serum aminotransferases or creatine phosphokinaseduring the study.

In summary, lovastatin ER was well tolerated inadults with hypercholesterolemia treated for 12weeks with 10-, 20-, 40-, or 60-mg/day doses, andproduced statistically significant and clinicallymeaningful dose-related reductions in LDL choles-terol, total cholesterol, and triglycerides, and in-creases in HDL cholesterol.1 These changes weregenerally as great as or greater than changes seenin a previous large-scale trial with correspondingdoses of immediate-release lovastatin, includingtwice-daily administration of the immediate releaseformulation. Lovastatin ER is safe and effective forthe treatment of adults with hypercholesterolemia,and may be associated with a lower risk of myalgiaor myositis because of the lower peak plasma con-centrations of 3-hydroxy-3-methylglutaryl-coen-zyme A reductase inhibitors associated with theextended-release delivery system.7

1. Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA,Gould AL, Hesney M, Higgins J, Hurley DP, et al. Expanded Clinical Evaluationof Lovastatin (EXCEL) study results. I: Efficacy in modifying plasma lipopro-teins and adverse event profile in 8245 patients with moderate hypercholesterol-emia. Arch Intern Med 1991;151:43–49.2. McClelland GA, Stubbs RJ, Fix JA, Pogany SA, Zentner GM. Enhancement of3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor effi-cacy through administration of a controlled-porosity osmotic pump dosage form.Pharm Res 1991;8:873–876.3. Sun JX, Phillips G, Shen J, Lukacsko P, Friedhoff L. Comparative pharma-cokinetics of lovastatin extended-release tablets and lovastatin immediate-releasetablets in humans. J Clin Pharmacol 2001;42:1–7.4. Davidson MH, Lukacslo P, Friedhoff L, Sterman A. A multiple-dose safety,pharmacokinetic, and pharmacodynamic study of an extended-release formula-tion of lovastatin compared to immediate-release lovastatin. Clin Ther, in press.5. Expert Panel on Detection Evaluation and Treatment of High Blood Choles-terol in Adults. Summary of the second report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation, and Treat-ment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA1993;269:3015–3023.6. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498–511.7. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant useof cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999;84:811–815.

Usefulness of Orlistat in the Treatment ofSevere Hypertriglyceridemia

Anthony S. Wierzbicki, MD, PhD, Timothy M. Reynolds, MD, PhD, andMartin A. Crook, MD, PhD

Type V hyperlipidemia is distinguished by grosshypertriglyceridemia (��1,770 mg/dl [��20

mmol/L]) and the presence of high concentrations ofchylomicrons, very-low density lipoprotein (VLDL),and their remnants in fasting plasma; it is often asso-ciated with pancreatitis.1 The condition is usuallytreated by combination drug therapy with fibrates,omega-3 fish oils, and nicotinic acid, and sometimeswith statins.1,2 However, the hyperlipidemia is usuallyonly partially controlled, triglycerides tend to remainat �20 mmol/L (1,770 mg/dl), and patients remain atrisk of developing pancreatitis. Orlistat inhibits gas-trointestinal lipases.3 Chylomicrons are synthesizedin the intestinal epithelium in response to the presenceof free-fatty acids.4 We hypothesized that a reductionof intestinal free-fatty acid concentration by orlistattherapy would reduce chylomicron synthesis, andhence, hypertriglyceridemia in these patients.

• • •Five patients with gross hypertriglyceridemia who

were receiving maximally tolerated doses of fibrates,statins, omega-3 fatty acids, and nicotinic acid therapy

