Pharmacy Division Ramathibodi Hospital


News 02/09/2544

Questions about the impact and effectiveness of generic drugs are intensifying as Eli Lilly's patent protection on Prozac ends this month.

At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL)cholesterol and apolipoprotein (apo) A-I than atorvastatin.

Contrary to some other findings, results from a new study indicate that pravastatin does reduce all subclasses of low density lipoproteins -- including small, intermediate and large LDL particles.

The 'Generic-ization' of Drugs: Will Patients Benefit?

[ Psychopharmacology Update 12(8):1, 4-5, 2001. © 2001 by Manisses Communications Group, Inc.]

Questions about the impact and effectiveness of generic drugs are intensifying as Eli Lilly's patent protection on Prozac ends this month. According to a May 30 th decision made by a three-judge panel of the U.S. Court of Appeals, Federal Circuit in Washington, D.C., the patent that would have protected Prozac until December 2003 is invalid. The decision will allow Barr Laboratories to step in as the first generic drug manufacturer to market fluoxetine.

With looming patent deadlines for the SSRI antidepressants - the blockbuster drugs of the 1990s - "generic-ization" is one of the most important developments in the pharmaceutical industry. As illustration of the competitiveness among pharmaceutical firms, the FDA accepted an Abbreviated New Drug Application (ANDA) from Barr Laboratories for a generic version of Allegra (fexofenadine). The patent, held by Aventis, does not expire until 2012.

According to the analysis of the Congressional Budget Office (CBO), generic drugs have increased their share of the prescription market from 18.6 percent in 1984 to 41.6 percent in 1996. Moreover, the CBO examined 21 brand name prescription drugs that lost patent protection between 1991 and 1993. During their first year of competition with generics, the brand name drugs lost an aver-age of 44 percent of their share to generic drugs. While the generics cost an average of 25 percent less than the original brand name drugs at retail prices. The cost of the brand name drugs did not decline.

However, the changes generic medications will bring, if any, are still up for debate. Take the case of antidepressants: Some industry analysts predict that while generic competition will bring the price of certain drugs down and provide a windfall to generic manufacturers, brand name drugs will retain most of their market share -- a win-win scenario for the pharmaceutical industry. In other words, the cost of medications overall will not fall, but access will rise.

Pharmaceutical Company Strategies

Most companies are following a two-pronged approach to the encroachment of generic medicines: 1) protecting and extending their existing patents and exclusivity agreements as much as possible, and 2) developing new compounds in order to move people to new patent-protected drugs.
The industry is working seriously on new drug development. For example, Lilly is developing duloxetine, a dual reuptake inhibitor that they hope will play the role that Prozac did in heralding a new generation of anti-depressants (see Psychopharmacology Update, July 2001). Overall, investment in R&D by research-based pharmaceutical companies has continued to increase in recent years.

In addition to major new drugs in development, some firms have also developed patented variations of existing drugs. Abbott Laboratories was able to combine valproic acid (Depakene) with sodium and receive a new generic name, divalproex sodium. With the addition of an entericcoating, Abbott was able to patent the new formulation as Depakote. Forest Laboratories has begun the FDA-approval process for escitalopram, an isomer of the SSRI citalopram (Celexa). On the other hand, Lilly announced last November that it was halting clinical trials of (r)-fluoxetine, what some were calling a "new and improved" Prozac. The single-isomer form of fluoxetine was in Phase III clinical trials, but reports of prolonged QTC (disruption of cardiac rhythms) have discouraged further development. However, Sepracor, the company that developed (r)-fluoxetine, has made an industry out of "the development of new drugs based on the separation of chemical isomers and active metabolites from currently marketed drugs" and has a number of isomers currently in development.

Questions About Generics

The FDA has maintained that generic drugs are safe and effective, but Gary Buehler, R.Ph., Director of the Office of Generic Drugs at the FDA, notes that "In this country, there is somewhat of a bias against generic drugs."
Some speculate that patent-holding companies encourage this suspicion. In fact, patent-holding firms have funded studies to try to show that generic drugs are not equivalent to brand name competitors.

In many states, legislation has been proposed (unsuccessfully, for the most part) which would limit access to generic narrow therapeutic index (NTI) drugs. NTI drugs have a narrow dosing range in which they can be effective and not produce adverse effects in patients, and pharmaceutical industry lobbyists argue that generic NTI drugs are not safe.

