- Email: [email protected]
Dose response, safety, and efficacy of an extended-release formulation of lovastatin in adults with hypercholesterolemia
data cannot be used to suggest this in other circumstances, such as toxic or infectious involvement of myocardium or with global ischemia where calpain-mediated proteolysis of cTnI has been observed,12 that smaller peptide fragments of troponin might not be released in response to reversible injury. Finally, we measured values at time points to mimic the clinical situation in which patients are often evaluated. We cannot totally exclude the possibility that results might be different if earlier and/or later samples had been obtained. Despite these caveats, these data strongly support the present paradigm of dividing patients into those with ischemia and those with infarction. These results suggest that for clinical purposes, detectable elevations of troponin do not occur with ischemia alone unless there is a component of cardiac injury. 1. Ottani F, Galvani M, Nicolini FA, Ferrini D, Pozzati A, Di Pasquale G, Jaffe AS. Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Am Heart J 2000;140:917–927. 2. ESC/ACC Committee. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959 –969.
3. Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H.
It’s time for a change to a troponin standard. Circulation 2000;102:1216 –1220. 4. Wu AH, Ford L. Release of cardiac troponin in acute coronary syndromes:
ischemia or necrosis? Clin Chim Acta 1999;284:161–174. 5. Sobel BE, LeWinter MM. Ingenuous interpretation of elevated blood levels of
macromolecular markers of myocardial injury: a recipe for confusion. J Am Coll Cardiol 2000;35:1355–1358. 6. Ishikawa Y, Saffitz JE, Mealman TL, Grace AM, Roberts R. Reversible myocardial ischemic injury is not associated with increased creatine kinase activity in plasma. Clin Chem 1997;43:467–475. 7. Baum H, Braun S, Gerhardt W, Gilson G, Hafner G, Muller-Bardorff M, Stein W, Klein G, Ebert C, Hallermayer K, Katus HA. Multicenter evaluation of a second-generation assay for cardiac troponin T. Clin Chem 1997;43:1877–1884. 8. Heeschen C, Goldmann BU, Langenbrink L, Matschuck G, Hamm CW. Evaluation of a rapid whole blood ELISA for quantification of troponin I in patients with acute chest pain. Clin Chem 1999;45:1789 –1796. 9. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echocardiography: recommendations for performance and interpretation of stress echocardiography. Stress Echocardiography Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104. 10. Thomas SA, Fallavollita JA, Lee TC, Feng J, Canty JM Jr. Absence of troponin I degradation or altered sarcoplasmic reticulum uptake protein expression after reversible ischemia in swine. Circ Res 1999;85:446 –456. 11. Sherman AJ, Klocke FJ, Decker RS, Decker ML, Kozlowski KA, Harris KR, Hedjbeli S, Yaroshenko Y, Nakamura S, Parker MA, Checchia PA, Evans DB. Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches. Am J Physiol Heart Circ Physiol 2000;278: H1320 –H1334. 12. Feng J, Schaus BJ, Fallavollita JA, Lee TC, Canty JM Jr. Preload induces troponin I degradation independently of myocardial ischemia. Circulation 2001; 103:2035–2037.
Dose Response, Safety, and Efficacy of an ExtendedRelease Formulation of Lovastatin in Adults With Hypercholesterolemia John R. Crouse III,
MD,
Peter Lukacsko, PhD, Robert Niecestro, Extended-Release Study Group
n the Expanded Clinical Evaluation of Lovastatin study (EXCEL), lovastatin 20 mg given twice daily Iproduced a significantly greater reduction in low-density lipoprotein (LDL) cholesterol than 40 mg given once daily.1 This is likely a result of efficient hepatic extraction and significant first-pass hepatic metabolism. These observations, and the demonstration in an animal model of enhanced efficacy associated with an extended-release form of simvastatin,2 suggested that an extended-release formulation of lovastatin would enhance efficacy. Lovastatin extended-release (ER) tablets, the formulation used in this clinical trial, was developed to present lovastatin to the liver in a more sustained and continuous manner. Pharmacokinetic analysis shows that lovastatin ER has delayed-delivery and extended-release properties, evidenced by a longer time to maximum plasma concentration and a From Wake Forest University School of Medicine, Winston-Salem, North Carolina; and Aura Laboratories, Inc, Division of Andrx Corporation, Fort Lauderdale, Florida. Dr. Crouse’s address is: Wake Forest University School of Medicine, Department of Medicine/Endocrinology, Hanes Building, Room 8017, Medical Center Boulevard, Winston-Salem, North Carolina 27157. E-mail: [email protected]. Manuscript received June 15, 2001; revised manuscript received and accepted September 28, 2001.
