The Power of Statins: Aggressive Lipid Lowering

Transcription

1 Clin. Cardiol. Vol. 26 (Suppl. III), III-25 III-31 (2003) The Power of Statins: Aggressive Lipid Lowering EVAN A. STEIN, M.D., PH.D. Medical Research Laboratories International, Cincinnati, Ohio, USA Address for reprints: Evan A. Stein, M.D., Ph.D. President, Medical Research Laboratories International Director, Metabolic and Atherosclerosis Research Center 2 Tesseneer Drive Highland Heights, KY 41076, USA ESteinMRL@aol.com Summary: A large body of evidence has demonstrated that reductions in low-density lipoprotein cholesterol (LDL-C) decrease the risk of coronary heart disease (CHD) and related adverse events. The greatest reductions in morbidity and mortality are attained in higher-risk patients, suggesting that targeting this group can maximize the cost-effectiveness of statins, since fewer patients need to be treated to prevent one event. High-risk individuals (those with preexisting CHD or CHD risk equivalents) require aggressive lipid lowering to achieve the stringent LDL-C goal levels established by the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III). The hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have assumed the central role in this setting because of their superior ability to reduce LDL-C across the spectrum of CHD risk. Rosuvastatin, a new agent in this class, reduces LDL-C to a significantly greater degree than atorvastatin, pravastatin, or simvastatin. The more aggressive goals put forward since ATP I (1987) have heightened interest in more efficacious statins. As a result, simvastatin, atorvastatin, and now rosuvastatin have been developed, adding sequentially greater LDL-C-reducing capacity for the physician. Substantially more patients, particularly high-risk patients, are thereby able to achieve NCEP ATP III target LDL-C levels with rosuvastatin. Other cholesterol-lowering drugs (bile acid sequestrants, niacin, plant stanols, and fibrates) are much less effective at lowering LDL-C and are much less well tolerated but may be useful when combined with statins. Novel classes of agents, such as cholesterol transport inhibitors, are currently under investigation and may likewise hold promise to help achieve ATP III goals when used in combination regimens initiated with a statin. Key words: coronary heart disease, hydroxymethylglutaryl coenzyme A reductase inhibitor, hypercholesterolemia, lipids, statins Introduction In recent decades, a wealth of evidence has confirmed that reductions in low-density lipoprotein cholesterol (LDL-C) significantly decrease the risk of coronary heart disease (CHD). 1 The beneficial impact on CHD risk is evident regardless of the method by which LDL-C is reduced. However, it is important to note that the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have produced the most dramatic and consistent reductions in both LDL-C and CHD (Table I). 1 8 The benefits of statins extend across the spectrum of CHD risk, with the greatest absolute reductions in morbidity and mortality occurring in higher-risk individuals. The cost-effectiveness of statin therapy can thereby be maximized by targeting high-risk patients. 3 Treating High-Risk Patients to Low-Density Lipoprotein Cholesterol Goal According to the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), persons with established CHD or CHD risk equivalents have the greatest likelihood of adverse outcomes. 1 The 10-year risk of a major adverse coronary event is > 20% in both groups. The target LDL-C level is < 2.59 mmol/l (< 100 mg/mg/dl) for these high-risk patients, but only a small minority are currently attaining this objective. For instance, a recent multicenter survey found that only 18% of 1,460 patients with established CHD and dyslipidemia achieved the LDL-C goal specified by the NCEP ATP II (Fig. 1). 9 The findings from this study were reinforced by another analysis focusing on 48,586 patients with CHD, of whom only 39% were taking lipid-lowering

