: The first patient entered the study in May

1997 and the last patient completed the study in March1998.

During the recruitment period, 226 potential sub-jects were screened and 130 patients (121 Cauca-sians), who met the eligibility requirements, wererandomized. Of these, 118 patients (91%) completedthe study, with 6 (4.6%), 3 (2.3%), and 3 (2.3%)patients in the placebo and simvastatin 40- and 80-mg/day groups, respectively, withdrawing from thestudy. Four subjects discontinued because of an ad-verse experience: 2 during period 1, one on simvasta-tin due to a rash and one on placebo with prostatecarcinoma; 1 during period 2 on placebo with anallergic reaction, and 1 during period 3 on placebowith back pain. Eight subjects withdrew consent for avariety of personal reasons: 7 during period 1, 3 onplacebo, 3 on simvastatin 80 mg, and 1 on simvastatin4 mg. The eighth patient was in period 2 on placebo.Baseline demographic characteristics for randomizedpatients are presented in Table I, and mean (or me-dian) baseline lipid values are presented in Table II.Twenty-four of the 130 patients had type 2 diabetes.Eight randomized patients were homozygous for theapolipoprotein E«2 allele (apoE2/2), a genotype con-

sistent with Fredrickson type III dys-lipidemia. All results are presentedas means (or medians) and SDs. The95% confidence intervals are shownwhere appropriate. All analyses usedthe intention-to-treat approach, i.e.,patients with a baseline measurementand at least 1 on-treatment measure-ment that was carried forward.

Changes in lipid and lipoproteinlevels: Tables III to V summarize thelipid and lipoprotein efficacy resultsobtained after 6 weeks of treatment.Mean changes from baseline forLDL cholesterol levels were 2%,229%, and236% for the placebo,and simvastatin 40- and 80-mg/daytreatments, respectively, and weresignificant (p,0.001) in the simva-statin subjects. Simvastatin treatmentreduced all apolipoprotein B–con-taining fractions, attaining reductionsin VLDL cholesterol of 44.6% (me-dian) and in non-HDL cholesterol of39.1% with the 80-mg dose. Triglyc-eride measurements, as expected,displayed considerable variability inpercent change from baseline for alltreatments, and thus a more robustrank analysis was used. The medianbaseline level for triglyceride-evalu-able patients was 389 mg/dl, withmedian percent changes from base-line of 23.5%, 227.8%, and233.0% observed for the placebo,and simvastatin 40-, and 80-mg/day

treatments. Significant pairwise differences were ob-served for each of the treatments (p,0.05). A signif-icant HDL cholesterol dose-response relation was ev-ident across the placebo to simvastatin 80-mg/daydoses, i.e., each of the pairwise comparisons of treat-ment means was significant (p,0.050). Mean HDLcholesterol baseline values were 39.0 mg/dl, and meanpercent changes in HDL cholesterol from baseline forplacebo, and simvastatin 40- and 80-mg/day treat-ments were 3.3%, 13.1%, and 15.7%, respectively.Apolipoprotein A–containing fractions showedchanges consistent with those observed for HDL cho-lesterol. Mean percent changes from baseline for apo-lipoprotein A-I were 4.0%, 8.2%, and 10.5% for theplacebo, and simvastatin 40- and 80-mg treatments,respectively. Similar changes were observed for li-poprotein A-I and A-I:A-II particles. Concordant withthe changes observed in the cholesterol fractions, pro-gressively increasing percent reductions across theplacebo to simvastatin 80-mg/day treatments were ob-served for LDL cholesterol/HDL cholesterol and totalcholesterol/HDL cholesterol (Table V). Again, pair-wise differences for each of the treatment comparisonswere significant (p,0.001), demonstrating a signifi-cant dose-response relation.