were recruited for this study. Therapeutic use of orl-istat was indicated based on Royal College of Physi-cians guidelines of body mass index � 27 kg/m2 anda high cardiovascular risk.5 Patients received orlistat120 mg 3 times daily with meals; their lipid profileswere reassessed after 3 to 6 months of therapy. Pre-vious therapy was continued as it was deemed uneth-ical to discontinue it in these patients. The biochemi-cal assessments performed comprised measurement oftriglycerides and cholesterol by standard automatedmethods, and if possible, determination of the triglyc-eride and cholesterol content of the chylomicron,VLDL, low-density lipoprotein, and high-density li-poprotein fractions by sequential density ultracentri-fugation. Multiple measurements (�3) of lipid pro-files before and after therapy were performed toreduce the substantial intraindividual variations in tri-glyceride levels (Table 1); the results are quoted as thegeometric mean value of these measurements. Datawere analyzed by nonparametric methods for multiplecomparisons of paired sample data. All patients hadestablished type V hyperlipidemia with chylomicrontriglycerides comprising �50% of the total plasmatriglycerides after a 14-hour fast, 80% of the patientshad had �1 episode of pancreatitis, and all had estab-lished secondary type 2 diabetes mellitus. Three pa-tients were on ciprofibrate 100 mg and 2 patients wereon fenofibrate 267 mg; 2 patients were also receivingadditional statin therapy with atorvastatin 20 or 80mg. Three patients required insulin therapy (55 to 90U daily) and 1 patient was taking metformin 850 mg

From the Department of Chemical Pathology, St. Thomas’ Hospital,London; and the Department of Chemical Pathology, Queen’s Hospi-tal, Burton-on-Trent Staffordshire, United Kingdom. Dr. Wierzbicki’saddress is: Department of Chemical Pathology, St. Thomas’ Hospital,Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail:Anthony.Wierzbicki@kcl.ac.uk. Manuscript received June 18, 2001;revised manuscript received and accepted September 27, 2001.

229©2002 by Excerpta Medica, Inc. All rights reserved. 0002-9149/02/$–see front matterThe American Journal of Cardiology Vol. 89 January 15, 2002 PII S0002-9149(01)02208-1

twice daily. These drug therapies resulted in a signif-icant reduction in triglycerides (p � 0.04) but not incholesterol (p � 0.46) from baseline values. Addi-tional orlistat therapy provided a further 35% decreasein triglycerides (p � 0.009) and 31% decrease incholesterol (p � 0.25). Small, but nonsignificant, im-provements were seen in hemoglobin A1c and bloodpressure with combination therapy and orlistat overbaseline values. In 1 patient, where complete ultracen-trifugation-derived lipid subfraction profiles wereavailable, orlistat reduced chylomicron triglyceridesby a further 34% after an initial 50% reduction withfibrate therapy, and the VLDL density fraction tri-glycerides were decreased by another 50% after aninitial 28% reduction. Despite orlistat therapy, aweight gain of 1.6 � 5.3 kg (2 � 5%; p � 0.56) wasobserved. Orlistat therapy was reasonably well toler-ated and patients were 70% compliant with therapy,including the patient who was on concurrent met-formin therapy.

• • •The treatment of type V hyperlipidemia with ultra-

low fat diets (�10 to 20 g/day) and additional use offibrates is well established.1 However, compliancewith these extreme diets is usually poor and not allpatients achieve triglyceride levels of �885 mg/dl(�10 mmol/L) with fibrates or combination lipid-

lowering drug therapy. Although few studies haveexamined the utility of fibrate-statin combination ther-apy in type V hyperlipidemia, 1 study of 12 patientswith type III hyperlipidemia with baseline triglycer-ides 14.3 mmol/L (1,100 mg/dl) and total cholesterol16.4 mmol/L (635 mg/dl) showed that combinationtherapy with clofibrate and lovastatin resulted in a75% decrease in triglycerides and a 67% decrease intotal cholesterol.6 Smaller but generally similar rela-tive reductions in triglycerides were achieved in thisstudy of patients with type V hyperlipidemia, but theabsolute changes were far greater. However, 1 patient(patient 2) showed a poor response to fibrate andfibrate-statin combination therapy or was poorly com-pliant with this drug regimen. The results presentedhere show that the addition of orlistat to conventionaltherapies results in a further 35% reduction in triglyc-erides (p � 0.009) and 31% reduction (p � 0.25) intotal cholesterol (p � 0.25). The reduction in triglyc-erides, despite weight gain, indicates that the effect islikely to be due to an intestinal effect on lipolysisrather than an improvement in lifestyle, diet, or othermedical therapy. The 35% improvement in triglycer-ides in patients with type V hyperlipidemia was�11% reduction achieved with orlistat in normotri-glyceridemic type 2 diabetic patients with type IIb

TABLE 1 Results of Therapy With Multiple Drugs and Orlistat in Type V Hypercholesterolemia

