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Hydroxymethylglutaryl coenzyme A reductase inhibitors as monotherapy in the treatment of hypercholesterolemia
Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors as Monotherapy in the Treatment of Hypercholesterolemia J. Findlay Walker, MD, and Deborah R. Shapiro, DrPH
ntil recently, the standard therapies available for the treatment of hyperlipoproteinemia, especially primary hypercholesterolemia, have been relatively limited both in number and in therapeutic usefulness. In general, the more effective agents have been poorly tolerated, whereasthe better-tolerated agentshave had very limited efficacy. To some extent, at least, the limitations of the available therapies have beenresponsible for the failure of the medical community to adopt vigorous therapeutic strategies for the modification of lipid abnormalities, which have been recognized as cardiovascular risk factors for at least 30 years. During the past decade,agentshave beendescribedthat lower serum cholesterol by inhibiting activity of the enzymehydroxymethylglutaryl coenzymeA (HMG CoA) reductase,one of the early and rate-limiting enzymesin the body’s intrinsic synthesisof cholesterol.The biosynthetic pathway is summarized in Figure 1.l Becausemost cholesterol in the body derives from intrinsic synthesis,not dietary intake, this was considered to be a desirable and specific target for therapeutic intervention. Among the HMG CoA reductaseinhibitors, lovastatin and simvastatin have eachbeenapprovedfor marketing in a number of countries. Lovastatin is marketed in the United States, Canada, Germany and Finland, among others, while simvastatin has been released in Sweden,the United Kingdom, The Netherlands, France and Italy. Pravastatin is in the late stagesof development, but is not yet marketed,whereasfluvastatin is undergoing early clinical studies. This article briefly reviews information on the comparative efficacy of lovastatin, simvastatin and standard therapy, basedon clinical studiesperformedaspart of the manufacturer’s drug development programs.
U
A variety of double-blind studiis have compared the efficacy of hydroxymethylglutaryl coenzyme A reductase inhibitors (lovastatin and simvastatin) with that of control agents (cholestyramine, fibrates and probucol) in patients with type IIA or IIB primary hypercholesterolemia. Results have shown that both lovastatin and simvastatin are more effective than the standard therapies with regard to reducing total and low-density lipoprotein cholesterol. Decreases in triglycerides and increases in highdensity lipoprotein cholesterol were generally greater with fibrates. Ongoing studiis are assessing the benefits of lovastatin and simvastatin in reducing the incidence of mortality from coronary artery disease, as well as causing regression of coronary atheroma. (Am J Cardid 1990;65:19F42F)
PATIENT
From Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey. Address for reprints: J. Findlay Walker, MD, Merck Sharp & Dohme Research Laboratories, Sumney Town Pike, West Point Building 35-7, West Point, Pennsylvania 09486.
POPULATIONS
AND STUDY DESIGN
Patients involved in these clinical programs had primary hypercholesterolemiaof the IIA or IIB phenotype, with total cholesterol levels, on dietary therapy, >240 mg/dl, and low-density lipoprotein cholesterol levels >165 mg/dl. The subjects had undergone a washout period from previous drug therapy, followed by dietary therapy for at least 4 weeks, before randomization. In studies conducted in the United States, a central laboratory was used for all lipid and other biochemical tests.In multinational studiesin other countries, a central laboratory wasnot feasible,in general,but care wastaken to assurethe quality of the methodsused;whereverpossible, Centers for DiseaseControl standardization, or an equivalent, was ensured.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 20,199O
19F
A SYMPOSIUM:
EVOLVING
FIGURE 1. Chobted from Am J Cardh#)
TABLE I
Numbers
ISSUES IN THE TREATMENT
biosydhetic
of Patients
pathway.
in Comparative
HMO CoA = hy&oxe
No. of Pts.
