Cerivastatin in Primary Hyperlipidemia:A Multicenter Analysis of Efficacy and

SafetyEvan Stein, MD, PhD

Cerivastatin, a novel, synthetic, and enantiomericallypure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been administered, in clin-ical trials, to >2,700 patients with primary hypercho-lesterolemia, of whom >1,000 received treatment forperiods of up to 1 year. A global, pooled analysis of theefficacy, safety, and tolerability of cerivastatin was per-formed on data obtained from all randomized, double-blind studies in which cerivastatin at doses of 0.025–0.4mg/day was compared with either placebo or activecomparator. All studies had a 10-week, diet-controlledrun-in period, the last 6 weeks of which included ad-ministration of single-blind placebo. Efficacy analysis ofthe pooled data at 8 weeks postrandomization showedthat in comparison with placebo, cerivastatin achievedsignificant dose-dependent reductions in low-density li-poprotein (LDL) cholesterol, the primary efficacy param-eter, of 14.2–36.1%. Reductions in LDL cholesterol wereaccompanied by significant reductions in total choles-terol and triglycerides, together with increases in high-density lipoprotein (HDL) cholesterol. The magnitude ofthe reduction in plasma triglycerides was strongly re-lated to baseline triglyceride levels. In patients with

baseline plasma triglycerides of >250 mg/dL, treatmentwith 0.4 mg/day cerivastatin decreased these levels by37%. Cerivastatin was well tolerated, with the type andincidence of clinical adverse effects comparable to thatof placebo and comparator drugs. The incidence of bio-chemical adverse effects was also similar to that seenwith either placebo or comparator drugs and was inde-pendent of the dose of cerivastatin. Less than 1% ofpatients treated with cerivastatin at doses of 0.025–0.4mg/day experienced clinically significant increases ineither hepatic transaminases (>33 the upper limit ofnormal) or creatine phosphokinase (>53 the upper limitof normal). The good tolerability of cerivastatin wasreflected in a low rate of premature withdrawal fromtreatment, below or comparable to that of placebo-treatment. The pooled efficacy and safety analyses haveshown that at doses equal to 1–3% of the doses of otherstatins, cerivastatin is a safe, well-tolerated, and highlyeffective HMG-CoA reductase inhibitor for the treatmentof type IIa (triglycerides <250 mg/dL) and IIb (triglyc-erides >250 mg/dL) hypercholesterolemia. Q1998 byExcerpta Medica, Inc.

Am J Cardiol 1998;82:40J–46J

In patients with primary hypercholesterolemia, de-creasing elevated levels of plasma low-density li-

poprotein (LDL) cholesterol is the primary target ofcholesterol-lowering therapy. Currently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductaseinhibitors (“statins”) are considered the drugs of firstchoice for the treatment of hypercholesterolemia inpatients who have failed to respond adequately todietary therapy. These drugs stimulate the clearance ofLDL cholesterol from the plasma via LDL receptors.By competitively and reversibly inhibiting HMG-CoAreductase, they decrease cholesterol synthesis, whichin turn leads to a compensatory increase in LDLcholesterol receptor activity and enhanced clearanceof plasma LDL cholesterol by the liver.1

Cerivastatin, a new, synthetic, potent, and enantio-metrically pure HMG-CoA reductase inhibitor, de-creases plasma LDL cholesterol at ultra-low doses. Itscapacity to decrease LDL cholesterol is derived fromits very high affinity for HMG-CoA reductase.2 Cer-ivastatin also possesses a high affinity for liver tissue,the target organ for drug action. As a consequence,there is little systemic exposure to either cerivastatin

or its active metabolites. Preclinical toxicology studieshave shown excellent tolerability of cerivastatin atdoses well in excess of those intended for clinicaluse.3

Among the statins, cerivastatin is notable for itsuncomplicated pharmacokinetic profile,4,5 its low po-tential for interaction with other drugs,6–10 and itssuitability for use in both young and elderly sub-jects,11 as well as those with impaired renal function.12

To date, cerivastatin has been studied in.2,700patients with primary hypercholesterolemia, and theresults have been compared with studies involving641 patients on placebo, simvastatin, lovastatin, prav-astatin, and/or gemfibrozil. The effects of cerivastatinhave also been studied in patients with mixed hyper-lipidemia and with familial hypercholesterolemia.Data from all the randomized, double-blind studieswith a placebo and/or comparator arm were includedin a global, pooled analysis of efficacy and safety, theresults of which provide the focus for this review.