2 III-26 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 TABLE I Effect of statin therapy on coronary heart disease risk Baseline Statin Placebo LDL-C On-treatment LDL-C event a event a RRR ARR Trial (mmol/l) mmol/l % reduction rate (%) rate (%) (%) (%) NNT 4S LIPID b CARE WOSCOPS AFCAPS/TexCAPS a Nonfatal myocardial infarction (MI) or coronary heart disease death in CARE, LIPID, WOSCOPS trials; nonfatal or fatal MI, unstable angina, or sudden cardiac death in AFCAPS/TexCAPS trial; nonfatal MI, coronary death, or resuscitated cardiac arrest in 4S trial. b vs. placebo. Abbreviations: 4S = Scandinavian Simvastatin Survival Study, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study, CARE = Cholesterol and Recurrent Event, LDL-C = low-density lipoprotein cholesterol, LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease, RRR = relative risk reduction, ARR = absolute risk reduction, NNT = numbers needed to treat, WOSCOPS = West of Scotland Coronary Prevention Study. Adapted from Ref. No. 3. agents, whereas only 25% achieved the target ATP II LDL-C level of 2.59 mmol/l ( 100 mg/mg/dl). 10 These observations underscore the need for a redoubling of efforts aimed at improving the recognition and treatment of elevated LDL-C, particularly among higher-risk patients. The practice of evidence-based medicine mandates close consideration of the relative attributes of the various lipid-lowering strategies in this regard. Current Treatment Options Current options for the treatment of dyslipidemia include the statins, bile acid sequestrants, fibrates, niacin, plant sterols, and stanol esters. These agents may be used either alone or in combination. Patients (%) n = 1, LDL-C (mg/dl) on treatment > 160 FIG. 1 Proportion of patients with coronary heart disease achieving low-density lipoprotein cholesterol (LDL-C) levels < 100 mg/dl in a multicenter survey. Data from Ref. No. 9; additional data courtesy of Thomas A. Pearson, M.D. Statins The statins are the most potent agents for reducing LDL- C. 1, 4 7 The response of LDL-C to statin therapy is predictable from agent to agent and from one dose level to another (Table II). 11, 12 After the starting dose, every doubling of the dose provides an additional 5 to 7% decrease in LDL- C. This consistency allows the clinician to select an initial statin dose that is likely to allow an individual patient to achieve a goal LDL-C level, based on the predicted average effect of the dose. Aggressive dose titration is warranted if the goal is not achieved. Such an approach is reasonable in light of the favorable risk benefit profile with increasing doses of statins. Numerous controlled trials have attested to the fact that the statins are well tolerated across clinically relevant dosage ranges. 1, 4 7 Rosuvastatin, a new statin with superior efficacy for reducing LDL-C, 13 is now available for clinical use. Rosuvastatin has also demonstrated a highly effective increase in HDL-C 13 and has been well tolerated in clinical trials across a broad range of patient types. 14, 15 Studies in patients with mild to moderate primary hypercholesterolemia have shown that decreases in LDL-C are significantly greater with rosuvastatin 5 mg or 10 mg than with atorvastatin 10 mg, pravastatin 20 mg, or simvastatin 20 mg at 12 weeks (p < 0.01 for rosuvastatin vs. each of the other statins; Table III). 14, 15 In addition, substantially greater proportions of high-risk patients are able to achieve the NCEP ATP III target LDL-C level of < 2.59 mmol/l (< 100 mg/mg/dl) with rosuvastatin than with the other agents in this class (Table III). 14, 15 The efficacy of rosuvastatin has been demonstrated in longer-term trials. A recent 52-week, multicenter, doubleblind trial compared the proportions of hypercholesterolemic patients able to achieve ATP II target LDL-C levels with rosuvastatin versus atorvastatin. 16 A total of 412 patients were randomized to initial treatment with rosuvastatin 5 or 10 mg or atorvastatin 10 mg for 12 weeks. During a subsequent 40-

3 E. A. Stein: The power of statins III-27 TABLE II Comparative efficacy of available statins 11 Dose (mg) % Reduction Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin TC LDL-C a a Extended-release formulation. Abbreviations: TC = total cholesterol, LDL-C = low-density lipoprotein cholesterol. Reprinted from Ref. No. 12 with permission. TABLE III Percentages of patients achieving National Cholesterol Education Program Adult Treatment Panel goal low-density lipoprotein cholesterol (LDL-C) level with various statins14, 15 High risk: Heart Low risk: Medium risk: disease or its risk 0 or 1 risk factor a 2 risk factors a equivalents a All patients (% at goal) (% at goal) (% at goal) (% at goal) Davidson Paoletti Davidson Paoletti Davidson Paoletti Davidson Paoletti Agent and dose et al. 14 et al. 15 et al. 14 et al. 15 et al. 14 et al. 15 et al. 14 et al. 15 Rosuvastatin 5 mg Rosuvastatin 10 mg Atorvastatin 10 mg 86 N/A 75 N/A 27 N/A 72 N/A Simvastatin 20 mg N/A 94 N/A 79 N/A 20 N/A 64 Pravastatin 20 mg N/A 87 N/A 43 N/A 5 N/A 48 a LDL-C goals: low risk, < 4.14 mmol/l (160 mg/mg/dl); medium risk, >3.36 mmol/l (130 mg/mg/dl); high risk, < 2.59 mmol/l (100 mg/mg/dl). Abbreviation: N/A = not applicable (drug not studied in trial). week dose-titration phase, the doses could be sequentially doubled to achieve