226
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 January 15, 2002
PhD,
and the Lovastatin
lower maximum plasma concentration of lovastatin compared with the immediate-release formulation. Also, lovastatin ER produced greater bioavailability of the prodrug, yet similar bioavailability of active metabolite, and active inhibitors of 3-hydroxy-3methylglutaryl-coenzyme A reductase, suggesting greater delivery of active drug to the target organ (liver).3,4 This clinical trial was designed to assess the dose response, efficacy, and safety of lovastatin ER in adults with hypercholesterolemia. •••
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed to assess the dose response, efficacy, and safety of 4 doses of lovastatin ER (10, 20, 40, and 60 mg once daily for 12 weeks) compared with placebo in adults with hypercholesterolemia. Patients were required to follow a National Cholesterol Education Program step I diet for 4 weeks before the screening visit. Patients taking lipid-modifying drugs were required to complete a 4-week washout before screening blood and urine samples were obtained. A 4-week diet and placebo run-in period preceded randomization to active treatment. Patients were then randomized to 1 of 5 treatment groups 0002-9149/02/$–see front matter PII S0002-9149(01)02207-X
TABLE 1 Least-Squares Mean Percent Changes in LDL Cholesterol, Total Cholesterol, HDL Cholesterol, and Triglycerides from Baseline After 12 Weeks of Treatment in Each Lovastatin ER Treatment Group Versus Placebo Least-Squares Mean Percent Change from Baseline Versus Placebo Treatment Lovastatin ER 10 mg (n ⫽ 33) Lovastatin ER 20 mg (n ⫽ 34)* Lovastatin ER 40 mg (n ⫽ 33) Lovastatin ER 60 mg (n ⫽ 35)
LDL Cholesterol
Total Cholesterol
HDL Cholesterol
Triglycerides
⫺25.21% ⫾ 2.53% p ⱕ0.0001 ⫺30.96% ⫾ 2.53% p ⱕ0.0001 ⫺37.23% ⫾ 2.53% p ⱕ0.0001 ⫺42.05% ⫾ 2.48% p ⱕ0.0001
⫺21.22% ⫾ 2.09% p ⱕ0.0001 ⫺24.05% ⫾ 2.07% p ⱕ0.0001 ⫺28.65% ⫾ 2.09% p ⱕ0.0001 ⫺32.43% ⫾ 2.05% p ⱕ0.0001
3.33% ⫾ 2.88% p ⫽ 0.2494 6.38% ⫾ 2.86% p ⫽ 0.0271 7.62% ⫾ 2.88% p ⫽ 0.0091 5.75% ⫾ 2.83% p ⫽ 0.0441
⫺25.11% ⫾ 6.70% p ⫽ 0.0003 ⫺21.03% ⫾ 6.65% p ⫽ 0.0019 ⫺18.35% ⫾ 6.70% p ⫽ 0.0069 ⫺32.84% ⫾ 6.59% p ⱕ0.0001
*Of the 34 patients in the group, 1 did not have an end point LDL cholesterol value. Values are expressed as least-squares mean ⫾ SE and p value. Least-squares mean, SE, and p value are from Dunnett’s test for comparing lovastatin ER groups to placebo with treatment group and center as factors. Baseline ⫽ average of last 2 values before starting double-blind treatment. End point ⫽ average of last 2 values during double-blind treatment. If 1 value was missing, the other was used.