101
Lovastatin vs placebo (familial hypercholesterolemia) Lovastatin vs placebo (nonfamilial hypercholesterolemia) Lovastatin vs cholestyramine Lovastatin vs probucol Lovastatin vs gemfibrozil Simvastatin vs placebo (familial and nonfamilial hypercholesterolemia) Simvastatin vs cholestyramine* Simvastatin vs probucol Simvastatin vs gemfibrozil Simvastatin vs bezafibrate
101 264 290 334 416 516 243 290 232
All direct comparative studiesweredouble-blind, with the exception of comparisons to cholestyramine, for which there is no easily available placebo. The doubleblind, comparative periods of the studies lasted 6 to 8 weekswhen the comparative agent was placeboand 12 to 14 weeks when active control agents were used. These periods were followed by long-term open extensions. Dosesof lovastatin ranged from 20 to 80 mg, given either II
Percent
Treatment
Changes in Lipid Variables-Comparative
Regimen
Lovastatin 20 mg* Lovastatin 40 mg Lovastatin 80 mg Cholestyramine Probucol Gemfibrozilt
Total (%)
The numbers of patients treated in comparativestudies with lovastatin and simvastatin are listed in Table I. Overall, in both programs, >60% of patients had familial hypercholesterolemia. Approximately 40% of the subjects had a history of ischemic heart disease. Tables II and III list the results of the studiesin terms of effectson total cholesterol,low- and high-density lipoprotein cholesterol, and the ratio of low- to high-density cholesterol for lovastatin and simvastatin, respectively. Both lovastatin and simvastatin were significantly more effective than were the control agentsin terms of decreasing total and low-density lipoprotein cholesterol.Modest * Data on tile, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.
Studies with Lovastatin LDL (%)
HDL (%)
LDL/HDL
-25 to -28 -27 to -38 -42 to -45 -27 +26 -24/-23
-16to-22
-18to-25
+6 to +13
-22 to -27 -30 to -34 -17
-26 to -32 -37 to -42 -23 -8 -13/-18
+5 to +13
-10 -ll/-16
(RepdntedwRhpennhsion
RESULTS
protocols.
TABLE
coemymeA.
as a single dosein the eveningor twice daily. Simvastatin was generally given in dosesof 10 to 40 mg oncedaily in the evening.Comparative agentswere given according to the recommendations of the respective manufacturers: cholestyramine2* at a dose of 12 g twice daily (or the maximal dosetolerated by the patient), probuco13v4 at 500 mg twice daily, gemfibrozil at 600 mg twice daily5* and bezafibrate at 200 mg 3 times daily.*
Studies
Study
*Two
OF HYPERCHOLESTEROLEMIA
+9to+12 +8 -23 18/12
* Because the percentage change at a given dose sometimes differed across studies, a range of response is given. if applicable. t The data from this study were analyzed in 2 strata: l-total cholesterol <300 mg/dl; II-total cholesterol >3YJ mg/dl. Responses are given for stratum HDL = hi&density lipoprotein cholesterol; LDL = lowdensity lipoprotein cholesterol; Total = total cholesterol.
20F
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
l/stratum
(%)
II.
TABLE III Percent Changes in Lipid Variables-Comparative Treatment
Regimen
Simvastatin 10 mg* Simvastatin 20 mg Simvastatin 40 mg Cholestyramine Probucol Gemfibrozilt Bezafibratet
Studies with Simvastatin
Total (%)
LDL (%)
HDL (%)
LDL/HDL
(%)
-21 -27 to -28 -30 to -33 -15to-21 -13 -16/-16 -17/-18
-27 -32 to -35 -40 to -41 -21 tp -29 -8 -2O/-18 -2o/-20
+4 to +10 +10to+14 +10to+13 +8 to +9 -27 17/14 14/23
-27 to -32 -36 to -40 -45 -25 to -34 +31 -28/-22 -25/-31
* Because the percentage change at a gwen dose sometimes differed across studies, a range of response is given. if applicable. +The data from these studies were analyzed !n 2 strata: l-total cholesterol <300 mg/dl: II-total cholesterol X300 mg/dl. Responsesare gwen for stratum I/stratum II. Abbrewatlons as I” Table Il.