OVERVIEW OF CLINICAL EFFICACYBackground: The pooled efficacy analysis included

patients who received at least 8 weeks of active ther-apy in Phase IIa studies as well as those from all thepivotal Phase IIb and III clinical trials. In all thesestudies cerivastatin was compared with placebo and/orcomparator hypolipidemic agents under randomized,

From the Medical Research Laboratories, Highland Heights, Kentucky.Address for reprints: Evan Stein, MD, PhD, Medical Research

Laboratories, 2 Tesseneer Drive, Highland Heights, Kentucky 41076,USA.

40J ©1998 by Excerpta Medica, Inc. 0002-9149/98/$19.00All rights reserved. PII S0002-9149(98)00436-6

double-blind conditions. All studies incorporated anidentical design with a 10-week diet-controlled run-inperiod, the last 6 weeks of which included adminis-tration of single-blind placebo. Eligible patients werethen randomized to once-daily cerivastatin at doses ofeither 0.025, 0.05, 0.1, 0.2, 0.3, or 0.4 mg, placebo, orthe comparator drug. Efficacy analyses for the pooleddata were performed 8 weeks postrandomization. Thisendpoint was chosen as the basis for evaluation be-cause the hypolipidemic effects of statins are fullyestablished by 8 weeks; patient compliance with drugtherapy is usually optimal over this period, and allstudies could meet this time-point for lipid measure-ments.

Demographics: The study population consisted of3,113 male and female patients with primary hyper-cholesterolemia, of whom 2,593 received cerivastatinand 520 placebo. Demographic characteristics of thestudy population, 60% of whom were male, are shownin Table I, together with baseline lipid levels whichwere broadly comparable in all patients.

Primary efficacy parameter, LDL cholesterol: Thepooled efficacy analyses showed that at doses of0.025–0.2 mg/day (Table II), cerivastatin producedsignificant dose-dependent reductions in LDL choles-terol of 14.2–28.2%, which increased to 31.3% and36.1% with doses of 0.3 and 0.4 mg/day, respectively(Figure 1).

Secondary efficacy parameters: Secondary efficacyparameters were changes from baseline in total cho-lesterol, triglycerides, and high-density lipoprotein(HDL) cholesterol. Cerivastatin produced significantdose-dependent reductions in total cholesterol of up to

26.8% (Figure 2), and reductions in plasma triglycer-ide levels of up to 36% with administration of 0.4mg/day. The reduction in triglycerides was dependenton baseline triglycerides and greatest in patients withthe highest triglyceride levels at baseline. In patientswith baseline triglycerides.250 mg/dL, cerivastatinat a dose of 0.4 mg decreased plasma triglycerides by36% compared with reductions of 10% in those withbaseline levels of,150 mg/dL (Figure 3). Like mostother statins, cerivastatin produced modest increasesin HDL cholesterol of 4–8% which were unrelated tothe dose of drug administered (Figure 4).

Subgroup evaluation: The size of the pooled popu-lation was sufficiently large to enable the efficacy ofcerivastatin to be analyzed in various subgroups.Thus, the effects of cerivastatin at doses in the range0.025–0.4 mg/day were compared in males and fe-males; young (,40 years), middle-aged (40–65years), and elderly patients (.65 years); in smokersand nonsmokers; in relation to alcohol consumption,concomitant medications, and concomitant risk fac-tors for coronary artery disease; as well as in patientswith different types of lipid abnormalities (type IIa vstype IIb hypercholesterolemia; type II is defined aselevated LDL cholesterol [.160 mg/dL], with IIa hav-ing triglycerides,250 mg/dL and IIb.250 mg/dL).