(placebo or one of the lovastatin ER doses: 10, 20, 40, or 60 mg). The study drug was administered once daily, one half hour before bedtime, for 12 weeks. Lovastatin ER is a formulation of lovastatin in a single composition osmotic tablet. This proprietary system uses osmotic modulating agents as well as polymer coatings to provide a zero-order release of the drug (i.e., a constant rate of release). The study was designed to enroll approximately 150 patients 21 to 70 years of age with hypercholesterolemia at 12 medical centers in the United States. Criteria for enrollment included: ability to provide informed consent, age 21 to 70 years, compliance with the step I diet for at least 4 weeks before study entry, and at least a 4-week washout of any lipid-modifying agents before the screening visit. Participants were enrolled according to eligibility for pharmacologic management of lipids in compliance with standards set by the National Cholesterol Education Program Adult Treatment Panel II guidelines.5 The primary efficacy variable was the percent change in LDL cholesterol from baseline to end point. Secondary efficacy variables were percent changes from baseline to end point in high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides. Clinical laboratory analyses were performed by Quintiles Laboratories, Ltd. (Smyrna, Georgia). For all efficacy variables, the baseline was defined as the average of the measurements taken after weeks 3 and 4 of the placebo run-in phase. The end points were defined as the averages of measurements taken after weeks 11 and 12 of double-blind treatment. LDL cholesterol was calculated using the Friedewald formula. If the triglyceride level was ⬍400 mg/dl, then LDL cholesterol was measured as total cholesterol ⫺ 共HDL cholesterol ⫹ 关triglyceride/5兴兲. If the triglyceride level was ⱖ400 mg/dl, then the LDL cholesterol level was measured directly. Incidence and frequency of adverse events, as well as changes in clinical laboratory parameters, physical examination, and vital signs were used to assess the safety and tolerability of the study drug. Of 287 patients screened for the study, 172 were
randomized. All 172 were included in the safety analysis, and 169 were included in the intent-to-treat efficacy analysis (i.e., were randomized, received at least 1 dose of study medication, and had at least 1 measurement obtained after taking study medication). Of the 172 patients randomized, 52.3% were men and 47.7% were women. The mean age of all randomized patients was 56.6 years (range 29 to 70). Overall, 44.8% of patients had ⬍2 risk factors for heart disease, 50.6% had ⱖ2 risk factors, and 4.7% had existing coronary heart disease, cerebrovascular disease, or peripheral vascular disease. The percentage of patients in each risk category was similar across the 5 treatment groups. Treatment compliance rates were similar in the 5 groups (range 95.5% to 98.3%). The primary and secondary efficacy results were obtained for the intent-to-treat population. In this population, the mean baseline LDL cholesterol in the placebo and active-treatment groups ranged from 172.8 to 180.6 mg/dl. The differences in least-squares mean percent reduction in LDL cholesterol compared with the placebo group were 25.21%, 30.96%, 37.23%, and 42.05% for the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively (Table 1). All of these differences were statistically significant (p ⱕ0.0001 for all comparisons). The observed LDL cholesterol reduction was sustained throughout the course of the study. Figure 1 displays the mean change in LDL cholesterol over 12 weeks by treatment group. In the intent-to-treat population, the mean baseline HDL cholesterol levels in the placebo and active treatment groups ranged from 43.5 to 48.9 mg/dl. The difference in least-squares mean percent increase in HDL cholesterol compared with the placebo group was statistically significant for the lovastatin ER 20-, 40-, and 60-mg groups (Table 1). Mean baseline total cholesterol levels in the placebo and active treatment groups ranged from 252.5 to 263.8 mg/dl. Differences in least-squares mean percent reductions in total cholesterol compared with the placebo group were statistically significant (p ⱕ0.0001) for all lovastatin ER dose groups (Table 1). Increases in HDL cholesterol and reductions in total cholesterol were near BRIEF REPORTS
227
FIGURE 1. Mean change from baseline in LDL cholesterol levels during the active treatment period in each study group (intent-to-treat population). Lov ⴝ lovastatin.
maximum by the 4-week time point and remained in a similar range throughout the course of the study. Mean baseline triglyceride levels in the placebo and active treatment groups ranged from 173.8 to 206.0 mg/dl. The differences in least-squares mean reductions in triglycerides compared with the placebo group were statistically significant for all lovastatin ER dose groups (Table 1). Reductions in triglyceride levels were near maximum by the 8-week time point and remained in a similar range throughout the course of the study. At least 1 treatment-emergent sign or symptom (TESS) was experienced during the study by 64.7% of patients in the placebo group, and 74.3%, 52.9%, 75.8%, and 63.9% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were no apparent trends by study arm in the incidence of TESS reported by body system. An investigator-determined, trial drug–related TESS was experienced by 32.4% of patients in the placebo group, and 31.4%, 23.5%, 18.2%, and 30.6% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were 6 withdrawals due to TESS; investigators considered 5 to be drug-related (1 in the placebo group, 1 in the lovastatin ER 10-mg group, 2 in the 20-mg group, and 1 in the 40-mg group). Musculoskeletal system TESS occurred in 23.5%, 14.3%, 8.8%, 12.1%, and 19.4% of patients in the placebo and lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. Within the musculoskeletal system, myalgia was reported for 17.6% of patients in the placebo group and in 0%, 5.9%, 3.0%, and 2.8% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were no patients from any group 228 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 89
with alanine aminotransferase or aspartate aminotransferase ⬎2 times the upper limit of normal, and no patients in the lovastatin ER groups with creatine phosphokinase ⬎5 times the upper limit of normal. •••