inhibit hepatic synthesis of fatty acids. Getibrozil has been shown to be effective in the primary prevention of coronary events, in the Helsinki Heart Study.‘O The HMG CoA reductaseinhibitors have a well-defined mechanismof action, involving specificinhibition of a key regulatory enzyme in the cholesterol biosynthetic cascade.The subsequentdecreasein intracellular cholesterol levels leads to enhancementof cellular low-density lipoprotein receptor activity, which increases the cell’s uptake of low-density lipoprotein cholesterol from the plasma.Circulating cholesterollevelsdecreaseasa result. After oral administration and absorption, lovastatin and simvastatin undergo substantial first-pass extraction by the liver,’ l allowing relatively little active drug to enter DISCUSSION The therapeutic options available for the treatment of the systemic circulation. Becausethe liver is one of the hypercholesterolemiahave beensomewhatlimited either principal sites of cholesterol synthesis,‘* this first-pass by relatively low degreesof efficacy or by poor tolerabil- extraction effectively means that the highest concentraity. Cholestyramine, the first of the lipid-lowering agents tions of active drug are found in the desirable target shown to be effective in primary prevention of coronary organ. With their highly specific mechanism of action, and events,6is poorly tolerated, especiallyat higher doses.’Its mechanismof action involves inhibition of enterohepatic remarkable efficacy as previously described,thesedrugs recirculation of bile acids, with a subsequentincreasein are likely to be highly desirable additions to the available the activity of low-density lipoprotein receptors on the lipid-lowering agents. As described by Tobert et alI3 in hepatic cell; this leads to increaseduptake of low-density this supplement,up to 5 yearsof experienceand 2 yearsof lipoprotein cholesterolfrom the plasma,for production of market experience with lovastatin in large numbers of more bile acids. Consequently, plasma cholesterol levels patients have revealed a good tolerability profile. Studiesare underway to documentthe benefit of these decrease.’ Probucol acts by a mechanism that is poorly under- drugs in reducing coronary mortality, as well as in causstood, but may involve enhancednon-receptor-mediated ing regressionof coronary atheroma. As these programs clearance of lipoproteins. It has also been reported to come to fruition, the HMG CoA reductase inhibitors prevent oxidative modification of lipoprotein particles.* should emerge as a mainstay of hypocholesterolemic Most of the decreasein cholesterollevelsseenwith probu- therapy. co1is attributable to reductions in high-density lipoprotein cholesterol,which may reflect decreasedsynthesisof REFERENCES 1. Alberts AW. Discovery, biochemistry, and biology of lovastatin. Am J Cardiol apolipoprotein A-I.g 1988,62:1OJ-15J. The fibrates-gemfibrozil, bezafibrate and others2. Lovastatin Study Group III. Therapeutic responses to lovastatin and cholestygenerally have a greater effect on triglyceride levelsthan ramine therapy for severe primary hypercholesterolemia. JAMA 1988;260:359366. on cholesterol,asconfirmed in thesestudies.Theirm,=h3. Lovastatin Study Group IV. A multicenter comparison of lovastatin and anisms of action are complex, but involve activation of probucol in the therapy of severe primary hypercholesterolemia (abstr). Arrerio1988;8:587a. lipoprotein lipase with subsequentenhancementof me- sclerosis 4. Simvastatin Multicenter Study Group II: Effects of simvastatin and probucol tabolism of triglyceride-rich lipoproteins. They may also in hypercholesterolemia. Am J Cardiol 1989,63:682-686. increasesin levels of high-density lipoprotein cholesterol were seenwith all agents except probucol; in severalinstances,the increasesseenwith the fibrates were significantly greater than thoseobservedwith lovastatin or simvastatin. Triglyceride levels are generally lowered to a greater extent by the fibrates than by HMG CoA reductase inhibitors. In the 2 studies reported here in which comparisons were made to gemfibrozil, that agent achieved reductions in triglycerides of 30 to 45%, compared with reductions of approximately 15%with lovastatin or simvastatin.5*
* Data on tile, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.