Since passage of the Drug Price Competition and Patent Restoration Act of 1984 (better known as the Hatch-Waxman Act), a company wishing to gain FDA approval for a generic version of an already-approved drug submits an Abbreviated New Drug Application (ANDA) that does not require the company to produce preclinical (animal) or clinical (human) data to prove safety and efficacy. Instead, they must show that it is comparable to the innovator drug in dosage form, strength, route of administration, quality, performance characteristics and intended use. The main issue is bioequivalence and, in particular, bioavailability -- i.e., does the drug deliver the same dose of the active ingredient into the bloodstream in the same amount of time.

The regulations for determining a test drug (generic competitor) bio-equivalent to a reference drug (usually a brand name drug) exist as series of "guidances" which have been variously modified over the years and touch on bioavailability and statistical issues as well as basic methodology. The standard bioequivalence study uses a crossover design in a relatively small number of subjects (24-36). Single doses of the test and reference drugs are given and blood or plasma concentrations are measured over time. The main pharmacokinetic outcomes measured are extent and rate of absorption. Extent of absorption is measured by area under the plasma concentration-time curve (AUC), calculated to the last measured concentration and extrapolated to infinity. Rate of absorption is measured by the time required to reach Cmax (maximum drug concentration).

The statistical guidance calls for the calculation of 90 percent confidence intervals for Cmax and AUC. In order for a drug to be considered bioequivalent, the confidence intervals must fall entirely between 80 and 125 percent of the reference drug. According to Rabindra Patnaik, Ph.D., Deputy Director for Bioequivalence at the FDA's Office of Generic Drugs, this means that a "difference of eight to 10 percent would make it very difficult for a drug to pass." Surveys published in The Journal of the American Medical Association have found observed average differences of three or four percent for both Cmax and AUC.

According to Patnaik, other reasons a drug may fail to be considered bioequivalent include: Despite the questions that have been raised, the FDA's Office of Generic Drugs maintains that generic equivalents are just as safe as safe and effective as brand name drugs.

"We want patients to be confident" in taking generic drugs, Buehler said.

With a substantial share of the prescription drug market, generic drugs are here to stay. However, rising drug costs make up a significant portion of rising medical costs overall, and this trend does not seem likely to be reversed any time soon.

FDA Under Pressure to Expedite Approval of Generic Drugs

The Greater Access to Pharmaceuticals Act was introduced to the Senate in May. If passed, the bill will eliminate the 30-month stay which the FDA grants to brand name firms whenever they file suit against a generic firm's patent challenge. The FDA has also been under pressure to speed up the process by which generic drugs get approved. While approval of new drugs is supported by industry "user fees" and may take around 12 months from submission to approval, the process for generics takes around 18 months. Often, an ANDA must go through two or three cycles as it is sent back to the company and to the FDA again. The Office of Generic Drugs is implementing a system by which applications that have already been submitted don't have to go "to the end of the queue" the next time around.

Revisiting Clozapine Bioequivalence

In September of last year, Psychopharmacology Update reported on a study conducted by researchers at the University of Texas that found evidence that generic and brand clozapine were not bioequivalent. The Texas study found a statistically significant difference in the mean Cmax between brand and generic clozapine and a "systematic bias" toward lower plasma concentrations for generic clozapine (they tested the formulation by Zenith Goldmine). They also found differences between Ka and Tmax, "indicating a difference in the rate of absorption between formulations."

In October, the story was picked up by the Wall Street Journal, prompting both of the generic manufacturers of clozapine to send out "Dear Doctor" letters defending the bioequivalence of generic clozapine.

At the time of the Psychopharmacology Update article, the Food and Drug Administration's Center for Drug Evaluation and Research declined to comment because they had not had a chance to review the data. Since that time they have issued a statement about the generic clozapine that does not address the findings of the study but points out that "the study was not actually designed to evaluate whether patients responded to the generic version as well as they did to Clozaril, nor could the reported results be interpreted to provide a basis for FDA regulatory action." It does state that the "FDA will continue to monitor reports regarding [Zenith's] drug product and has recommended that Zenith conduct a new bioequivalence study." (The full statement can be found at

In an interview with Psychiatric Times, Ereshefsky noted that while the naturalistic design of his study had potential for more confounding variables than a strict bioequivalence study, his results indicated the need for further research, research which the FDA has not done.