In this double-blind, placebo-controlled study, 12 weeks of therapy with the lovastatin ER formulation produced clinically important changes in all lipid and lipoprotein levels measured. Dose response was demonstrated in reduction of LDL cholesterol levels; a doubling of the dose from 10 to 20 mg and from 20 to 40 mg resulted in 5.7% and 6.3% greater reductions, respectively. These reductions are consistent with those observed with other statins with which a doubling of the dose lowers LDL cholesterol by an additional 6%.6 A 50% increase in dose (from 40 to 60 mg) produced a 4.8% greater LDL cholesterol reduction. As expected, the percentage of patients achieving their National Cholesterol Education Program II goal LDL cholesterol levels increased with dose, with 94.3% of patients achieving their goal at the 60-mg dose. Among patients receiving lovastatin ER 60 mg, the mean baseline LDL cholesterol was approximately 180 mg/dl; this mean LDL cholesterol level requires approximately 28% reduction to achieve an LDL cholesterol of ⬍130 mg/dl. In fact, ⱖ40% reduction in LDL cholesterol was seen in 60% of patients receiving lovastatin ER 60 mg. Lovastatin ER was well tolerated with very few patients withdrawn due to TESS, and there were no meaningful differences in terms of the frequency, severity, or relation to study drug between the treatment groups. There were no clinically significant changes in JANUARY 15, 2002
serum aminotransferases or creatine phosphokinase during the study. In summary, lovastatin ER was well tolerated in adults with hypercholesterolemia treated for 12 weeks with 10-, 20-, 40-, or 60-mg/day doses, and produced statistically significant and clinically meaningful dose-related reductions in LDL cholesterol, total cholesterol, and triglycerides, and increases in HDL cholesterol.1 These changes were generally as great as or greater than changes seen in a previous large-scale trial with corresponding doses of immediate-release lovastatin, including twice-daily administration of the immediate release formulation. Lovastatin ER is safe and effective for the treatment of adults with hypercholesterolemia, and may be associated with a lower risk of myalgia or myositis because of the lower peak plasma concentrations of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors associated with the extended-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 Evaluation of Lovastatin (EXCEL) study results. I: Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991;151:43–49. 2. McClelland GA, Stubbs RJ, Fix JA, Pogany SA, Zentner GM. Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy 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 pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets 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 formulation of lovastatin compared to immediate-release lovastatin. Clin Ther, in press. 5. 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. 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 use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999;84:811– 815.
Usefulness of Orlistat in the Treatment of Severe Hypertriglyceridemia Anthony S. Wierzbicki, MD, PhD, Timothy M. Reynolds, Martin A. Crook, MD, PhD ype V hyperlipidemia is distinguished by gross hypertriglyceridemia (⬎⬎1,770 mg/dl [⬎⬎20 T mmol/L]) and the presence of high concentrations of chylomicrons, very-low density lipoprotein (VLDL), and their remnants in fasting plasma; it is often associated with pancreatitis.1 The condition is usually treated by combination drug therapy with fibrates, omega-3 fish oils, and nicotinic acid, and sometimes with statins.1,2 However, the hyperlipidemia is usually only partially controlled, triglycerides tend to remain at ⬎20 mmol/L (1,770 mg/dl), and patients remain at risk of developing pancreatitis. Orlistat inhibits gastrointestinal lipases.3 Chylomicrons are synthesized in the intestinal epithelium in response to the presence of free-fatty acids.4 We hypothesized that a reduction of intestinal free-fatty acid concentration by orlistat therapy would reduce chylomicron synthesis, and hence, 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 From the Department of Chemical Pathology, St. Thomas’ Hospital, London; and the Department of Chemical Pathology, Queen’s Hospital, Burton-on-Trent Staffordshire, United Kingdom. Dr. Wierzbicki’s address is: Department of Chemical Pathology, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: [email protected]. Manuscript received June 18, 2001; revised manuscript received and accepted September 27, 2001. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 January 15, 2002
MD, PhD,
and
were recruited for this study. Therapeutic use of orlistat was indicated based on Royal College of Physicians guidelines of body mass index ⬎ 27 kg/m2 and a high cardiovascular risk.5 Patients received orlistat 120 mg 3 times daily with meals; their lipid profiles were reassessed after 3 to 6 months of therapy. Previous therapy was continued as it was deemed unethical to discontinue it in these patients. The biochemical assessments performed comprised measurement of triglycerides and cholesterol by standard automated methods, and if possible, determination of the triglyceride and cholesterol content of the chylomicron, VLDL, low-density lipoprotein, and high-density lipoprotein fractions by sequential density ultracentrifugation. Multiple measurements (⬎3) of lipid profiles before and after therapy were performed to reduce the substantial intraindividual variations in triglyceride levels (Table 1); the results are quoted as the geometric mean value of these measurements. Data were analyzed by nonparametric methods for multiple comparisons of paired sample data. All patients had established type V hyperlipidemia with chylomicron triglycerides comprising ⬎50% of the total plasma triglycerides after a 14-hour fast, 80% of the patients had had ⱖ1 episode of pancreatitis, and all had established secondary type 2 diabetes mellitus. Three patients were on ciprofibrate 100 mg and 2 patients were on fenofibrate 267 mg; 2 patients were also receiving additional statin therapy with atorvastatin 20 or 80 mg. Three patients required insulin therapy (55 to 90 U daily) and 1 patient was taking metformin 850 mg 0002-9149/02/$–see front matter PII S0002-9149(01)02208-1
229
3. Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H.