5. Tikkanen MJ, Helve E, JPLttell A, Kaarsalo E, Lehtonen A, Malbecq W, Oksa H, P&&kinen P, Salmi J, Veharanta T, Viikari J, AHrynen M, and the Finnish Lovastatin Study Group. Comparison between lovastatin and gemtibrozil in the treatment of primary hypercholesterolemia. The Finnish multicenter study. Am J Cardiol I988,62:35J-43J.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 20,199O
21F
A SYMPOSIUM:
EVOLVING
ISSUES IN THE TREATMENT
OF HYPERCHOLESTEROLEMIA
6. Lipid Research Clinics Program. The Lipid Research Clinics Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in the incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:351-374. 7. Brown MS, Goldstein JL. Drugs used in the treatment of hyperlipidemias. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. The Pharmacological Basis of Therapeutics. New York: Macmillan, 1985~827-845. 8. Steinberg D. Metabolism of lipoproteins and their role in the pathogenesis of atherosclerosis. Atherosclerosis Reu 1988:18:1-23. 9. Nest4 PJ, Billington T. Effects of probucol on low-density lipoprotein removal and high-density lipoprotein synthesis. Atherosclerosis 1981:38:203-209, 10. Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen
22F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med J987:3J7:J237mJ245. II. Duggan DE, Chen IW, Bayne WF, Halpin RA, Duncan CA, Schwartz MS, Stubbs RJ, Vickers S. Physiological disposition of lovastatin. Drug Metab Dispos 1989;166-173. 12. Tunley SD, Dutschy JM. Cholesterol metabolism and excretion. In: Arias I, Pepper H, Schacter D, Shaforty DA, eds. The Liver, Biology and Pathology. New York: Raven Press, 1982:467. 13. Tobert JA, Shear CL, Chremos AN, Mantell GE. Clinical experience with lovastatin. Am J Cardiol 1990;65:23F-26F.
ntil recently, the standard therapies available for the treatment of hyperlipoproteinemia, especially primary hypercholesterolemia, have been relatively limited both in number and in therapeutic usefulness. In general, the more effective agents have been poorly tolerated, whereasthe better-tolerated agentshave had very limited efficacy. To some extent, at least, the limitations of the available therapies have beenresponsible for the failure of the medical community to adopt vigorous therapeutic strategies for the modification of lipid abnormalities, which have been recognized as cardiovascular risk factors for at least 30 years. During the past decade,agentshave beendescribedthat lower serum cholesterol by inhibiting activity of the enzymehydroxymethylglutaryl coenzymeA (HMG CoA) reductase,one of the early and rate-limiting enzymesin the body’s intrinsic synthesisof cholesterol.The biosynthetic pathway is summarized in Figure 1.l Becausemost cholesterol in the body derives from intrinsic synthesis,not dietary intake, this was considered to be a desirable and specific target for therapeutic intervention. Among the HMG CoA reductaseinhibitors, lovastatin and simvastatin have eachbeenapprovedfor marketing in a number of countries. Lovastatin is marketed in the United States, Canada, Germany and Finland, among others, while simvastatin has been released in Sweden,the United Kingdom, The Netherlands, France and Italy. Pravastatin is in the late stagesof development, but is not yet marketed,whereasfluvastatin is undergoing early clinical studies. This article briefly reviews information on the comparative efficacy of lovastatin, simvastatin and standard therapy, basedon clinical studiesperformedaspart of the manufacturer’s drug development programs.