Parameter

Patients

All1 2 3 4 5

Age (yrs) 35 30 47 39 54 41 � 8.6Sex M F M F MBody mass index (kg/m2) 30.7 32.1 34.7 33.5 33.8 33.0 � 1.4Baseline dataWeight (kg) 92 95 110 93 89 96 � 8Blood pressure (mm Hg) 130/80 155/80 165/94 148/86 160/90 152 � 14/86 � 6Triglycerides (mg/dl) 4115 2300 6372 13053 6133 6,398 � 3,681

(mmol/L) 46.5 26.0 72.0 147.5 69.3 72.3 � 41.6Total cholesterol (mg/dl) 405 281 529 873 1135 645 � 313

(mmol/L) 10.5 7.28 13.7 22.6 29.4 17 � 8HbA1c (%) 6.1 6.7 12.0 12.8 10.4 9.6 � 3.1

Fibrate and combination therapiesTreatment F F,Ins F,S, Ins F,S, M,Ins F,M, InsBlood pressure (mm Hg) 130/80 155/80 140/84 140/82 148/83 143 � 9/82 � 2Triglycerides (mg/dl) 1946 3336 2717 3725 2123 2770 � 681

(mmol/L) 22.0 37.7 30.7 42.1 24.0 31.3 � 7.7Total cholesterol (mg/dl) 246 398 436 1061 421 514 � 313

(mmol/L) 6.4 10.3 11.3 27.5 10.9 13.3 � 8.1Change in triglycerides (%) �53 45 �57 �71 �65 �41 � 43Change in cholesterol (%) �39 41 �18 6 �63 �14 � 36HbA1c (%) 7.7 6.9 8.8 11.6 8.6 8.7 � 1.8

Additional orlistat therapyWeight (kg) 95 95 106 91 100 97 � 5BP (mm Hg) 130/80 155/80 145/85 140/80 140/85 142 � 9/82 � 3Triglycerides (mg/dl) 1221 785 9371 1708 1929 1,318 � 442

(mmol/L) 13.8 8.9 10.6 19.3 21.8 14.9 � 5.0Total cholesterol (mg/dl) 193 198 317 409 544 336 � 131

(mmol/L) 5.0 5.13 8.22 10.6 14.1 8.7 � 3.4Change in triglycerides (%) �70 �66 �86 �87 �69 �76 � 9Change in cholesterol (%) �52 �29 �40 �53 �52 �45 � 9HbA1c (%) 7.3 6.9 9.7 11.1 8.4 8.7 � 1.7

Triglycerides and total cholesterol concentrations are presented as geometric mean results. F � fibrate; HbA1c � hemoglobin A1c; INs � insulin; M � metformin;S � statin.

230 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 89 JANUARY 15, 2002

hyperlipidemia.7 The results of this study suggest thatorlistat is a useful adjunct to conventional therapies inthe treatment of severe hypertriglyceridemia.

Orlistat, a gastric lipase inhibitor, reduces in-testinal chylomicron synthesis in response to fattyacids. The addition of orlistat to fibrate-statin com-bination therapy resulted in a further 35% reduc-tion in triglycerides in 5 patients with type V hy-perlipidemia.

1. Bhatnagar D. Hypertriglyceridaemia. In: Betteridge DJ, Illingworth DR, Shep-

herd J, eds. Lipoproteins in Health and Disease. London, UK: Edward Arnold,1999:737–751.2. Wierzbicki AS, Reynolds TM. Familial hyperchylomicronaemia. Lancet 1997;348:1524.3. Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for themanagement of obesity. Pharmacotherapy 2000;20:270–279.4. van Greevenbroek MM, de Bruin TW. Chylomicron synthesis by intestinalcells in vitro and in vivo. Atherosclerosis 1998;141(suppl 1):S9–S16.5. Royal College of Physicians Working Party. Clinical management of over-weight and obese patients. Royal College of Physicians, London, United King-dom, 1998.6. Illingworth DR, O’Malley JP. The hypolipidemic effects lovastatin and clofi-brate alone and in combination in patients with type III hyperlipoproteinemia.Metabolism 1990;39:403–409.7. Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR,Crockett SE, Kaplan RA, Comstock J, et al. Role of orlistat in the treatment ofobese patients with type 2 diabetes. Diabetes Care 1998;21:1288–1294.