It’s time for a change to a troponin standard. Circulation 2000;102:1216 –1220. 4. Wu AH, Ford L. Release of cardiac troponin in acute coronary syndromes:
ischemia or necrosis? Clin Chim Acta 1999;284:161–174. 5. Sobel BE, LeWinter MM. Ingenuous interpretation of elevated blood levels of
macromolecular markers of myocardial injury: a recipe for confusion. J Am Coll Cardiol 2000;35:1355–1358. 6. Ishikawa Y, Saffitz JE, Mealman TL, Grace AM, Roberts R. Reversible myocardial ischemic injury is not associated with increased creatine kinase activity in plasma. Clin Chem 1997;43:467–475. 7. Baum H, Braun S, Gerhardt W, Gilson G, Hafner G, Muller-Bardorff M, Stein W, Klein G, Ebert C, Hallermayer K, Katus HA. Multicenter evaluation of a second-generation assay for cardiac troponin T. Clin Chem 1997;43:1877–1884. 8. Heeschen C, Goldmann BU, Langenbrink L, Matschuck G, Hamm CW. Evaluation of a rapid whole blood ELISA for quantification of troponin I in patients with acute chest pain. Clin Chem 1999;45:1789 –1796. 9. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echocardiography: recommendations for performance and interpretation of stress echocardiography. Stress Echocardiography Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104. 10. Thomas SA, Fallavollita JA, Lee TC, Feng J, Canty JM Jr. Absence of troponin I degradation or altered sarcoplasmic reticulum uptake protein expression after reversible ischemia in swine. Circ Res 1999;85:446 –456. 11. Sherman AJ, Klocke FJ, Decker RS, Decker ML, Kozlowski KA, Harris KR, Hedjbeli S, Yaroshenko Y, Nakamura S, Parker MA, Checchia PA, Evans DB. Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches. Am J Physiol Heart Circ Physiol 2000;278: H1320 –H1334. 12. Feng J, Schaus BJ, Fallavollita JA, Lee TC, Canty JM Jr. Preload induces troponin I degradation independently of myocardial ischemia. Circulation 2001; 103:2035–2037.
Dose Response, Safety, and Efficacy of an ExtendedRelease Formulation of Lovastatin in Adults With Hypercholesterolemia John R. Crouse III,
MD,
Peter Lukacsko, PhD, Robert Niecestro, Extended-Release Study Group
n the Expanded Clinical Evaluation of Lovastatin study (EXCEL), lovastatin 20 mg given twice daily Iproduced a significantly greater reduction in low-density lipoprotein (LDL) cholesterol than 40 mg given once daily.1 This is likely a result of efficient hepatic extraction and significant first-pass hepatic metabolism. These observations, and the demonstration in an animal model of enhanced efficacy associated with an extended-release form of simvastatin,2 suggested that an extended-release formulation of lovastatin would enhance efficacy. Lovastatin extended-release (ER) tablets, the formulation used in this clinical trial, was developed to present lovastatin to the liver in a more sustained and continuous manner. Pharmacokinetic analysis shows that lovastatin ER has delayed-delivery and extended-release properties, evidenced by a longer time to maximum plasma concentration and a From Wake Forest University School of Medicine, Winston-Salem, North Carolina; and Aura Laboratories, Inc, Division of Andrx Corporation, Fort Lauderdale, Florida. Dr. Crouse’s address is: Wake Forest University School of Medicine, Department of Medicine/Endocrinology, Hanes Building, Room 8017, Medical Center Boulevard, Winston-Salem, North Carolina 27157. E-mail: [email protected]. Manuscript received June 15, 2001; revised manuscript received and accepted September 28, 2001.