TABLE III Treatment Effects of Placebo and Simvastatin 40 and 80 mg/day onFasting Levels of Apolipoprotein B–Containing Fractions (all evaluable patients)

Baseline(SD)*

Week 6(SD)* % D† 95% CI‡

D vs 40 mg(p value)

D vs 80 mg(p value)

Non-HDL Cholesterol

Placebo 240 242.0 0.8 20.9, 3.0 ,0.001 ,0.00140 mg 241 163 231.6 233.6, 229.8 ,0.00180 mg 242 146 239.1 241.4, 237.7

Apolipoprotein B

Placebo 169 175 3.8 2.8, 6.4 ,0.001 ,0.00140 mg 169 130 223.1 224.3, 220.8 ,0.00180 mg 169 117 230.6 232.1, 228.6

LDL Cholesterol

Placebo 156 159 2.1 1.1, 5.9 ,0.001 ,0.00140 mg 156 111 228.9 230.3, 225.4 ,0.00180 mg 156 99 235.5 237.2, 232.5

LDL Apolipoprotein

Placebo 141 147 3.9 1.5, 9.0 ,0.001 ,0.00140 mg 142 112 221.1 223.6, 216.1 0.00280 mg 142 99 228.9 231.3, 223.9

VLDL Cholesterol

Placebo 77 73 23.5 29.1, 2.1 ,0.001 ,0.00140 mg 76 48 236.9 242.2, 231.7 ,0.00180 mg 77 44 244.6 249.5, 239.6

*Baseline values and percent change are median values for VLDL cholesterol, triglycerides, andlipoprotein(a), and mean values for the other parameters.

†Percent change from baseline.‡95% confidence interval (CI) for the mean or median as reported.

408 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 86 AUGUST 15, 2000

Patients with type 2 diabetes mellitus: A subgroup of24 patients with type 2 diabetes was analyzed sepa-rately and compared with patients without diabetes forthe key lipid parameters. Patients with type 2 diabeteshad a median age of 59 years, and 13 were men (54%)and 11 were women (46%). The treatment-by-sub-group effects (diabetes vs nondiabetes) were exam-ined for significance for each of the key lipid param-eters (Table VI), and none were significant (p.0.100)(i.e., the treatment effects were consistent betweendiabetic and nondiabetic patients).

Tolerability: The percentage of patients reportingclinical adverse events attributed by the investigatorsto drug treatment was comparable during the placebo(4 patients, 3.2%), 40-mg simvastatin (8 patients,6.5%), and 80-mg simvastatin (5 patients, 4.0%) treat-ment periods. During the study there were 4 seriousnonfatal, non-drug–related clinical adverse events (1[prostatic neoplasm] during placebo, 1 [chest pain] inthe simvastatin 40-mg/day group, and 2 [urolithiasis,right arm pain] in the simvastatin 80-mg/day treat-ment). No patient was withdrawn because of a drug-related adverse event in the placebo or simvastatin40-mg/day groups, and 1 patient was withdrawn dur-ing the 80-mg/day treatment because of a rash. Therewere no cases of myopathy, and the incidence ofmyalgia was 1%, 2%, and 1% for the placebo, andsimvastatin 40- and 80-mg/day treatments, respec-tively, with none considered drug related by the in-vestigators. After 6 weeks of treatment with simvasta-tin 80-mg/day, 1 patient experienced a transient ele-vation in both alanine aminotransferase (.4 times the

upper limit of normal) and aspartateaminotransferase (.3 times the up-per limit of normal).

DISCUSSIONThis study set out to determine if

monotherapy with simvastatin athigher doses of 40 and 80 mg/daywas effective in the treatment ofmixed hyperlipidemia. The hypothe-ses were tested by using a placebo-controlled, crossover study in whichall subjects received the 3 treatments.Mixed hyperlipidemia was carefullydefined as LDL cholesterol.130mg/dl and triglyceride levels be-tween 300 and 700 mg/dl. These cri-teria insured selection of patientswith a dyslipidemic syndrome char-acterized by elevated cholesterol(i.e., apolipoprotein B–containing li-poproteins, or LDL cholesterol andVLDL cholesterol), elevated triglyc-erides, and relatively low HDL cho-lesterol levels. The results clearlydemonstrate that the higher doses ofsimvastatin (40 and 80 mg/day)alone significantly altered the lipid(total cholesterol and triglyceride),lipoprotein (LDL, VLDL, HDL), and

apolipoprotein (apolipoprotein B and AI) profiles ofpatients with mixed hyperlipidemia.