the ATP II LDL-C goal. Compared with atorvastatin, rosuvastatin produced statistically significantly greater decreases in LDL-C at Weeks 12 and 52. Moreover, ATP II goal levels of LDL-C were achieved at 52 weeks in 98% of patients who started on rosuvastatin 10 mg, including 97% of those classified as being at high risk. Another trial, using an identical design, randomized 477 patients to initial treatment with rosuvastatin 5 or 10 mg, pravastatin 20 mg, or simvastatin 20 mg. 17 Again, reductions in LDL-C at Weeks 12 and 52 were significantly greater with rosuvastatin than with pravastatin or simvastatin. At both time points, the proportion of patients attaining NCEP ATP II goal LDL-C levels was higher in the rosuvastatin groups than in the pravastatin or simvastatin groups. Rosuvastatin has also proved effective in more severely affected patients with heterozygous familial hypercholesterolemia (FH). In a double-blind, multicenter trial, 622 patients with heterozygous FH were randomized to receive rosuvastatin or atorvastatin at initial once-daily doses of 20 mg, which were force-titrated to 40 mg and then to 80 mg at 6-week intervals. 18 The patients were required to have LDL-C levels 5.17 mmol/l ( 200 mg/dl) and mmol/l ( 500 mg/dl) at study entry. By 18 weeks, a significantly greater decrease in LDL-C had been achieved with rosuvastatin 80 mg than with atorvastatin 80 mg (58 vs. 50%, respectively; p < 0.001). Goal LDL-C levels, as specified by ATP II, were reached by 61% of the rosuvastatin group, as opposed to 46% of the atorvastatin group. Notably, in high-risk patients with CHD, the LDL-C target of 2.59 mmol/l ( 100 mg/dl) was attained by 24% of the rosuvastatin group, compared with only 3% of the atorvastatin group. This trial also found a significantly greater increase in high-density lipoprotein cholesterol (HDL-C) with rosuvastatin than with atorvastatin (12 vs. 3%, respectively; p<0.001). Another new statin, pitavastatin, has been reported to produce moderate LDL-C reductions ranging from 39 to 49% at doses up to 4 mg/day. 12 Pitavastatin is undergoing pivotal trials in Japan and Europe. In a 12-week double-blind, randomized trial, 240 patients received daily doses of pitavastatin 2 mg or pravastatin 10 mg. 19 In the pitavastatin group, the goal LCL-C level of < 140 mg/dl was reached by 75%, compared with 36% in the pravastatin group. Both drugs were well tolerated in the treatment of primary hypercholesterolemia. In a smaller trial in patients with heterozygous FH, 25 patients received pitavastatin 2 mg daily for 8 weeks, followed by 4 mg daily for up to 2 years. 20 Low-density lipoprotein cholesterol decreased by

4 III-28 Clin. Cardiol. Vol. 26 (Suppl. III) April % from baseline at Week 8, and by 49% at Week 12. Effects of the statin remained stable during the entire trial period. Other Lipid-Lowering Drugs Because of their lesser effects on LDL-C, agents other than statins are much less likely to be effective as monotherapy in patients with hypercholesterolemia. The bile acid sequestrants (cholestyramine, colestipol, and colesevelam) are difficult to use as sole therapy because high doses tend to be poorly tolerated. Lower doses are better tolerated but only moderately effective, reducing LDL-C by 10 to 20%. 21 To achieve the latter degree of reduction, patients must take fairly high doses of the powder formulations, which are generally unacceptable to all but the most motivated individuals. A newer tablet formulation, colesevelam, may be more acceptable to patients, although six pills must be taken each day. Another drawback to the use of bile acid sequestrants is the potential for a mild increase in triglyceride levels. Niacin, the oldest lipid-lowering drug, reduces LDL-C by 10 to 25%, but the degree of effect is again limited by patient tolerance. 22 An additional consideration is the fact that niacin is absolutely contraindicated in patients with hepatic dysfunction or peptic ulcer disease and should be used with caution in those with diabetes, gout, or hyperuricemia. 23 On the other hand, niacin alone is capable of raising HDL-C levels by as much as 30%. Most recently, plant sterol esters and stanol esters have attracted interest for their ability to reduce cholesterol. These phytosterols and phytostanols, when esterified with fatty acids, partially block cholesterol absorption in the gut. Modest reductions in LDL-C, on the order of 10 to 15%, can be obtained when these agents are taken as daily food supplements. 