FDA Under Pressure to Expedite Approval of Generic Drugs

The Greater Access to Pharmaceuticals Act was introduced to the Senate in May. If passed, the bill will eliminate the 30-month stay which the FDA grants to brand name firms whenever they file suit against a generic firm's patent challenge. The FDA has also been under pressure to speed up the process by which generic drugs get approved. While approval of new drugs is supported by industry "user fees" and may take around 12 months from submission to approval, the process for generics takes around 18 months. Often, an ANDA must go through two or three cycles as it is sent back to the company and to the FDA again. The Office of Generic Drugs is implementing a system by which applications that have already been submitted don't have to go "to the end of the queue" the next time around.

A Comparison of Simvastatin and Atorvastatin up to Maximal Recommended Doses in a Large Multicenter Randomized Clinical Trial

* This study was conducted in 54 clinics in 16 countries and supported by a grant from Merck Research Laboratories, Rahway, New Jersey

D. Roger Illingworth1, John R. Crouse III2, Donald B. Hunninghake3, Michael H. Davidson4, Ivan D. Escobar5, Anton F. H. Stalenhoef6, Gyorgy Paragh7, Patrick T. S. Ma8, Minzhi Liu9, Michael R. Melino9, Laura O'Grady9, Michele Mercuri9 and Yale B. Mitchel9 for the Simvastatin Atorvastatin HDL Study Group

1The Oregon Health Sciences University, Portland, Oregon, USA
2Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
3Heart Disease Prevention Clinic, Minneapolis, Minnesota, USA
4Chicago Center for Clinical Research, Chicago, Illinois, USA
5Asociación Colombiana de Diabetes, Santa Fé de Bogotá, Colombia
6Academisch Ziekenhuis Nijmegen, Nijmegen, The Netherlands
7Belgyogyaszati Klinika, Debrecen, Hungary
8Bridgeland Medical Center, Calgary, Alberta, Canada
9Merck Research Laboratories, Rahway, New Jersey, USA

[Current Medical Research and Opinion 17(1):43-50, 2001]


Objective: At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL)cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind,dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety.
Primary Hypothesis: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels.
Methods: A total of 826 hypercholesterolemic patients were enrolled in this double blind,randomized, parallel, 36-week, dose escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks.
Results: During the first 12 weeks of the study,simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin,while producing slightly lower reductions in low density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison,simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses.In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine amino transferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%).
Conclusions: At the doses compared in this study, simvastatin led to greater increases in HDL CHOLESTEROL and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.


The results from several large intervention studies have unequivocally demonstrated that decreasing low-density lipoprotein (LDL) cholesterol levels with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduces the risk of coronary heart disease (CHD)[1-5]. Additional studies have shown that statin therapy can help a large proportion of dyslipidemic patients achieve their LDL cholesterol goal, as defined by US and European guidelines[6-8]. Although lowering LDL cholesterol is the primary therapeutic goal in the treatment of dyslipidemias[9-11], the cardioprotective role of high-density lipoprotein (HDL) cholesterol and the need to increase it are becoming more widely accepted[1,9]. Levels of HDL cholesterol are inversely related to the risk of CHD, and it has been estimated that every 1-2 mg/dl (0.03-0.05 mmol/l) increase in HDL cholesterol is associated with a 2-3% reduction in risk of developing CHD[12].

In addition to dose-dependent reductions in LDL CHOLESTEROL and triglycerides, statins increase HDL cholesterol and apolipoprotein A-I (apo A-I), the major protein constituent of HDL. Results from recent clinical studies have shown that simvastatin increased HDL CHOLESTEROL and apo A-I significantly more than atorvastatin,suggesting that statins differ in their capacity to raise HDL cholesterol[13-14]. In order to evaluate these differential effects further, a 36-week, multicenter,double-blind, dose-titration study was performed to compare the HDL cholesterol- and apo A-I-raising effects and safety of simvastatin (40-80 mg/day) with those of atorvastatin (20-80 mg/day) at doses expected to provide similar reductions in LDL cholesterol and at their maximal doses.



Ethical review board approval was obtained at each study center and all patients provided written informed consent. A total of 826 patients (436 men and 390 women) participated in the study. Men, postmenopausal women, or women highly unlikely to conceive, aged 21-70, were eligible for inclusion.Patient entry criteria included LDL cholesterol> 160 mg/dl (4.2 mmol/l) and triglycerides < 350mg/dl (4.0 mmol/l). Patients receiving immunosuppressant drugs, systemic azole antifungal agents or anticoagulants,were not eligible to participate in this study. Patients receiving bile acid sequestrants, HMG COA reductase inhibitors, or nicotinic acid as lipid-lowering agents, discontinued these therapies 6 weeks before study initiation. Patients receiving fibrates as lipid lowering agents discontinued these therapies 8 weeks before the start of the study.