226
©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 January 15, 2002
PhD,
and the Lovastatin
lower maximum plasma concentration of lovastatin compared with the immediate-release formulation. Also, lovastatin ER produced greater bioavailability of the prodrug, yet similar bioavailability of active metabolite, and active inhibitors of 3-hydroxy-3methylglutaryl-coenzyme A reductase, suggesting greater delivery of active drug to the target organ (liver).3,4 This clinical trial was designed to assess the dose response, efficacy, and safety of lovastatin ER in adults with hypercholesterolemia. •••
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed to assess the dose response, efficacy, and safety of 4 doses of lovastatin ER (10, 20, 40, and 60 mg once daily for 12 weeks) compared with placebo in adults with hypercholesterolemia. Patients were required to follow a National Cholesterol Education Program step I diet for 4 weeks before the screening visit. Patients taking lipid-modifying drugs were required to complete a 4-week washout before screening blood and urine samples were obtained. A 4-week diet and placebo run-in period preceded randomization to active treatment. Patients were then randomized to 1 of 5 treatment groups 0002-9149/02/$–see front matter PII S0002-9149(01)02207-X
TABLE 1 Least-Squares Mean Percent Changes in LDL Cholesterol, Total Cholesterol, HDL Cholesterol, and Triglycerides from Baseline After 12 Weeks of Treatment in Each Lovastatin ER Treatment Group Versus Placebo Least-Squares Mean Percent Change from Baseline Versus Placebo Treatment Lovastatin ER 10 mg (n ⫽ 33) Lovastatin ER 20 mg (n ⫽ 34)* Lovastatin ER 40 mg (n ⫽ 33) Lovastatin ER 60 mg (n ⫽ 35)
LDL Cholesterol
Total Cholesterol
HDL Cholesterol
Triglycerides
⫺25.21% ⫾ 2.53% p ⱕ0.0001 ⫺30.96% ⫾ 2.53% p ⱕ0.0001 ⫺37.23% ⫾ 2.53% p ⱕ0.0001 ⫺42.05% ⫾ 2.48% p ⱕ0.0001
⫺21.22% ⫾ 2.09% p ⱕ0.0001 ⫺24.05% ⫾ 2.07% p ⱕ0.0001 ⫺28.65% ⫾ 2.09% p ⱕ0.0001 ⫺32.43% ⫾ 2.05% p ⱕ0.0001
3.33% ⫾ 2.88% p ⫽ 0.2494 6.38% ⫾ 2.86% p ⫽ 0.0271 7.62% ⫾ 2.88% p ⫽ 0.0091 5.75% ⫾ 2.83% p ⫽ 0.0441
⫺25.11% ⫾ 6.70% p ⫽ 0.0003 ⫺21.03% ⫾ 6.65% p ⫽ 0.0019 ⫺18.35% ⫾ 6.70% p ⫽ 0.0069 ⫺32.84% ⫾ 6.59% p ⱕ0.0001
*Of the 34 patients in the group, 1 did not have an end point LDL cholesterol value. Values are expressed as least-squares mean ⫾ SE and p value. Least-squares mean, SE, and p value are from Dunnett’s test for comparing lovastatin ER groups to placebo with treatment group and center as factors. Baseline ⫽ average of last 2 values before starting double-blind treatment. End point ⫽ average of last 2 values during double-blind treatment. If 1 value was missing, the other was used.
(placebo or one of the lovastatin ER doses: 10, 20, 40, or 60 mg). The study drug was administered once daily, one half hour before bedtime, for 12 weeks. Lovastatin ER is a formulation of lovastatin in a single composition osmotic tablet. This proprietary system uses osmotic modulating agents as well as polymer coatings to provide a zero-order release of the drug (i.e., a constant rate of release). The study was designed to enroll approximately 150 patients 21 to 70 years of age with hypercholesterolemia at 12 medical centers in the United States. Criteria for enrollment included: ability to provide informed consent, age 21 to 70 years, compliance with the step I diet for at least 4 weeks before study entry, and at least a 4-week washout of any lipid-modifying agents before the screening visit. Participants were enrolled according to eligibility for pharmacologic management of lipids in compliance with standards set by the National Cholesterol Education Program Adult Treatment Panel II guidelines.5 The primary efficacy variable was the percent change in LDL cholesterol from baseline to end point. Secondary efficacy variables were percent changes from baseline to end point in high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides. Clinical laboratory analyses were performed by Quintiles Laboratories, Ltd. (Smyrna, Georgia). For all efficacy variables, the baseline was defined as the average of the measurements taken after weeks 3 and 4 of the placebo run-in phase. The end points were defined as the averages of measurements taken after weeks 11 and 12 of double-blind treatment. LDL cholesterol was calculated using the Friedewald formula. If the triglyceride level was ⬍400 mg/dl, then LDL cholesterol was measured as total cholesterol ⫺ 共HDL cholesterol ⫹ 关triglyceride/5兴兲. If the triglyceride level was ⱖ400 mg/dl, then the LDL cholesterol level was measured directly. Incidence and frequency of adverse events, as well as changes in clinical laboratory parameters, physical examination, and vital signs were used to assess the safety and tolerability of the study drug. Of 287 patients screened for the study, 172 were