U
A variety of double-blind studiis have compared the efficacy of hydroxymethylglutaryl coenzyme A reductase inhibitors (lovastatin and simvastatin) with that of control agents (cholestyramine, fibrates and probucol) in patients with type IIA or IIB primary hypercholesterolemia. Results have shown that both lovastatin and simvastatin are more effective than the standard therapies with regard to reducing total and low-density lipoprotein cholesterol. Decreases in triglycerides and increases in highdensity lipoprotein cholesterol were generally greater with fibrates. Ongoing studiis are assessing the benefits of lovastatin and simvastatin in reducing the incidence of mortality from coronary artery disease, as well as causing regression of coronary atheroma. (Am J Cardid 1990;65:19F42F)
PATIENT
From Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey. Address for reprints: J. Findlay Walker, MD, Merck Sharp & Dohme Research Laboratories, Sumney Town Pike, West Point Building 35-7, West Point, Pennsylvania 09486.
POPULATIONS
AND STUDY DESIGN
Patients involved in these clinical programs had primary hypercholesterolemiaof the IIA or IIB phenotype, with total cholesterol levels, on dietary therapy, >240 mg/dl, and low-density lipoprotein cholesterol levels >165 mg/dl. The subjects had undergone a washout period from previous drug therapy, followed by dietary therapy for at least 4 weeks, before randomization. In studies conducted in the United States, a central laboratory was used for all lipid and other biochemical tests.In multinational studiesin other countries, a central laboratory wasnot feasible,in general,but care wastaken to assurethe quality of the methodsused;whereverpossible, Centers for DiseaseControl standardization, or an equivalent, was ensured.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 20,199O
19F
A SYMPOSIUM:
EVOLVING
FIGURE 1. Chobted from Am J Cardh#)
TABLE I
Numbers
ISSUES IN THE TREATMENT
biosydhetic
of Patients
pathway.
in Comparative
HMO CoA = hy&oxe
No. of Pts.
101
Lovastatin vs placebo (familial hypercholesterolemia) Lovastatin vs placebo (nonfamilial hypercholesterolemia) Lovastatin vs cholestyramine Lovastatin vs probucol Lovastatin vs gemfibrozil Simvastatin vs placebo (familial and nonfamilial hypercholesterolemia) Simvastatin vs cholestyramine* Simvastatin vs probucol Simvastatin vs gemfibrozil Simvastatin vs bezafibrate
101 264 290 334 416 516 243 290 232
All direct comparative studiesweredouble-blind, with the exception of comparisons to cholestyramine, for which there is no easily available placebo. The doubleblind, comparative periods of the studies lasted 6 to 8 weekswhen the comparative agent was placeboand 12 to 14 weeks when active control agents were used. These periods were followed by long-term open extensions. Dosesof lovastatin ranged from 20 to 80 mg, given either II
Percent
Treatment
Changes in Lipid Variables-Comparative
Regimen
Lovastatin 20 mg* Lovastatin 40 mg Lovastatin 80 mg Cholestyramine Probucol Gemfibrozilt
Total (%)
The numbers of patients treated in comparativestudies with lovastatin and simvastatin are listed in Table I. Overall, in both programs, >60% of patients had familial hypercholesterolemia. Approximately 40% of the subjects had a history of ischemic heart disease. Tables II and III list the results of the studiesin terms of effectson total cholesterol,low- and high-density lipoprotein cholesterol, and the ratio of low- to high-density cholesterol for lovastatin and simvastatin, respectively. Both lovastatin and simvastatin were significantly more effective than were the control agentsin terms of decreasing total and low-density lipoprotein cholesterol.Modest * Data on tile, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.
Studies with Lovastatin LDL (%)
HDL (%)
LDL/HDL
-25 to -28 -27 to -38 -42 to -45 -27 +26 -24/-23
-16to-22
-18to-25
+6 to +13
-22 to -27 -30 to -34 -17
-26 to -32 -37 to -42 -23 -8 -13/-18
+5 to +13
-10 -ll/-16
(RepdntedwRhpennhsion
RESULTS
protocols.