Study Design

This dose-escalation study was double-blind,randomized and parallel-group in design. Following a four-week diet run-in period, patients meeting eligibility requirements were randomly assigned to receive simvastatin or atorvastatin for 36 weeks. In order to blind patients and investigators to treatment, patients received active tablets and identical matching placebo tablets for the other drug.The study involved three-dose comparison periods without intervening washout periods. The first period was six weeks in duration and compared simvastatin 40 mg/day with atorvastatin 20 mg/day.The second six-week period compared simvastatin 80 mg/day with atorvastatin 40 mg/day. Patients completing the first 12 weeks of the study with creatine kinase (CK) levels five-times the upper limit of normal (ULN) were eligible to participate in the third and final treatment period. This treatment period was 24 weeks in duration and compared the highest doses of each drug, simvastatin 80 mg/day,with atorvastatin 80 mg/day. Results from the first 12 weeks of the study focusing on the lipid altering efficacy of simvastatin and atorvastatin were published in a previous report[15].

Efficacy and Safety Criteria

The predefined primary efficacy endpoint was the change from baseline in HDL cholesterol averaged across the two dose comparisons in the initial 12 weeks of the study[15]. Secondary endpoints included change from baseline averaged across Weeks 6 and 12 in apo A-I and LDL cholesterol, between-group comparisons of change in HDL cholesterol for each of the three periods, and the incidence of investigator assessed drug-related clinical gastrointestinal and musculoskeletal adverse experiences during period 3 (maximal doses of both drugs).

Laboratory Methods

Plasma samples from fasting patients were shipped overnight at controlled temperature to Medical Research Laboratories International (Highland Heights, Kentucky, USA, and Brussels, Belgium), a laboratory certified by the National Heart, Lung, and Blood Institute - Centers of Disease Control Part III Program, for assay of plasma lipids, lipoproteins, and apo A-I by previously defined methods[16], as well as serum chemistry safety assays.

Statistical Analysis

All analyses were performed using an intention-to-treat analysis. Thirteen of the 826 randomized patients did not have on-treatment measurements because they were withdrawn from the study before their first laboratory assessment. Therefore 813 patients were included in the intention-to-treat population. All within-group and between-group comparisons were performed using an analysis of variance model that included terms for treatment,study center, and HDL cholesterol stratum. Data are expressed as least squares mean or median ± SE. Significance was accepted at the p < 0.050 level.


Baseline Characteristics

Demographics and baseline characteristics for the two treatment groups are provided in Table 1. The treatment groups were generally comparable with regard to baseline parameters, including lipid and lipoprotein levels, with the exception of a chance gender difference: 43% and 52% of the patients in the simvastatin and atorvastatin groups, respectively, were women.

Changes in Lipid Variables

Treatment with simvastatin led to a greater increase in mean plasma concentrations of HDL cholesterol and apo A-I compared with atorvastatin, and the between group differences in HDL cholesterol and apo A-I were more pronounced at the higher dose comparisons (Figure 1). Based on the average change from baseline across all time points during Period 3 (Weeks 18-36),the absolute between-group differences for simvastatin 80 mg and atorvastatin 80 mg were 4.5% for HDL cholesterol and 6.0% for apo A-I ( p < 0.001 for both between-group comparisons). Similarly, the between group differences for simvastatin 80 mg and atorvastatin 40 mg were 3.3% for HDL cholesterol and 4.6% for apo A-I ( p < 0.001 for both between-group comparisons). At the lowest dose comparison, the between-group differences for simvastatin 40 mg and atorvastatin 20 mg were 1.2% for HDL cholesterol ( p = 0.112) and 1.6% for apo A-I ( p = 0.041). Results for the average change from baseline across weeks 6 and 12 in HDL CHOLESTEROL (predefined primary end point) and apo-A1 were presented in a previous report[15]. Briefly, the increases in HDL cholesterol with simvastatin and atorvastatin were 9.1% and 6.8%, respectively, with the difference between the groups being 2.3%( p < 0.001). Subgroup analyses performed by age,triglyceride levels and, as was shown by Crouse et al.[13],by gender and baseline HDL cholesterol levels,revealed a consistent advantage of simvastatin over atorvastatin in raising HDL-C and apo A-I (data not shown).