Effects on LDL cholesterol and other apolipoproteinB–containing lipoproteins: Apolipoprotein B–contain-ing lipoproteins, and LDL cholesterol in particular, areestablished primary targets of cardiovascular preven-tion and remain the main therapeutic targets in pa-tients at risk for coronary heart disease.15 AlthoughHMG-CoA reductase inhibitors have been used inmillions of patients worldwide, and studied in thou-sands of hypercholesterolemic patients in controlledclinical studies, less is known about their effects inpatients with mixed hyperlipidemia. In this study,LDL cholesterol changes were large and dose depen-dent, with the expected 6% dose-dependent additionalefficacy achieved by doubling the dose.16 Similar toprevious observations with atorvastatin in patientswith elevated triglyceride,17,18LDL cholesterol reduc-tions with simvastatin in patients with mixed hyper-lipidemia were less than those seen in patients withhypercholesterolemia and relatively normal triglycer-ides in whom simvastatin 40 and 80 mg/day reducedLDL cholesterol by 40% and 47%, respectively.19

This reduced LDL cholesterol response in subjectswith mixed hyperlipidemia, in whom circulating lev-els of VLDL, LDL, and often intermediate-densitylipoprotein or remnants are increased, is consistentwith increased competition for the LDL receptor bythe more triglyceride-rich apolipoprotein B–contain-ing lipoproteins, especially those enriched in apoli-poprotein E. In patients with mixed hyperlipidemia,particularly those with the familial form, type 2 dia-

TABLE IV Treatment Effects of Placebo and Simvastatin 40 and 80 mg/day onFasting Levels of Apolipoprotein A–Containing Fractions

Baseline(SD)*

Week 6(SD)* % D† 95% CI‡

D vs 40 mg(p value)

D vs 80 mg(p value)

HDL Cholesterol

Placebo 39 40 3.3 2.5, 6.2 ,0.001 ,0.00140 mg 39 44 13.1 12.3, 16.0 0.03380 mg 39 45 15.7 15.0, 18.7

Apolipoprotein A-I

Placebo 144 149 4.0 2.7, 5.8 ,0.001 ,0.00140 mg 144 154 8.2 6.9, 10.0 0.03080 mg 144 158 10.5 9.2, 12.2

Lipoprotein A-I

Placebo 42.4 43.1 2.9 0.4, 5.7 0.004 ,0.00140 mg 42.5 45.2 8.3 5.6, 10.9 0.05780 mg 42.5 46.8 11.8 9.0, 14.3

Lipoprotein A-I:A-II

Placebo 100 105 5.0 3.2, 7.2 ,0.001 ,0.00140 mg 101 109 9.1 7.7, 11.6 0.24280 mg 101 111 10.7 9.2, 13.1

*Baseline values and percent change are median values for VLDL cholesterol, triglycerides, andlipoprotein(a), and mean values for the other parameters.

†Percent change from baseline.‡95% confidence interval (CI) for the mean or median as reported.

PREVENTIVE CARDIOLOGY/SIMVASTATIN IN MIXED HYPERLIPIDEMIA 409

betes or dysbetalipoproteinemia, increased levels oftriglyceride-rich lipoprotein combined with elevatedLDL is believed to be more atherogenic than in sub-jects with isolated LDL elevation. In these conditions,the particles are smaller and more cholesterol-en-riched than in patients with isolated hypertriglyceri-demia.4 In the present study, VLDL cholesterol levelswere substantially reduced by 36.9% and 44.6% withsimvastatin 40 and 80 mg/day, respectively. Similarreductions were observed for non-HDL cholesterol.Non-HDL cholesterol has been proposed as a morereliable parameter to assess coronary heart disease riskand treatment efficacy, especially in mixed hyperlip-idemia because it includes all of the apolipoproteinB–containing or atherogenic lipoproteins.20 Reduc-tions in the ratio between total apolipoprotein B andnon-HDL cholesterol were also comparable, indicat-ing that changes were achieved mainly through areduction in the number of particles, and not througha redistribution of cholesterol between differentatherogenic lipoprotein classes.