Frequency of Creatine Kinase Elevation DuringTreatment With Fluvastatin

Renee Benghozi, MD, Michele Bortolini, MD, Yan Jia, PhD, Jonathan L. Isaacsohn, MD,August J. Troendle, MD, and Leonard Gonasun, PhD

S tatins (3-hydroxy-3-methylglutaryl-coenzyme Areductase inhibitors) have become the most fre-

quently prescribed agents for the treatment of hyper-cholesterolemia because of the compelling evidenceof their effect on reducing cardiovascular eventrates.1,2 They are generally well tolerated and have afavorable safety profile. Although rare, a major ad-verse event of statins is myopathy, defined as creatinekinase (CK) increase to �10 times the upper limit ofnormal (ULN) with accompanying symptoms of mus-cle pain or weakness.3 If the myopathy is not recog-nized and drug therapy continues, rhabdomyolysis andacute renal failure may result. Statin treatment is al-ways long term, and thus, attention to the possibilityof myopathy continues to be important. There may besignificant differences in the frequency of myopathyand/or CK elevations associated with different statins.This study used a pooled analysis to evaluate thefrequency of CK elevation associated with fluvastatintreatment.

• • •The data from all fluvastatin studies conducted by

Novartis Pharmaceuticals (East Hanover, New Jersey)from 1987 to 2001 were evaluated for this analysis.Patients who received placebo, 20 and 40 mg ofLescol capsules or 80 mg extended-release tablets(Lescol XL) and who had a postbaseline CK measure-ment were included in the pooled analysis. Data frompatients receiving active comparators or from patientsreceiving fluvastatin in combination with another lip-id-lowering therapy were excluded. The studies in-

cluded in the pooled analysis formed the basis of theregistration dossier for Lescol capsules submittedthroughout the world for patients with primary hyper-cholesterolemia and mixed dyslipidemia. The pooleddata also included the 1999 registration dossier forapproval of the fluvastatin extended-release formula-tion, and 3 additional active control studies with flu-vastatin extended-release 80 mg. Other studies in-cluded a double-blind multicenter study to examinethe reduction of cardiac events during long-term treat-ment with fluvastatin,4 a study to determine the effectof fluvastatin on restenosis after successful percutane-ous coronary angioplasty,5 an angiographic end-pointstudy6 that investigated the effects of fluvastatin oncoronary atherosclerosis in patients with elevated low-density lipoprotein cholesterol, and a group of phaseIV studies. Results from a trial to evaluate the efficacyand safety of fluvastatin extended-release 80 mg inelderly patients were also included. These pooledstudies involved 8,951 individual patients.

Total mean exposure varied among the 4 treatmentgroups. The mean exposure was 27.6 weeks for theplacebo group, 16.5 weeks for the fluvastatin 20-mggroup, 30.1 weeks for the fluvastatin 40-mg group,and 17.5 weeks for the fluvastatin extended-release80-mg group. The minimum and maximum exposureranged from 0.4 to 141.3 weeks for the placebo group,0.1 to 156.0 weeks for the fluvastatin 20-mg group,0.1 to 146.3 weeks for the fluvastatin 40-mg group,and 0.7 to 55.6 weeks for the fluvastatin extended-release 80-mg group.

The total number and percentage of patients withCK �10 times the ULN were examined by treatmentgroup; the total number and percentage of patientswith CK �5 times the ULN were examined by treat-ment group and by gender and age category (�65years, �65 years). Additionally, for each treatmentgroup, the total number and percentage of patients

From Novartis Pharma LTD, Basel, Switzerland; Novartis Pharmaceu-ticals Corporation, East Hanover, New Jersey; and Medpace LLC,Cincinnati, Ohio. This study was supported by a grant from NovartisPharmaceuticals Corporation, East Hanover, New Jersey. Dr. Gona-sun’s address is: Novartis Pharmaceuticals Corporation, 1 HealthPlaza New Jersey 07936. E-mail: leonard.gonasun@pharma.novartis.com. Manuscript received May 31, 2001; revised manu-script received and accepted August 27, 2001.

231©2002 by Excerpta Medica, Inc. All rights reserved. 0002-9149/02/$–see front matterThe American Journal of Cardiology Vol. 89 January 15, 2002 PII S0002-9149(01)02209-3