Figure 1. Least-squares mean ( ±SE) percentage change from baseline in (A) high-density lipoprotein cholesterol (HDL cholesterol) and (B) apolipoprotein A-I (Apo A-I). Asterisks indicate a significant between-group difference (*p < 0.050, ***p < 0.001).
Treatment with atorvastatin led to greater reductions in LDL cholesterol and triglyceride levels compared with simvastatin for the three dose comparisons, although the magnitudes of the differences were small relative to the substantial total reductions produced by both drugs in plasma lipids and lipoproteins. Based on the average change from baseline at Weeks 6, 12 and 18 to 36, dose comparisons of simvastatin 40 mg versus atorvastatin 20 mg (Period 1), simvastatin 80 mg versus atorvastatin 40 mg (Period 2), and simvastatin 80 mg versus atorvastatin 80 mg (Period 3), produced mean reductions in LDL cholesterol of 42.4 versus 46.1%, 48.8 versus 51.3%, and 48.1 versus 53.6%, respectively ( p 0.001, all between-group comparisons). Median reductions in triglycerides for the same treatment group comparisons were 22.4 versus 23.6%, 25.9 versus 31.6%, and 23.6 versus 31.3%, respectively ( p 0.05 for all between-group comparisons). Both drugs also produced large reductions in the ratios of LDL cholesterol/HDL cholesterol (LDL/HDL) and total cholesterol/HDL CHOLESTEROL (TC/HDL). For the LDL/HDL cholesterol ratio, the percentage decreases with simvastatin versus atorvastatin were 45.9% versus 48.9% ( p < 0.001) during Period 1, 52.2 versus 53.1% (p = 0.257) during Period 2, and 50.6 versus 53.9% ( p < 0.001) during period 3, respectively ( p values refer to between group comparisons). Similar changes in the TC/HDL CHOLESTEROL ratios were observed over the three treatment periods (data not shown).

Safety Data

Table 2 shows the clinical and laboratory safety profiles for simvastatin and atorvastatin as assessed by the incidence of adverse experiences that investigators judged as possibly, probably or definitely drug- related.With regard to clinical adverse experiences, both drugs were well tolerated during the first two periods of the study; however, significantly more patients on atorvastatin than simvastatin experienced drug-related clinical adverse experiences during the final 24 weeks (92 [23.4%] versus 46 [11.9%], respectively; p <0.001). This difference was due mainly to a greater incidence of drug-related gastrointestinal symptoms in the atorvastatin group (41 [10%] versus 13 [3%] patients in the atorvastatin 80 mg and simvastatin 80 mg groups, respectively; p < 0.001). The most common drug-related gastrointestinal symptom was diarrhea, which was reported in 15 patients treated with atorvastatin 80 mg and two patients treated with simvastatin 80 mg. Three patients on atorvastatin 80 mg discontinued treatment due to diarrhea,whereas none of the patients receiving simvastatin discontinued treatment for this reason. With regard to laboratory adverse experiences (Table 2), both drugs were well tolerated during the first two periods of the study; however, in Period 3, significantly more patients on atorvastatin than simvastatin experienced drug-related laboratory adverse experiences (48 [12.2%] versus 15 [3.9%], respectively; p < 0.001) and discontinued treatment due to a laboratory adverse experience (16 [4.1%] versus 3 [0.8%], respectively;p < 0.05).