randomized. All 172 were included in the safety analysis, and 169 were included in the intent-to-treat efficacy analysis (i.e., were randomized, received at least 1 dose of study medication, and had at least 1 measurement obtained after taking study medication). Of the 172 patients randomized, 52.3% were men and 47.7% were women. The mean age of all randomized patients was 56.6 years (range 29 to 70). Overall, 44.8% of patients had ⬍2 risk factors for heart disease, 50.6% had ⱖ2 risk factors, and 4.7% had existing coronary heart disease, cerebrovascular disease, or peripheral vascular disease. The percentage of patients in each risk category was similar across the 5 treatment groups. Treatment compliance rates were similar in the 5 groups (range 95.5% to 98.3%). The primary and secondary efficacy results were obtained for the intent-to-treat population. In this population, the mean baseline LDL cholesterol in the placebo and active-treatment groups ranged from 172.8 to 180.6 mg/dl. The differences in least-squares mean percent reduction in LDL cholesterol compared with the placebo group were 25.21%, 30.96%, 37.23%, and 42.05% for the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively (Table 1). All of these differences were statistically significant (p ⱕ0.0001 for all comparisons). The observed LDL cholesterol reduction was sustained throughout the course of the study. Figure 1 displays the mean change in LDL cholesterol over 12 weeks by treatment group. In the intent-to-treat population, the mean baseline HDL cholesterol levels in the placebo and active treatment groups ranged from 43.5 to 48.9 mg/dl. The difference in least-squares mean percent increase in HDL cholesterol compared with the placebo group was statistically significant for the lovastatin ER 20-, 40-, and 60-mg groups (Table 1). Mean baseline total cholesterol levels in the placebo and active treatment groups ranged from 252.5 to 263.8 mg/dl. Differences in least-squares mean percent reductions in total cholesterol compared with the placebo group were statistically significant (p ⱕ0.0001) for all lovastatin ER dose groups (Table 1). Increases in HDL cholesterol and reductions in total cholesterol were near BRIEF REPORTS
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FIGURE 1. Mean change from baseline in LDL cholesterol levels during the active treatment period in each study group (intent-to-treat population). Lov ⴝ lovastatin.
maximum by the 4-week time point and remained in a similar range throughout the course of the study. Mean baseline triglyceride levels in the placebo and active treatment groups ranged from 173.8 to 206.0 mg/dl. The differences in least-squares mean reductions in triglycerides compared with the placebo group were statistically significant for all lovastatin ER dose groups (Table 1). Reductions in triglyceride levels were near maximum by the 8-week time point and remained in a similar range throughout the course of the study. At least 1 treatment-emergent sign or symptom (TESS) was experienced during the study by 64.7% of patients in the placebo group, and 74.3%, 52.9%, 75.8%, and 63.9% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were no apparent trends by study arm in the incidence of TESS reported by body system. An investigator-determined, trial drug–related TESS was experienced by 32.4% of patients in the placebo group, and 31.4%, 23.5%, 18.2%, and 30.6% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were 6 withdrawals due to TESS; investigators considered 5 to be drug-related (1 in the placebo group, 1 in the lovastatin ER 10-mg group, 2 in the 20-mg group, and 1 in the 40-mg group). Musculoskeletal system TESS occurred in 23.5%, 14.3%, 8.8%, 12.1%, and 19.4% of patients in the placebo and lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. Within the musculoskeletal system, myalgia was reported for 17.6% of patients in the placebo group and in 0%, 5.9%, 3.0%, and 2.8% of patients in the lovastatin ER 10-, 20-, 40-, and 60-mg groups, respectively. There were no patients from any group 228 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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with alanine aminotransferase or aspartate aminotransferase ⬎2 times the upper limit of normal, and no patients in the lovastatin ER groups with creatine phosphokinase ⬎5 times the upper limit of normal. •••
In this double-blind, placebo-controlled study, 12 weeks of therapy with the lovastatin ER formulation produced clinically important changes in all lipid and lipoprotein levels measured. Dose response was demonstrated in reduction of LDL cholesterol levels; a doubling of the dose from 10 to 20 mg and from 20 to 40 mg resulted in 5.7% and 6.3% greater reductions, respectively. These reductions are consistent with those observed with other statins with which a doubling of the dose lowers LDL cholesterol by an additional 6%.6 A 50% increase in dose (from 40 to 60 mg) produced a 4.8% greater LDL cholesterol reduction. As expected, the percentage of patients achieving their National Cholesterol Education Program II goal LDL cholesterol levels increased with dose, with 94.3% of patients achieving their goal at the 60-mg dose. Among patients receiving lovastatin ER 60 mg, the mean baseline LDL cholesterol was approximately 180 mg/dl; this mean LDL cholesterol level requires approximately 28% reduction to achieve an LDL cholesterol of ⬍130 mg/dl. In fact, ⱖ40% reduction in LDL cholesterol was seen in 60% of patients receiving lovastatin ER 60 mg. Lovastatin ER was well tolerated with very few patients withdrawn due to TESS, and there were no meaningful differences in terms of the frequency, severity, or relation to study drug between the treatment groups. There were no clinically significant changes in JANUARY 15, 2002
