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Efficacy and Long-Term Adverse Effect Pattern of Lovastatin

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Efficacy and Long-Term Adverse Effect Pattern of Lovastatin Efficacy and Long-Term Adverse Effect Pattern of Lovastatin Jonathan A. Tobert, MB, PhD ovastatin is a potent inhibitor of HMG CoA re- The efficacy of lovastatin, a potent inhibitor of ductase,’ which has been available in the United HMO CoA reductase, has been established by nu- L States since September 1987 for the treatment of merous studies. At doses of 40 mg administered primary hypercholesterolemia.The remarkable efficacy twice daily, lovastatin produces a mean reduction in of lovastatin as a lipid-lowering drug was demonstrated total plasma cholesterol of 33%, attributable to a initially in normocholesterolemic volunteers,2 subse- reduction in low-density lipoprotein cholesterol of quently in small studies in patients with heterozygous 41%. The drug also produces a mean increase in familial hypercholesterolemia3-6and nonfamilial hyper- high-density lipoprotein cholesterol of 9%, and a cholesterolemia5,7and later in 5 multicenter controlled reduction in the high- and low-density lipoprotein studies involving over 1,000 patients. The first 2 large cholesterol ratio of 44%. studies8s9used a double-blind placebo-controlled design; The serious reported adverse effects of lovasta- subsequently,lovastatin was compared with cholestyra- tin are myopathy (0.5%) and asymptomatic but mine (open study),lOprobucol (double-blind study)” and marked and persistent increases in transaminases later gemtibrozil (double-blind study). ** (1.9%). Both are reversible when therapy is discon- The efficacy and mechanism of action of lovastatin tinued. Myopathy has occurred mainly in patients have been evaluated in detail in several recent re- with complicated histories who were receiving con- views.13-15In brief, the effect of lovastatin on plasma comitant therapy with immunosuppressive drugs, cholesterolis similar in patients with familial and nonfa- gemfibrozil or niacin. In an ongoing long-term safe- milial forms of hypercholesterolemia(Fig. 1). The mean ty study, 744 patients have received lovastatin for percent reductions in total plasma and low-density lipo- an average duration of 2.5 years up to March protein (LDL) cholesterol in lovastatin-treated patients 1988. Fifteen patients (2.0%) have been with- were approximately twice those in cholestyramine-treat- drawn because of drug-attributable adverse events: ed patients when both drugs were administered at full raised transaminases (9), skin rash (2), gastroin- dosage(Fig. 2). When data from approximately 200 pa- testinal symptoms (2), myopathy (1) and insomnia tients who receiveddietary therapy plus lovastatin, 40 mg (1). No effect of the drug on the human lens has twice daily, in 4*-l1 of the multicenter studies were been observed up to the date mentioned above. pooled, the following mean changes from baseline (di- Lovastatin has been available in the United etary therapy alone) were obtained: total plasma choles- States since September 1987. By March 1988, the terol, -33%; total plasma triglycerides, -24% (median); drug had been prescribed for approximately LDL cholesterol, -41%; very low density lipoprotein 250,000 patients. This clinical experience has con- (VLDL) cholesterol, -35% (median); high-density lipo- firmed the tolerability observed in clinical trials. protein (HDL) cholesterol,+9%; LDL/HDL cholesterol The good adverse-effect profile of lovastatin is thus ratio, -44%; apolipoprotein B, -29%; apolipoprotein A- now supported both by a substantial body of data I, +9%; and apolipoprotein A-II, +18%. in patients treated for over 2 years in clinical trials, In his comprehensive1988 review,13 Grundy conclud- and by experience in clinical use with a large num- ed that lovastatin and other HMG CoA reductaseinhibi- ber of patients since the drug has been available for tors are a promising new class of cholesterol-lowering prescription. drugs that should lower the risk of coronary heart disease (Am J Cardiol 1988;62:28J-341) by 50 to 60%, while appearing to be remarkably free of serious side effects, with the rare exception of rhabdo- myolysis. Grundy also pointed out that there was insuffi- cient long-term experience to rule out the possibility of new adverse events appearing during prolonged use in large patient populations. However, a substantial amount of data on long-term use has now been accumulated, much of which is unpublished. The purposeof this review From the Department of Clinical Research, Merck Sharp & Dohme is to summarize the published and unpublished data Res’earch Laboratories, Rahway, New Jersey. available on both the short- and long-term adverse ef- Address for reprints: Jonathan A. Tobert, MB, PhD, Department of Clinical Research, Merck Sharp & Dohme Research Laboratories, fects of lovastatin as of March 1988. Lovastatin was first Rahway, New Jersey 07065. administered to patients with hypercholesterolemia in 28J THE AMERICAN JOUKNAL OF CARDIOLOGY VOLUME 62 1982.16The maximal duration of therapy in any patient were taking none of the 3 concomitant therapies in ques- up to March 1988 was therefore 5 years. Five years’ tion. Most of the patients were women, whereas the pa- experience is available in only a few patients, but 200 tient population as a whole is about two-thirds men. patients have reached 3 years with lovastatin therapy; Three patients had various biliary disorders that could 700, 2 years; and 1,000, 1 year. The total number of have reduced biliary clearance, an important route of patients in clinical trials exceeded4,000 in March 1988, elimination for lovastatin. l 7 Concomitant therapy with and will exceed 8,000 by December 1988. immunosuppressant drugs including cyclosporine with The clinical adverseevents reported with an incidence gemfibrozil or niacin, or a combination, appearsto great- of 1% or more in short-term (up to 6 months) controlled clinical studies are summarized in Table I.17 In these studies, the participating clinics rated the adverseevents reported by patients as definitely, probably, possibly, probably not or definitely not drug related. The clinical adverseevents that were thus reported as being possibly, probably or definitely drug related are shown in Table II. The adverseevents were usually mild and transient, and as shown later, rarely causedthe dis- ;[[j: continuation of treatment. The most seriousreported ad- verse effects of lovastatin are myopathy, and asymptom- I I III I I I III1 atic but marked and persistent increasesin transamin- mgldl -4 -2 0 2 4 6 6 10 12 14 16 16 mmol/L ases. Myopathy is not listed in either Tables I or II Weeks becauseit has been observedin only 1lo of 756 patients participating in controlled (vs uncontrolled) studies. As FIGURE 1. Effect of lovastatin on plasma cholesterol at mini- mal (20 mg/day) and maximal (SO mg/day) recommended will be describedin detail, it usually occurred in patients dose0s FWed &c/es, study in familial hypercholesterol- with complicated medical histories who were receiving emias; open &c/es, study in nonfamilial hypercholesterol- concomitant therapy with immunosuppressant drugs, emia.s Each point (& standard deviation) represents the mean gemfibrozil or niacin, which were not used during the of 15 to 21 observations. (Adapted with permission from Ann controlled studies. Persistent increasesin transaminases Intern Meds and JAMA.g greater than 3 times the upper limit of normal were also not observedin the controlled studies,which is probably a consequenceof the fact that this effect usually occurred after at least 3 months of therapy. MYOPATHY Myopathy, defined as muscle pain or weakness,or both, plus a creatine kinase (CK) value of at least 10 TOTAL-C LDL-C times the upper limit of normal, has been reported in 17 8 O (<0.5%) of approximately 4,000 patients who had partic- ipated in clinical trials up to March 1988.10,16J8-20CK 5 usually increased to between 8,000 and 30,000 U/liter, 6I- -10 with the highest reported value at 223,000 U/liter. There 5 is very little correlation betweenthe magnitude of the CK 0 elevation and the intensity of the symptoms.In 2 of the 17 t5 -20 patients, both of whom had a cardiac transplant and were a receiving immunosuppressant therapy including cyclo- sporine, a frank rhabdomyolysis that precipitated renal 2 failure occurred.ls-ZoThese 2 patients and the other 15 g -30 recovered promptly when therapy with lovastatin was discontinued. The duration of therapy before the onset of myopathy varied from a few weeksto over 2 years. Some -40 of the late-appearing cases are probably related to changes in concomitant therapy. The clinical features of these 17 patients with myopa- thy, and their concomitant therapy with cyclosporine, gemfibrozil and niacin are listed in Table III. It is evident FIGURE 2. Mean percent changes with 95% confidence inter that most of thesepatients have a variety of complicating vals in total cholesterol (C), low-density lipoprotein (LDL) cho factors, particularly cardiac transplantation with immu- lesterol, and high-density lipoprotein (HDL) cholesterol.10 Cho- nosuppressanttherapy. However, the phenomenon has lestyramine 12 g twice daily (n = 55) is represented by c/ear bars, lovastatin 20 mg twice daily (n = 85) by hatched bars, been observedin 4 patients with no particular complicat- and lovastatin 40 mg twice daily (n = 88) by black bars. (Re- ing factors other than ischemic heart disease,3 of whom produced with permission from JAMA.lD) THE AMERICAN JOURNAL OF CARDIOLOGY NOVEMBER 11, 1988 29J A SYMPOSIUM: HMG CoA REDUCTASE INHIBITORS ly increasethe risk of myopathy (Table IV). When none has been reported to produce cholestasis.22In 6 patients of theseconcomitant therapies was present,the incidence who had cardiac transplants, were receiving cyclosporine of myopathy was lessthan 1 in 500. Although niacin was therapy and did not have myopathy, the plasma levels of involved in only 3 patients, its role as a risk factor is active metabolites of lovastatin were also elevated to an supported by the fact that in all 3 casesmyopathy oc- averageof about 4 times the expectedvalue. On the other curred a few weeksafter it had been added to the thera- hand, the plasma concentrations of active metabolites of peutic regimen of patients taking lovastatin for several lovastatin were not usually elevated in patients receiving months.
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