Persistent hepatic elevations of alanine aminotransferase(ALT) and/or aspartate aminotransferase(AST) greater than three-times ULN are considered clinically important. During the first two periods of the study, no patients in either treatment group sustained such elevations. However, during Period 3,there was a significantly higher incidence of clinically important ALT elevations with atorvastatin 80 mg than with simvastatin 80 mg ( p = 0.002). A total of 17 patients experienced consecutive elevations greater than three-times ULN in ALT; 15/391 (3.8%) were taking atorvastatin 80 mg and 2/384 (0.5%) were taking simvastatin 80 mg (Table 3). Similarly, of these 17 patients, 10/391 (2.6%) and 1/384 (0.3%) patients in the atorvastatin and simvastatin 80 mg treatment groups, respectively, had consecutive greater than three-fold elevations in AST ( p = 0.011 between group comparison). The between-group disparity in the incidence of clinically important ALT elevations was especially prominent among women. Clinically significant ALT elevations occurred in 12/199 (6%)of women treated with atorvastatin 80 mg compared with 1/161 (0.6%) of women treated with simvastatin 80 mg. In addition to the prominent increases in ALT and AST levels in the atorvastatin-treated patients, 12 of these patients (3.1%) had greater than three-fold elevations above ULN in gamma-glutamyl transpeptidase (GGT), and four patients also demonstrated greater than three-fold elevations above ULN in alkaline phosphatase (ALP) (Table 3). In contrast, neither of the two simvastatin-treated patients with clinically important ALT elevations experienced clinically important ALP elevations. While taking atorvastatin, four patients exhibited increases in bilirubin levels above the ULN(normal range < 1.10 mg/dl). All of these patients had normal levels of bilirubin during the baseline period. Hepatitis was not diagnosed clinically in any of the patients with clinically important aminotransferase elevations, although two atorvastatin-treated women with clinically important aminotransferase elevations complained of asthenia and fatigue, and three reported pruritus. In both groups, the onset of clinically important aminotransferase elevations occurred within 6-12 weeks after starting treatment with the 80 mg dose of either atorvastatin or simvastatin. The elevated levels typically declined to normal within 4-5 weeks after discontinuing treatment. No patients in either treatment group experienced myopathy, as defined by muscle symptoms and a greater than ten-fold increase in CK level.


This study confirmed that, across a range of doses,simvastatin produced greater increases in HDL CHOLESTEROL and apo A-I levels than atorvastatin.These findings confirm the earlier data from both a comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin (the CURVES study)[16], and a previous comparative study of simvastatin versus atorvastatin[13], that demonstrated the superiority of simvastatin over atorvastatin in raising HDL CHOLESTEROL. The clinical relevance of the differential effect of simvastatin versus atorvastatin on the lipid profile shown in the present study is presently unknown. However, in a recent placebo-controlled gemfibrozil study in men with CHD and low HDL CHOLESTEROL levels, small increases in HDL cholesterol levels of 6% (from 32 mg/dl to 34 mg/dl),accompanied by reductions in triglyceride levels of 31% (from 115 mg/dl to 60 mg/dl), resulted in a 22% reduction in major cardiovascular events, suggesting that modest increases in HDL cholesterol may be important[17]. These results are consistent with a large primary prevention study where gemfibrozil reduced the risk of CHD events in hypercholesterolemic patients[18], but are inconsistent with another large outcome study that showed no benefit of bezafibratein patients with CHD[19].

Simvastatin and atorvastatin were well tolerated during the first two periods of the study; however,during the third period, patients receiving atorvastatin 80 mg had a significantly higher incidence of clinical adverse experiences than those receiving simvastatin 80 mg, with the difference being mainly confined to the gastrointestinal system.In addition, during the third period, the incidence of clinically relevant liver function abnormalities was significantly higher in the atorvastatin group than in the simvastatin group, and this difference was particularly prominent in women. Although atorvastatin 80 mg lowered LDL cholesterol by an additional 6% compared to simvastatin 80 mg, this was accompanied by the less favorable effects of atorvastatin on HDL cholesterol and apo A-I. The mechanisms underlying the differential effects of simvastatin and atorvastatin on HDL cholesterol and apo A-I, as well as on safety and tolerability, remain unidentified. It is conceivable that these efficacy and safety differences may be related to their different chemical structures or the longer plasma half-life of atorvastatin compared with simvastatin[20-21].

Acknowledgements. This study was supported by Merck Research Laboratories, Rahway, New Jersey. We wish to thank the following investigators for participating in the study: USA: J. R. Crouse, M. H. Davidson, C. A.Dujovne, D. B. Hunninghake, H. Bays, M. Blazing, T.C. Fagan, I. J. Goldberg, D. R. Illingworth, W. Insull,W. Kaye, A. K. Khachadurian, R. Knopp, T.Littlejohn, J. McKenney, M. McGowan, J. A.Merenich, P. Samuel, H. Schrott, D. L. Sprecher, D.Stein, E. A. Stein, P. Toth, S. R. Weiss, J. H. Zavoral,B. Zedler. International: J. Frohlich, R. Habib, J. J. P.Kastelein, L. Ose, P. Barter, D. Sullivan, F. Heller, I.D. Escobar, A. Obon, R. McPherson, R. Cheung, P. T.S. Ma, S. York, B. Tomlinson, A. F. H. Stalenhoef,Gy. Paragh, C. Posados, E. Meaney, H. Istad, R.Scott, H. White, V. Kukharchuk, C. E. Tan, M.Eriksson, O. Wiklund, H. Lithell, A. G. Olsson, P.Durrington, J. Reckless and C. A. Seymour. The authors also wish to thank Dr Alan Meehan and Dr Amy Johnson-Levonas of Merck & Co, Inc, for assisting in the preparation of this manuscript.