serum aminotransferases or creatine phosphokinase during the study. In summary, lovastatin ER was well tolerated in adults with hypercholesterolemia treated for 12 weeks with 10-, 20-, 40-, or 60-mg/day doses, and produced statistically significant and clinically meaningful dose-related reductions in LDL cholesterol, total cholesterol, and triglycerides, and increases in HDL cholesterol.1 These changes were generally as great as or greater than changes seen in a previous large-scale trial with corresponding doses of immediate-release lovastatin, including twice-daily administration of the immediate release formulation. Lovastatin ER is safe and effective for the treatment of adults with hypercholesterolemia, and may be associated with a lower risk of myalgia or myositis because of the lower peak plasma concentrations of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors associated with the extended-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 Evaluation of Lovastatin (EXCEL) study results. I: Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991;151:43–49. 2. McClelland GA, Stubbs RJ, Fix JA, Pogany SA, Zentner GM. Enhancement of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor efficacy 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 pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets 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 formulation of lovastatin compared to immediate-release lovastatin. Clin Ther, in press. 5. 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. 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 use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999;84:811– 815.
Usefulness of Orlistat in the Treatment of Severe Hypertriglyceridemia Anthony S. Wierzbicki, MD, PhD, Timothy M. Reynolds, Martin A. Crook, MD, PhD ype V hyperlipidemia is distinguished by gross hypertriglyceridemia (⬎⬎1,770 mg/dl [⬎⬎20 T mmol/L]) and the presence of high concentrations of chylomicrons, very-low density lipoprotein (VLDL), and their remnants in fasting plasma; it is often associated with pancreatitis.1 The condition is usually treated by combination drug therapy with fibrates, omega-3 fish oils, and nicotinic acid, and sometimes with statins.1,2 However, the hyperlipidemia is usually only partially controlled, triglycerides tend to remain at ⬎20 mmol/L (1,770 mg/dl), and patients remain at risk of developing pancreatitis. Orlistat inhibits gastrointestinal lipases.3 Chylomicrons are synthesized in the intestinal epithelium in response to the presence of free-fatty acids.4 We hypothesized that a reduction of intestinal free-fatty acid concentration by orlistat therapy would reduce chylomicron synthesis, and hence, 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 From the Department of Chemical Pathology, St. Thomas’ Hospital, London; and the Department of Chemical Pathology, Queen’s Hospital, Burton-on-Trent Staffordshire, United Kingdom. Dr. Wierzbicki’s address is: Department of Chemical Pathology, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: [email protected]. Manuscript received June 18, 2001; revised manuscript received and accepted September 27, 2001. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 January 15, 2002
MD, PhD,
and
were recruited for this study. Therapeutic use of orlistat was indicated based on Royal College of Physicians guidelines of body mass index ⬎ 27 kg/m2 and a high cardiovascular risk.5 Patients received orlistat 120 mg 3 times daily with meals; their lipid profiles were reassessed after 3 to 6 months of therapy. Previous therapy was continued as it was deemed unethical to discontinue it in these patients. The biochemical assessments performed comprised measurement of triglycerides and cholesterol by standard automated methods, and if possible, determination of the triglyceride and cholesterol content of the chylomicron, VLDL, low-density lipoprotein, and high-density lipoprotein fractions by sequential density ultracentrifugation. Multiple measurements (⬎3) of lipid profiles before and after therapy were performed to reduce the substantial intraindividual variations in triglyceride levels (Table 1); the results are quoted as the geometric mean value of these measurements. Data were analyzed by nonparametric methods for multiple comparisons of paired sample data. All patients had established type V hyperlipidemia with chylomicron triglycerides comprising ⬎50% of the total plasma triglycerides after a 14-hour fast, 80% of the patients had had ⱖ1 episode of pancreatitis, and all had established secondary type 2 diabetes mellitus. Three patients were on ciprofibrate 100 mg and 2 patients were on fenofibrate 267 mg; 2 patients were also receiving additional statin therapy with atorvastatin 20 or 80 mg. Three patients required insulin therapy (55 to 90 U daily) and 1 patient was taking metformin 850 mg 0002-9149/02/$–see front matter PII S0002-9149(01)02208-1
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