Subgroup analyses of the pooled efficacy datashowed that of the various parameters assessed, themost marked differences in response to cerivastatinoccurred in females and older patients (Table II). Thegreater response to cerivastatin, measured in terms ofreductions in LDL cholesterol, may however havebeen due to differences in body mass between males

TABLE II Mean Percent Change in Low Density Lipoprotein Cholesterol at Week 8 for Selected Patient Subgroups (EfficacyPopulation)

Cerivastatin

Placebo0.025 mg 0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 mg

All 214.2 215.8 222.4 228.2 231.3 236.1 0.3Male 212.6 214.7 221.3 226.8 229.4 234.6 0.4Female 216.3 217.4 224.2 230.0 234.2 237.6 0.1#40 years 27.9 213.2 220.8 226.8 226.1 232.8 21.4.40 years ,65 years 214.0 215.8 221.6 227.8 231.3 235.8 0.4$65 years 217.8 217.9 225.5 230.1 233.4 238.0 0.7Type IIa lipid abnormality 214.1 215.8 223.8 229.4 232.9 236.4 0.1Type IIb lipid abnormality 214.8 215.7 220.0 226.3 228.7 234.2 0.7

TABLE I Baseline Demographics and Lipid Parameters (Patients Valid for Efficacy)

Cerivastatin

Placebo(n 5 520)

0.025 mg(n 5 218)

0.05 mg(n 5 590)

0.1 mg(n 5 487)

0.2 mg(n 5 758)

0.3 mg(n 5 408)

0.4 mg(n 5 132)

Male (%) 57.0 62.0 62.0 58.0 61.0 54.0 57.0Mean age (yr) 54.0 53.0 54.3 53.6 55.5 55.8 54.4Mean weight (kg) 75.0 76.8 77.3 77.9 79.3 77.6 76.2LDL-C (mg/dL) 217.2 216.8 208.0 203.5 206.7 215.4 211.6Total-C (mg/dL) 297.5 298.8 294.1 288.4 295.2 298.4 296.0HDL-C (mg/dL) 52.3 49.5 48.3 49.2 49.9 54.2 51.2Trig (mg/dL) 140.2 162.9 189.2 181.7 198.3 144.8 167.4

LDL-C 5 low-density lipoprotein cholesterol; Total-C 5 total cholesterol; HDL-C 5 high-density lipoprotein cholesterol; Trig 5 triglyceride.

A SYMPOSIUM: ADVANCES IN HMG-COA REDUCTASE INHIBITION 41J

and females and young and elderly subjects and there-fore related to the effects of drug dosage rather than toany intrinsic gender or age-related responses to thedrug. These findings in older subjects may be clini-cally relevant in treating these subgroups, which formthe majority of subjects treated with statins.

OVERVIEW OF SAFETY ANDTOLERABILITY

Background: The pooled safety analyses includedall patients in the cerivastatin Phase II and III clinicaltrials who were randomized to and received any doseof cerivastatin during either double-blind, controlledefficacy periods of 4–32 weeks or double-blind, pla-cebo-controlled efficacy periods of 4–24 weeks.Longer-term safety was assessed in patients who hadreceived treatment with cerivastatin for periods of up

to 1 year in the long-term extension phases to thepivotal Phase IIb or Phase III trials.

Throughout the trials, patients were routinely mon-itored for adverse clinical and biochemical events,with particular emphasis given to changes in serumtransaminases (alanine transaminase and aspartatetransaminase) and creatine phosphokinase levels.

Demographics: The total study population for thesafety analysis consisted of 4,009 patients with pri-mary hypercholesterolemia, of whom 2,839 receivedcerivastatin at doses of 0.025–0.4 mg/day, 529 re-ceived comparator statins, and 641 received placebo.The 1-year study population consisted of a total of1,442 patients, of whom 1,155 received cerivastatinand 287 received comparator statins. Tables III and IVshow the median and mean duration of therapy in theplacebo-controlled and long-term extension studies,respectively.

FIGURE 1. Mean percent change in low-density lipoprotein cholesterol (LDL-C) from baselineto endpoint (week 8) in patients valid for efficacy. n 5 number of subjects on each dose ofcerivastatin or on placebo.

FIGURE 2. Mean percent change in total cholesterol (Total-C) from baseline to endpoint(week 8) in patients valid from efficacy. n 5 number of subjects on each dose of cerivastatinor on placebo.