TABLE
coemymeA.
as a single dosein the eveningor twice daily. Simvastatin was generally given in dosesof 10 to 40 mg oncedaily in the evening.Comparative agentswere given according to the recommendations of the respective manufacturers: cholestyramine2* at a dose of 12 g twice daily (or the maximal dosetolerated by the patient), probuco13v4 at 500 mg twice daily, gemfibrozil at 600 mg twice daily5* and bezafibrate at 200 mg 3 times daily.*
Studies
Study
*Two
OF HYPERCHOLESTEROLEMIA
+9to+12 +8 -23 18/12
* Because the percentage change at a given dose sometimes differed across studies, a range of response is given. if applicable. t The data from this study were analyzed in 2 strata: l-total cholesterol <300 mg/dl; II-total cholesterol >3YJ mg/dl. Responses are given for stratum HDL = hi&density lipoprotein cholesterol; LDL = lowdensity lipoprotein cholesterol; Total = total cholesterol.
20F
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
l/stratum
(%)
II.
TABLE III Percent Changes in Lipid Variables-Comparative Treatment
Regimen
Simvastatin 10 mg* Simvastatin 20 mg Simvastatin 40 mg Cholestyramine Probucol Gemfibrozilt Bezafibratet
Studies with Simvastatin
Total (%)
LDL (%)
HDL (%)
LDL/HDL
(%)
-21 -27 to -28 -30 to -33 -15to-21 -13 -16/-16 -17/-18
-27 -32 to -35 -40 to -41 -21 tp -29 -8 -2O/-18 -2o/-20
+4 to +10 +10to+14 +10to+13 +8 to +9 -27 17/14 14/23
-27 to -32 -36 to -40 -45 -25 to -34 +31 -28/-22 -25/-31
* Because the percentage change at a gwen dose sometimes differed across studies, a range of response is given. if applicable. +The data from these studies were analyzed !n 2 strata: l-total cholesterol <300 mg/dl: II-total cholesterol X300 mg/dl. Responsesare gwen for stratum I/stratum II. Abbrewatlons as I” Table Il.
inhibit hepatic synthesis of fatty acids. Getibrozil has been shown to be effective in the primary prevention of coronary events, in the Helsinki Heart Study.‘O The HMG CoA reductaseinhibitors have a well-defined mechanismof action, involving specificinhibition of a key regulatory enzyme in the cholesterol biosynthetic cascade.The subsequentdecreasein intracellular cholesterol levels leads to enhancementof cellular low-density lipoprotein receptor activity, which increases the cell’s uptake of low-density lipoprotein cholesterol from the plasma.Circulating cholesterollevelsdecreaseasa result. After oral administration and absorption, lovastatin and simvastatin undergo substantial first-pass extraction by the liver,’ l allowing relatively little active drug to enter DISCUSSION The therapeutic options available for the treatment of the systemic circulation. Becausethe liver is one of the hypercholesterolemiahave beensomewhatlimited either principal sites of cholesterol synthesis,‘* this first-pass by relatively low degreesof efficacy or by poor tolerabil- extraction effectively means that the highest concentraity. Cholestyramine, the first of the lipid-lowering agents tions of active drug are found in the desirable target shown to be effective in primary prevention of coronary organ. With their highly specific mechanism of action, and events,6is poorly tolerated, especiallyat higher doses.’Its mechanismof action involves inhibition of enterohepatic remarkable efficacy as previously described,thesedrugs recirculation of bile acids, with a subsequentincreasein are likely to be highly desirable additions to the available the activity of low-density lipoprotein receptors on the lipid-lowering agents. As described by Tobert et alI3 in hepatic cell; this leads to increaseduptake of low-density this supplement,up to 5 yearsof experienceand 2 yearsof lipoprotein cholesterolfrom the plasma,for production of market experience with lovastatin in large numbers of more bile acids. Consequently, plasma cholesterol levels patients have revealed a good tolerability profile. Studiesare underway to documentthe benefit of these decrease.’ Probucol acts by a mechanism that is poorly under- drugs in reducing coronary mortality, as well as in causstood, but may involve enhancednon-receptor-mediated ing regressionof coronary atheroma. As these programs clearance of lipoproteins. It has also been reported to come to fruition, the HMG CoA reductase inhibitors prevent oxidative modification of lipoprotein particles.* should emerge as a mainstay of hypocholesterolemic Most of the decreasein cholesterollevelsseenwith probu- therapy. co1is attributable to reductions in high-density lipoprotein cholesterol,which may reflect decreasedsynthesisof REFERENCES 1. Alberts AW. Discovery, biochemistry, and biology of lovastatin. Am J Cardiol apolipoprotein A-I.g 1988,62:1OJ-15J. The fibrates-gemfibrozil, bezafibrate and others2. Lovastatin Study Group III. Therapeutic responses to lovastatin and cholestygenerally have a greater effect on triglyceride levelsthan ramine therapy for severe primary hypercholesterolemia. JAMA 1988;260:359366. on cholesterol,asconfirmed in thesestudies.Theirm,=h3. Lovastatin Study Group IV. A multicenter comparison of lovastatin and anisms of action are complex, but involve activation of probucol in the therapy of severe primary hypercholesterolemia (abstr). Arrerio1988;8:587a. lipoprotein lipase with subsequentenhancementof me- sclerosis 4. Simvastatin Multicenter Study Group II: Effects of simvastatin and probucol tabolism of triglyceride-rich lipoproteins. They may also in hypercholesterolemia. Am J Cardiol 1989,63:682-686. increasesin levels of high-density lipoprotein cholesterol were seenwith all agents except probucol; in severalinstances,the increasesseenwith the fibrates were significantly greater than thoseobservedwith lovastatin or simvastatin. Triglyceride levels are generally lowered to a greater extent by the fibrates than by HMG CoA reductase inhibitors. In the 2 studies reported here in which comparisons were made to gemfibrozil, that agent achieved reductions in triglycerides of 30 to 45%, compared with reductions of approximately 15%with lovastatin or simvastatin.5*
* Data on tile, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.
5. Tikkanen MJ, Helve E, JPLttell A, Kaarsalo E, Lehtonen A, Malbecq W, Oksa H, P&&kinen P, Salmi J, Veharanta T, Viikari J, AHrynen M, and the Finnish Lovastatin Study Group. Comparison between lovastatin and gemtibrozil in the treatment of primary hypercholesterolemia. The Finnish multicenter study. Am J Cardiol I988,62:35J-43J.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 20,199O
21F
A SYMPOSIUM:
EVOLVING
ISSUES IN THE TREATMENT
OF HYPERCHOLESTEROLEMIA
6. Lipid Research Clinics Program. The Lipid Research Clinics Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in the incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:351-374. 7. Brown MS, Goldstein JL. Drugs used in the treatment of hyperlipidemias. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. The Pharmacological Basis of Therapeutics. New York: Macmillan, 1985~827-845. 8. Steinberg D. Metabolism of lipoproteins and their role in the pathogenesis of atherosclerosis. Atherosclerosis Reu 1988:18:1-23. 9. Nest4 PJ, Billington T. Effects of probucol on low-density lipoprotein removal and high-density lipoprotein synthesis. Atherosclerosis 1981:38:203-209, 10. Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen
22F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med J987:3J7:J237mJ245. II. Duggan DE, Chen IW, Bayne WF, Halpin RA, Duncan CA, Schwartz MS, Stubbs RJ, Vickers S. Physiological disposition of lovastatin. Drug Metab Dispos 1989;166-173. 12. Tunley SD, Dutschy JM. Cholesterol metabolism and excretion. In: Arias I, Pepper H, Schacter D, Shaforty DA, eds. The Liver, Biology and Pathology. New York: Raven Press, 1982:467. 13. Tobert JA, Shear CL, Chremos AN, Mantell GE. Clinical experience with lovastatin. Am J Cardiol 1990;65:23F-26F.