Address for correspondence and reprint requests: D. Roger Illingworth, MD, PhD, Division of Endocrinology, Diabetes, & Clinical Nutrition (L465), The Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201, USA. Email:; Tel.: 503-494-2004; Fax: 503-494-6986

Table 1. Baseline summary table of patient demographics and lipid variables

Characteristic Simvastatin N = 405) Atorvastatin (N = 408)

female 172 (42.5%) 211 (51.7%)
male 233 (57.5%) 197 (48.3%)
Mean (SD) baseline lipid levels (mg/dl)*:

HDL cholesterol 50 (11) 51 (12)
apo A-1 150 (25) 154 (28)
LDL cholesterol 209 (51) 206 (49)
total cholesterol 295 (50) 292 (51)
triglycerides 179 (73) 177 (67)
LDL/HDL 4.4 (1.6) 4.2 (1.3)
TC/HDL 6.2 (1.8) 6.0 (1.5)
Abbreviations: apo A-I, apolipoprotein A-I; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL/HDL, ratio of LDL cholesterol and HDL cholesterol; TC/HDL, ratio of total cholesterol and HDL cholesterol
*Multiplication factors for converting lipid values from mg/dl to mmol/l: HDL cholesterol and LDL cholesterol, 0.026; triglycerides, 0.011

Table 2. Overall safety profile of simvastatin and atorvastatin

Study period Period 1 Period 2 Period 3
Duration 6 Weeks 6 Weeks 24 Weeks
Treatment group S 40 mg A 20 mg S 80 mg A 40 mg S 80 mg A 80 mg
Clinical AE 3/414 (0.7%) 3/412 (0.7%) 24/399 (6.0%) 36/404 (8.9%) 46/385 (11.9%) 92/394* (23.4%)
Discontinuation due to clinical AE 0/414 (0%) 0/412 (0%) 7/399 (1.8%) 5/404 (1.2%) 9/385 (2.3%) 11/394 (2.8%)
Laboratory AE 3/414 (0.7%) 3/412 (0.7%) 3/399 (0.8%) 4/404 (1.0%) 15/385 (3.9%) 48/394* (12.2%)
Discontinuation due to laboratory AE 0/414 (0%) 0/412 (0%) 0/399 (0%) 0/404 (0%) 3/385 (0.8%) 16/394 (4.1%)
AE: Adverse experience considered to be possibly, probably or definitely drug-related; S: simvastatin; A: atorvastatin
*Significant between treatment-group difference ( p < 0.001)

Table 3. Confirmed three-fold ULN elevations in aminotransferases, with associated liver function tests. Values shown are the first ALT elevation (test) greater than three times the ULN and the repeat levels, and the values for AST, ALP, GGT, and bilirubin corresponding to the first ALT value.

Age/sex ALT (u/l) (ULN 25) Repeat ALT (u/l) AST (u/l) (ULN 22) ALP (u/l) (ULN 72) GGT (u/l) (ULN 29) Bilirubin (mg/dl) (ULN 1.10)

Patients randomized to atorvastatin
48/F 440 669 329 179 222 0.72
41/F 234 344 162 116 118 0.89
52/F 291 260 133 227 150 1.21
49/F 194 280 163 72 134 0.62
60/M 273 179 160 68 78 0.83
69/F 137 94 171 441 1088 1.40
66/F 135 162 95 232 152 1.24
55/F 127 197 79 104 74 0.47
37/F 119 96 254 82 95 2.07
59/F 112 110 65 90 122 0.47
69/M 111 95 84 272 579 0.47
58/F 103 195 59 126 174 0.57
61/F 102 142 72 196 151 0.58
53/F 87 120 50 207 192 0.57
37/M 87 89 66 62 18 0.96

Patients randomized to simvastatin
46/M 350 369 176 74 132 0.89
45/F 82 108 58 51 24 0.42
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; GGT = gamma glutamyl transpeptidase