42J THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 82 (4B) AUGUST 27, 1998

Adverse events: The pooled safety analyses showedthat the type and incidence of adverse events wassimilar in the cerivastatin, placebo, and active com-parator groups. Of the 10 most frequently reportedadverse events, no significant differences were evidentin incidence rates between treatment with cerivastatinand either placebo or active comparators (Table V).Similarly, there was no significant difference betweencerivastatin, at any dose, placebo, and active compar-ators in the incidence of adverse events that wereattributed to study treatment. In all treatment groups,headache and gastrointestinal disturbances were themost common drug-related adverse events (Table VI).Overall adverse events were rarely serious and led todiscontinuation of therapy during acute administrationin only 1.6% of all cerivastatin-treated patients com-

pared with 3.2% of patients receiving active compar-ators and 2.2% of patients on placebo. Discontinuationrates during long-term therapy were 1.9–4.7% in thecerivastatin treatment groups compared with 3.1% forcomparator agents.

Hepatic enzymes: Treatment with HMG-CoA re-ductase inhibitors has been associated with occasionaland usually transient increases in serum transaminaselevels. The pooled safety analysis showed that therewere no significant differences between cerivastatin,active comparators of cerivastatin, and placebo withrespect to clinically significant increases in levels ofeither alanine transaminase or aspartate transaminase.Importantly, there was no evidence of any dose-related increases in transaminase levels with cerivas-

FIGURE 4. Mean percent change in high-density lipoprotein cholesterol (HDL-C) from base-line to endpoint (week 8) in patients valid for efficacy. n 5 number of subjects on each doseof cerivastatin or on placebo.

FIGURE 3. Mean percent change in triglycerides (Trig) from baseline to endpoint (week 8) inrelation to baseline triglyceride levels (efficacy population). n 5 number of subjects on eachdose of cerivastatin or on placebo.

A SYMPOSIUM: ADVANCES IN HMG-COA REDUCTASE INHIBITION 43J

tatin up to the maximum dose tested, 0.4 mg/day(Table VII).

Muscle enzymes: In all treatment groups, elevationsin creatine phosphokinase of 5–103 the upper limit ofnormal occurred with an incidence of,1% and therewas no association with muscle pain. There was alsono evidence to indicate that clinically significant in-creases in levels of creatine phosphokinase were re-lated to increasing doses of cerivastatin (Table VII).Creatine phosphokinase values.103 the upper limitof normal were not noted at the highest doses ofcerivastatin tested and were scattered equally through-out the lower doses of cerivastatin, placebo, and com-parator groups. There were no cases of clinical myo-sitis.

DISCUSSION AND CONCLUSIONSCerivastatin, a new third-generation HMG-CoA

reductase inhibitor, has been administered to.2,700patients worldwide in a series of Phase II and IIIclinical studies designed to evaluate its efficacy,safety, and tolerability in the treatment of primary

hypercholesterolemia. As the results of the pooledefficacy and safety analyses have clearly demon-strated, cerivastatin is an efficacious, safe, and well-tolerated statin and a potentially important addition tothe armamentarium of hypolipidemic agents for thetreatment of hypercholesterolemia.

Compared with placebo-treated patients, cerivasta-tin at doses in the range 0.1–0.4 mg/day producedsignificant dose-dependent reductions in LDL choles-terol. The decrease of.28% achieved with 0.2 mg/day cerivastatin are in the range of LDL cholesterolreduction produced by 40 mg/day pravastatin in therecent West of Scotland Coronary Prevention Study(WOSCOPS)13 and the Cholesterol and RecurrentEvents (CARE) trial,14 and the reductions of.36%with 0.4 mg/day cerivastatin are comparable to thoseseen with 20–40 mg/day simvastatin in the Scandi-navian Simvastatin Survival Study (4S).15 These land-mark primary and secondary coronary prevention tri-als, respectively, have demonstrated for the first timethat treatment with these 2 statins not only signifi-cantly decreases the risk of coronary events and deathdue to coronary artery disease but also decreases therisk of all-cause mortality. The reductions in LDLcholesterol achievable with cerivastatin suggest that atmicrogram doses cerivastatin should be both clinicallyand therapeutically beneficial.