Effects on HDL cholesterol: Of particular clinical in-terest was the observation of large and dose-relatedincreases in HDL cholesterol with simvastatin therapy(3.3%, 13.1%, and 15.7% for placebo, and simvastatin40 and 80 mg, respectively). This is in contrast to

observations in patients with primaryhypercholesterolemia, for whom re-ported increases in HDL cholesterolare typically more modest in the 4%to 6% range.19,21The large increasesin HDL in patients with mixed hy-perlipidemia were supported by as-sociated increases in total apoli-poprotein A-I (8.2% and 10.5% on40 and 80 mg/day, respectively, vs4.0% on placebo). These increases inapolipoprotein A-I were concomitantwith marked reductions in triglycer-ide-rich lipoproteins, also known tocontain increased concentrations ofapolipoprotein A-I. These observa-tions indicate that the increases inapolipoprotein A-I concentration re-flected increases in the number ofHDL cholesterol particles rather thanan enrichment in the cholesterol con-tents of HDL. This finding was sub-stantiated by a high, statistically sig-nificant increase (p,0.005) in li-poprotein A-I during treatment withsimvastatin.

Effects on triglycerides: Althoughan independent role for triglyceridesin promoting risk for coronary heartdisease is still controversial, manyepidemiologists regard triglycerideelevations as an important medicalproblem,22 and physicians regard itas a challenging therapeutic di-lemma, especially in patients withmixed hyperlipidemia. This study

demonstrated significant, large, and dose-dependentmedian reductions in triglyceride levels of 27.8% and33% from baseline after 6 weeks of treatment withsimvastatin 40 and 80 mg/day, respectively. The bal-anced crossover design and inclusion of a placebotreatment period increases the strength of these resultsbecause each subject serves as their own control in theassessment of triglyceride dose dependence. Addition-ally, determination of any triglyceride regression tothe mean effect was assessed by the placebo treatmentresponse. These data are consistent with findings byBruckert et al,6 who analyzed the comparative efficacyof simvastatin (mean dose about 30 mg/day) and sev-eral fibric acid derivatives and suggested that simva-statin produced a larger percent reduction in triglyc-erides when baseline levels were high. In a pooledanalysis of nearly 2,700 patients who participated instudies with a number of different HMG-CoA reduc-tase inhibitors, Stein et al23 reported a large and dose-dependent effect of HMG-CoA reductase inhibitors inpatients with mixed hyperlipidemia. Stein et al alsodescribed a consistent 1:1 ratio for triglyceride andLDL cholesterol reductions in subjects with mixedhyperlipidemia, a finding confirmed in this prospec-tive study. The present study, in which the mediantriglyceride level of all patients randomized at base-

TABLE V Treatment Effects of Placebo and Simvastatin 40 and 80 mg/day onFasting Levels of Other Lipid End Points

Baseline(SD)*

Week 6(SD)* % D† 95% CI‡

D vs 40 mg(p value)

D vs 80 mg(p value)

Triglycerides

Placebo 389 376 23.5 29.4, 2.4 ,0.001 ,0.00140 mg 389 278 227.8 232.2, 223.3 0.00780 mg 391 263 233.0 237.6, 228.4

Total Cholesterol

Placebo 279 282 1.3 0.0, 3.2 ,0.001 ,0.00140 mg 279 207 225.3 226.9, 223.6 ,0.00180 mg 280 191 231.4 233.2, 230.0

LDL/HDL Cholesterol

Placebo 4.1 4.1 20.8 22.4, 2.2 ,0.001 ,0.00140 mg 4.2 2.7 236.5 238.5, 233.9 ,0.00180 mg 4.2 2.3 243.7 246.1, 241.5