24 Some type of fat-soluble delivery system, such as margarine or salad dressing, is required. Both phytosterols and phytostanol esters are available over the counter in the United States but are used more frequently in European and Scandinavian countries. The fibrates are not considered primary drugs for patients with elevated LDL-C, as these agents are principally effective for reducing triglycerides and increasing HDL-C. 25 Decreases in LDL-C with fibrates are highly dependent on baseline triglyceride levels. Patients with very high triglyceride levels may actually experience increases in LDL-C when treated with a fibrate. Some fibrates are reasonably effective for reducing LDL-C in patients with relatively low triglycerides. The third-generation fibrates (such as fenofibrate) seem more effective than the older agents (gemfibrozil or clofibrate) in this regard. Combination Therapy If monotherapy does not succeed in reducing LDL-C to the target level, combination treatment may be considered. Most combination regimens now use statins as the foundation. Low to moderate doses of a bile acid sequestrant can be added to statin therapy in patients with relatively normal triglyceride levels. Niacin can be added to a statin in patients with mild hypertriglyceridemia and relatively low HDL-C levels. Combination therapy with all three classes of drugs may be necessary for high-risk patients who have more severe dyslipidemia, FH, or combined hyperlipidemia, or for younger individuals with moderate hypercholesterolemia. However, when combination therapy is considered, it is important to bear in mind that some combinations that include statin therapy are less well tolerated than statin monotherapy and may put patients at greater risk for serious adverse events. Myopathy, which may be characterized by muscle aches, weakness, and soreness, in conjunction with creatine kinase levels higher than 10 times the upper limit of normal, is rarely seen with statin monotherapy, but this may occur with greater frequency when the statin is combined with certain other drugs. 26 Drugs implicated in reduced tolerability, greater risk of adverse events, or both when combined with statins include cyclosporine, gemfibrozil, niacin, macrolide antibiotics, certain antifungal agents, and inhibitors of the cytochrome P450 pathway. Amiodarone and amlodipine have also been recognized as potentiators with simvastatin recently. These tolerability concerns and adverse events may impair patient compliance with therapy, and the potential risk-to-benefit ratio of certain combination therapies with high-dose statin therapy for LDL lowering must be considered within this context. New Approaches to Lipid Modification Several new classes of hypocholesterolemic agents are currently under investigation. Blockers of the ileal sodium-dependent bile acid transport system have been known for more than 30 years, and several such compounds have been tested in animal models Only recently, however, have certain intestinal bile acid transport inhibitors reached the early stages of clinical development. Data on one of these agents, 264W94, have been reported in a phase I/II study; patients with moderately elevated LDL-C were randomized to receive 264W94 in doses of 16 or 64 mg (in two divided doses) alone or in combination with simvastatin, or simvastatin alone. 32 The 16 mg dose lowered LDL-C by 8% over baseline and by 11% compared with placebo, whereas the 64 mg dose produced a 12 to 14% reduction relative to placebo. Of the patients taking the higher dose, 64% had LDL-C reductions of 15 to 25%. With the combination of simvastatin and the 16 mg dose of 264W94, an additional 20% of patients were able to lower their LDL-C levels by > 35%. Although no serious adverse effects were noted, the drug was associated with dose-dependent gastrointestinal side effects, primarily diarrhea. Cholesterol transport inhibitors are another promising group of lipid-lowering drugs. One such compound, ezetimibe, is a selective inhibitor of cholesterol absorption that has been shown to be active at or near the enterocyte brush border membrane. 33 Pooled data from two 12-week multicenter, double-blind, placebo-controlled studies showed that ezetimibe significantly reduced LDL-C and increased HDL-C levels in patients with primary hypercholesterolemia. 34 A total of 54%