In common with currently available statins, ceriv-astatin shows a log-linear dose–response, producingan incremental 6% reduction in LDL cholesterol eachtime the dose was doubled. Studies on lovastatin,16

pravastatin,17 fluvastatin,18 and simvastatin19 suggestthat doses of 80, 40, 80, and 80 mg, respectively, areclose to the dose-ceiling for these agents, with dosesabove these levels either not having been explored orhaving been found to be associated with unacceptableside effects. The present pooled analyses on cerivas-tatin indicate that the log-linear dose–response mayextend beyond doses of 0.4 mg. Indeed, a recent Phase

TABLE III Median Treatment Duration in Days (Placebo-Controlled Studies)

CerivastatinActive

Comparator* Placebo0.025 mg 0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 mg

Number 263 421 584 882 372 138 403 641Min 7.0 2.0 1.0 1.0 1.0 4.0 2.0 1.0Median 84.00 88.00 108.50 84.00 113.50 56.00 88.00 84.00Max 105.0 196.0 201.0 203.0 198.0 78.0 203.0 201.0

Min 5 minimum; Max 5 maximum.*Active comparators 5 lovastatin, simvastatin.

TABLE IV Mean Treatment Duration (Days 6 SD) for Patients Completing 1 Year of Treatment

CerivastatinActive

Comparator*0.025 mg 0.05 mg 0.1 mg 0.2 mg 0.3 mg

Days of treatment 372.1 362.1 363.1 362.1 346.4 363.26 29.2 6 26.4 6 25.0 6 25.8 6 13.5 6 29.8

*Active comparators 5 lovastatin, simvastatin.

TABLE V Percent Incidence Rates of the 10 Most FrequentAdverse Events

Cerivastatin(All Doses)*

ActiveComparator† Placebo

Flu syndrome 6.3 8.9 4.8Headache 6.5 7.8 7.0Pharyngitis 6.3 7.7 7.5Rhinitis 4.7 5.5 5.9Abdominal pain 3.1 5.4 4.1Diarrhea 3.3 4.8 3.9Back pain 4.1 3.6 3.4Sinusitis 3.5 4.1 3.3Arthralgia 3.6 3.6 2.8Myalgia 2.0 3.6 1.1

*Cerivastatin 0.025–0.4 mg/day.†Active comparator 5 lovastatin, simvastatin.

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IIa study has shown that doubling the dose of ceriv-astatin to 0.8 mg/day produced reductions in LDLcholesterol of 44%, consistent with a continued log-linear dose–response, and comparable to the reduc-tions achieved with higher doses of the most effectivestatins.20 Although of only 4 weeks duration, this dosewas not associated with any incremental increases inclinical or laboratory abnormalities.

Similar to other statins,21 cerivastatin not only sig-nificantly decreased levels of LDL cholesterol but alsohad a beneficial effect on the entire lipid profile ofhypercholesterolemic patients. Significant dose-de-pendent reductions occurred in total cholesterol andtriglycerides together with modest increases in HDLcholesterol. As recently reported for other statins22,23

reduction in triglyceride levels observed with cerivas-tatin was more pronounced, the higher the baselineplasma triglyceride level, indicating that cerivastatinis suitable for treatment of both type IIa and IIb orcombined hyperlipidemia.

Based on the pooled safety analysis, cerivastatinhas an exceptionally good safety profile, with an in-

cidence of adverse effects comparable to that of pla-cebo. In contrast to existing statins, there was noevidence of any dose-related increase in adverse ef-fects with cerivastatin.24 Unique among the statinclass, cerivastatin produces its lipid-lowering effectsat microgram rather than milligram doses. This ultra-low dosage regimen is thought to contribute to itsgood safety profile.