Total/HDL Cholesterol

Placebo 7.5 7.5 21.2 23.6, 0.5 ,0.001 ,0.00140 mg 7.5 5.0 233.3 236.0, 231.9 ,0.00180 mg 7.6 4.5 240.0 243.0, 238.9

Lipoprotein(a)

Placebo 8.0 9.0 1.0 0.2, 1.8 0.319 0.14040 mg 8.0 8.0 1.0 0.3, 1.7 0.62980 mg 8.0 8.0 1.0 0.2, 1.8

*Baseline values and % change are median values for VLDL cholesterol, triglycerides, and lipopro-tein(a), and mean values for the other parameters.

†Percent change from baseline.‡95% confidence interval (CI) for the mean or median as reported.

410 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 86 AUGUST 15, 2000

line was 389 mg/dl, confirms and extends the efficacyof simvastatin up to a dose of 80 mg/day in patientswith mixed hyperlipidemia. This study also confirmsand extends data reported by Stein et al7 in whichsimvastatin 10 mg/day reduced triglycerides 20% in aprospective and randomized but open-label study of56 patients with more modest mixed hyperlipidemia(median triglyceride 231 mg/dl). Thus, simvastatin 40and 80 mg/day produces large and significant dose-dependent reductions in apolipoprotein B–containinglipoproteins and significant increases in in apolipopro-tein AI–containing lipoproteins.

Acknowledgment: We express sincere gratitude tothe patients who volunteered to participate in thestudy, the clinic study coordinators (Leah Adams,Brian Gebhart, Glenn Lamkin, Leslie Votaw, SherrieViosca, Nancy Burgin, Erving London, Kevin Curtis,Ann Berenbaum), the Merck Medical Research Asso-ciates (Glorilyn Nelson-Plaza, Theresa Sheehan, EricOlson, Dennis Watkins, Emma Gonzalez, Allan Rees,Jacqueline Smith, Maureen MacDonald, and Van J.Medina), and Medical Program Coordinators (PatriciaBetz-Schiff, Hae Sook Lee, Laura O’Grady). Specialthanks go to Drs. Jonathan Isaacsohn (Metabolic andAtherosclerosis Center, Cincinnati, Ohio), DonaldHunninghake (University of Minnesota, Minneapolis,Minnesota), David Robertson (Emory University, At-lanta, GA), Leonard Keilson (Center for Lipids andCardiovascular Health, Portland, Maine), and StuartWeiss (Endocrine and Metabolic Clinic, San Diego,California) for participating in the study and providingtheir professional assistance.

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TABLE VI Treatment Effects of Placebo and Simvastatin 40 and 80 mg/day on Testing Levels of Lipids and Lipoproteins in PatientsWith and Without Type 2 Diabetes*

Group Treatment LDL-C† VLDL-C† TG† Non-HDL-C† HDL-C†

Type 2 Diabetes Placebo 5.0 (13.3) 21.1 (39.4) 21.6 (38.3) 2.6 (11.9) 1.1 (9.2)S 40 mg 228.7 (23.7) 240.2 (34.2) 227.5 (27.6) 233.4 (16.0) 9.0 (15.0)S 80 mg 239.5 (8.9) 249.2 (46.2) 233.0 (46.6) 242.7 (17.8) 13.0 (13.3)

No Diabetes Placebo 0.9 (16.9) 5.1 (31.0) 24.0 (32.9) .8 (14.7) 3.2 (12.8)S 40 mg 231.1 (19.3) 234.4 (30.5) 228.3 (24.7) 232.8 (17.3) 12.3 (15.8)S 80 mg 235.8 (17.8) 243.1 (25.7) 233.4 (23.6) 238.0 (13.8) 15.7 (17.6)

*Values are expressed as median (SD) percent change from baseline at week 6.†Treatment by subgroup (diabetic vs nondiabetic) interaction for each of the treatments was not significant (p .0.100 for all lipid parameters).Pairwise comparisons for each of the treatments were significant, p ,0.050.C 5 cholesterol; S 5 simvastatin; TG 5 triglycerides.

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