  1. Downs JR, Clearfield M, Weis, S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/Tex CAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615-22
  2. Scandinavian Simvastatin Survival Study Group.Randomized trial of cholesterol lowering in 4444patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9
  3. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin inpatients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339(19):1349-57
  4. West of Scotland Coronary Prevention Study Group.Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97(15):1440-45
  5. Pfeffer MA, Sacks FM, Moye LA et al. Cholesterol and recurrent events: a secondary prevention trial for normolipidemic patients. CARE Investigators. Am J Cardiol 1995;76(9):98C-106C
  6. Garmendia F, Brown AS, Reiber I, Adams PC.Attaining United States and European guideline LDL cholesterol levels with simvastatin in patients with coronary heart disease (the GOALLS Study). Curr Med Res Opin 2000;16(3):208-19
  7. McVey D, Patel H, Eminton Z, Maton S. An assessment of the efficacy of atorvastatin in treating patients with dyslipidaemia to target LDL-cholesterol goals: the atorvastatin matrix study. Int J Clin Pract 1999;53(7):509-13
  8. Brown AS, Bakker-Arkema RG, Yellen L et al. Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low density-lipoprotein cholesterol goals with atorvastatin,fluvastatin, lovastatin, and simvastatin. J Am Coll Cardiol 1998;32(3):665-72
  9. 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(23);3015-23
  10. Second Joint Task Force of European and other Societies on Coronary Prevention. Prevention of coronary heart disease in clinical practice. Eur Heart J 1998;19(10):1434-503
  11. Wood D. European and American recommendations for coronary heart disease prevention. Eur Heart J 1998;19(Suppl 2):A12-A19
  12. Gordon DJ, Probstfield JL, Garrison RJ et al. High density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79(1):8-15
  13. Crouse JR III, Frohlich J, Ose L, Mercuri M, Tobert JA.Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999;83(10):1476-7
  14. Mikhailidis DP, Wierzbicki AS. HDL-cholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin. Curr Med Res Opin 2000;16(2):139-46
  15. Kastelein JJP, Isaacsohn JL, Ose L et al. for the Simvastatin Atorvastatin HDL Study Group.Comparison of effects of simvastatin versus atorvastatin on high density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol 2000;86(2):221-3
  16. Jones P, Kafonek S, Laurora I, Hunninghake D for the CURVES investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin,lovastatin, and fluvastatin in patients with hypercholesterolemia (The CURVES study). Am J cardiol 1998;81(5):582-7
  17. Rubins HB, Robins SJ, Collins D et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410-18
  18. Frick MH, Elo O, Haapa K et al. Helsinki Heart Study:primary-prevention trial with gemfibrozil in middle aged men with dyslipidemia. Safety of treatment,changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317(20):1237-45
  19. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides inpatients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study. Circulation 2000;102(1):21-7
  20. Naoumova RP, Dunn S, Rallidis L et al. Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin. J Lipid Res 1997;38(7):1496-500
  21. Furberg CD. Natural statins and stroke risk.Circulation 1999;99(2):185-8

Pravastatin Reduces Levels of Both Small and Large LDL Particles

WESTPORT, CT (Reuters Health) Aug 27 - Contrary to some other findings, results from a new study indicate that pravastatin does reduce all subclasses of low density lipoproteins — including small, intermediate and large LDL particles — researchers report in the current issue of Atherosclerosis.

"Other studies have found that statins were ineffective in reducing the most atherogenic LDL subclasses — the small particles," Dr. Robert S. Rosenson from Northwestern University Medical School in Chicago told Reuters Health.

Dr. Rosenson and colleagues used NMR spectroscopy to study frozen plasma samples for 292 participants in the Pravastatin Limitation of Atherosclerosis in the Coronaries trial. "We looked at the response to pravastatin as a function of baseline LDL size and we looked at patients with predominantly small LDL, intermediate LDL and large LDL particles," Dr Rosenson said.

Pravastatin was effective in reducing LDL levels to the same extent in all three groups, he said. The subclasses of LDL size that were reduced depended on the predominant subclass, Dr. Rosenson added.

For example, pravastatin was most effective in reducing small particles for patients with small LDL, while for patients with large LDL, pravastatin reduced the large and intermediate LDL particles to a greater extent than the small particles. "Statins should be considered a sledgehammer, because they reduce whichever LDL subclass is predominant," Dr. Rosenson said.

For patients with predominantly small LDL particles, reducing the concentration of small LDL particles will increase the average LDL particle size, Dr. Rosenson said. "So patients with small LDL do not get the least benefit from a statin, but get the greatest benefit," he stressed.

Atherosclerosis 2001;158(2):000-000.

Back To Top © 2001-2009 RxRama ---- All rights reserved.