Hepatotoxicity and myotoxicity are the most seri-ous adverse effects associated with HMG-CoA reduc-tase inhibitors, with the frequency of significant ab-normalities in hepatic transaminases usually related tothe dose of drug.24 Creatine phosphokinase abnormal-ities and myocytis may be more related to statin ca-tabolism, as agents dependent solely on metabolismby the microsomal cytochrome P-450 (CYP3A4) en-zyme pathway may be more likely to result in toxic-ity.25 The unique catabolism of cerivastatin by thehepatic cytochrome system indicates far less likeli-hood for such toxicity.9,10 Clinically significant in-creases in either aspartate transaminase/alaninetransaminase or creatine phosphokinase were rare af-

TABLE VII Percent Incidence Rates of Biochemical Adverse Effects

CerivastatinActiveComp*

(n 5 529)Placebo

(n 5 641)0.025 mg(n 5 263)

0.05 mg(n 5 421)

0.1 mg(n 5 584)

0.2 mg(n 5 882)

0.3 mg(n 5 512)

0.4 mg(n 5 138)

ALT.2 to #3 3 ULN — 0.78 0.58 0.26 1.56 — 1.30 0.53.3 to #5 3 ULN — 0.26 0.19 — 0.22 — 0.22 0.18.5 3 ULN — 0.26 0.19 0.13 0.22 — — 0.18

AST.2 to #3 3 ULN 0.39 0.49 0.36 — 0.61 — 0.79 0.33.3 to #5 3 ULN — — — 0.24 0.41 — — 0.16.5 3 ULN — — 0.18 0.12 — — — 0.16

CPK.5 to #10 3 ULN 0.47 — — 0.55 — 0.88 0.47 0.39.10 3 ULN 0.47 0.29 — 0.28 — — 0.23 0.39

Comp 5 comparator; ALT 5 alanine transaminase; AST 5 aspartate transaminase; CPK 5 creatine phosphokinase; ULN 5 upper limit of normal.*Active comparator 5 lovastatin, simvastatin.

TABLE VI Percent Most Frequent Treatment-Related Adverse Events

CerivastatinActiveComp*

(n 5 403)Placebo

(n 5 641)0.025 mg(n 5 263)

0.05 mg(n 5 421)

0.1 mg(n 5 584)

0.2 mg(n 5 882)

0.3 mg(n 5 512)

0.4 mg(n 5 138)

Headache 0.4 4.5 2.9 4.2 5.7 2.2 4.5 3.6Dyspepsia 1.5 1.7 2.7 2.4 1.2 0.7 2.5 2.2Abdominal pain 1.5 2.4 3.4 2.0 1.6 1.4 3.0 3.3Diarrhea 2.3 3.8 1.9 1.5 1.6 3.6 2.7 2.7Asthenia 1.5 1.9 1.5 1.5 2.9 1.4 1.6 2.0Back pain 0.8 1.7 2.2 0.7 1.2 1.4 0.5 1.2Flatulence 1.1 1.7 1.4 1.5 2.5 1.4 2.0 1.7Rash 1.5 1.2 2.2 0.9 0.8 0.0 3.2 1.6Nausea 1.5 1.2 1.0 1.4 1.6 0.0 3.0 1.1Myalgia 1.5 0.7 0.3 1.1 0.8 1.4 2.7 0.5Arthralgia 0.8 1.9 1.5 0.9 1.6 0.0 2.0 0.3Constipation 0.4 0.7 1.4 0.7 2.0 2.2 1.7 2.0Sinusitis 0.0 1.2 0.7 0.6 1.6 0.0 1.0 0.9

Comp 5 comparator.*Active comparator 5 lovastatin, simvastatin.

A SYMPOSIUM: ADVANCES IN HMG-COA REDUCTASE INHIBITION 45J

ter treatment with cerivastatin and, unlike most otherstatins, were unrelated to drug dosage.

Premature discontinuation of therapy usually pro-vides a useful measure of overall drug tolerability. Ingeneral, HMG-CoA reductase inhibitors are well-tol-erated agents, with only 1–4.6% of patients discon-tinuing therapy because of adverse events.24 Rates ofwithdrawal in the present study were similarly low forpatients receiving cerivastatin.

In conclusion, this pooled analysis of the efficacyand safety of cerivastatin has shown that at doses of upto 0.4 mg/day, cerivastatin is an effective, safe, andwell-tolerated agent for the treatment of type IIa andIIb primary hypercholesterolemia. The absence of anydose-related increases in either clinical or laboratoryabnormalities suggests that, at currently approveddoses, cerivastatin is highly effective and that the dosemay be safely increased to provide potentially greaterlipid-lowering effects without compromising safety.

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