5 E. A. Stein: The power of statins III-29 of the lower-dose group (ezetimibe 5 mg) and 68% of the higher-dose group (ezetimibe 10 mg) achieved LDL-C reductions of > 15%. Levels of LDL-C were reduced by > 25% in 15% of the 5 mg group and in 22% of the 10 mg group. Only the 10 mg dose is still in clinical development. Probably the greatest promise for ezetimibe lies in its combined use with a statin. One study showed that the addition of ezetimibe 10 mg to preexisting simvastatin therapy lowered LDL-C by an additional 18%. 35 In another trial, the addition of ezetimibe 10 mg to atorvastatin therapy reduced LDL-C by an additional 15.7%. 36 In yet another, addition of ezetimibe to fluvastatin lowered LDL-C by an additional 18.2%. 37 Moreover, combination therapy with ezetimibe and the fibric acid derivative fenofibrate has been shown to reduce LDL-C by 22.8% more than fenofibrate alone. 38 In a phase III study randomizing 827 patients to receive ezetimibe 10 mg or placebo, ezetimibe lowered LDL-C 17.7% from baseline, compared with a decrease of 0.8% seen with placebo (p < 0.01). 39 In patients with FH, ezetimibe 10 mg coadministered with atorvastatin (40 mg or 80 mg) or simvastatin (40 mg or 80 mg) resulted in clinically significant reductions in LDL-C compared with the 80 mg dose of either of the statins alone. 40 Remaining Questions Will more aggressive lipid lowering that yields changes beyond those achieved in previous controlled trials produce greater clinical benefit? Insights into this issue have emerged from three key trials. The Post Coronary Artery Bypass Graft Trial enrolled 1,351 patients with known CHD and LDL-C levels of 3.4 to 4.5 mmol/l ( mg/dl). 41 The patients were randomized to either moderate LDL-C lowering with low-dose lovastatin (2.5 5 mg/day) or more aggressive treatment with high doses (40 80 mg/day). During an average follow-up of 4.3 years, the mean LDL-C level was 2.4 to 2.5 mmol/l (93 97 mg/dl) with aggressive treatment, as opposed to 3.4 to 3.5 mmol/l ( mg/dl) with moderate treatment (p < 0.001). The mean percentage of grafts with atherosclerotic progression was only 27% in the aggressive-treatment group, compared with 39% in the moderate-treatment group (p < 0.001). In the Atorvastatin versus Revascularization Treatment (AVERT) study, 314 patients with CHD were randomized to receive high-dose atorvastatin (80 mg/day) or to undergo percutaneous transluminal coronary angioplasty (PTCA) followed by usual care (which could include lipidlowering therapy). 42 The patients were required to have LDL-C levels 3.0 mmol/l ( 115 mg/dl) at baseline. An LDL-C reduction of 46% was achieved with high-dose atorvastatin as opposed to 18% with PTCA plus usual care. At 18 months, the incidence of ischemic events was 13 versus 21% in these two groups, respectively (p = 0.048). More recently, the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study examined the effect of aggressive lipid lowering on carotid atherosclerotic progression in patients with severe FH. 43 At 2 years, the mean LDL-C fell by 51% in patients randomized to receive atorvastatin 80 mg, compared with 41% in those randomized to simvastatin 40 mg. Carotid intima media thickness decreased by mm from baseline in the atorvastatin group (p = ), but increased by mm in the simvastatin group (p = ). The difference between the two treatment groups was highly statistically significant (p = ). Evidence from these trials suggests that more aggressive lipid lowering may result in reduced atherosclerotic progression. Another question is whether reducing LDL-C to very low levels can substantially affect the residual risk of CAD observed in treated patients in clinical trials? In the recent Heart Protection Study, high-risk patients benefited by LDL reduction even in those with baseline LDL-C levels < 100 mg/dl. 8 It is to be anticipated that the ongoing trials Treating to New Targets (TNT), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) will provide more definitive answers to the question of whether greater LDL-C reductions confer additional benefit and whether treatment to very low levels can further improve clinical outcomes. Conclusion Despite remarkable progress in the management of hypercholesterolemia during the past two decades, several challenges remain. Of great concern is the fact that many persons at high risk of CHD-related adverse events are still not receiving any type of lipid-lowering therapy. Even when such treatment is instituted, most patients, especially high-risk patients, do not achieve the goal LDL-C level established by the NCEP ATP III. More attention must be focused on the aggressive reduction of LDL-C with statins, alone or in combination with established therapies or novel agents, such as cholesterol absorption inhibitors. The anticipated introduction of more effective statins, such as rosuvastatin or pitavastatin, should provide an important new opportunity for achieving LDL-C treatment goals and protecting against CHD events in highrisk populations. References 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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