Drug Criteria & Outcomes-HMG-CoA reductase inhibitors in treating dyslipidemias
Drug Criteria & Outcomes-HMG-CoA reductase inhibitors in treating dyslipidemias
Stephanie Shamsie, PharmD, BCPS
Lesley Dolan, PharmD
Department of Pharmacy Services
Scott & White Hospital
Temple, TX
Introduction
Elevated low-density lipoprotein (LDL-C) is a well-established risk factor for coronary heart disease (CHD). Therefore, LDL-C reduction is a primary goal in prevention of CHD. As a result, HMG-CoA reductase inhibitors, or statins, have a major role in the treatment of dyslipidemias.
This role is supported by recent literature, which demonstrates use of statins can reduce total morbidity and mortality in patients with and without prior CHD.1,2
Emerging evidence also strongly suggests that decreased high-density lipoprotein cholesterol (HDL-C) levels, elevated triglycerides (TG), and elevated LDL-C to HDL-C ratios also are clinically significant risk factors for developing CHD; correcting those abnormalities appears to reduce the risk of CHD.3,4,5 Therefore, reversing those risk factors should be considered important objectives, albeit secondary to lowering LDL-C. Two of the newer statins, simvastatin and atorvastatin, are somewhat more effective than the other statins in their ability to lower TG. Another new statin, cerivastatin, is similar to the older statins in its ability to lower TG.
Mechanism of action
All statins reduce cholesterol by the same mechanism of action. To varying degrees, the statins decrease hepatic production of cholesterol by competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a cholesterol precursor. The decreased cholesterol production results in increased hepatic LDL receptor production. Molecules that bind the LDL receptor are taken up by the liver, and their contents are metabolized and eliminated from the body. These LDL receptors bind very low-density lipoprotein (VLDL) and LDL molecules. Because VLDLs are composed of 50% to 65% TG, TG levels also are decreased. Atorvastatin is thought to reduce TG more than other statins by causing greater depletion of cholesterol in the liver, which results in decreased VLDL synthesis and secretion.6
Pharmacokinetics
Refer to table, p. 1, for a summary of the pharmacokinetic properties of the statins.
Pharmacokinetic Properties of the Statins |
||||||
| Fluva | Lova | Simva | Prava | Atorva | Ceriva | |
| Food increases absorption | No | Yes (take with food) | No | No | Yes (efficacy unchanged) | No |
| Crosses blood-brain barrier | No | Yes | Yes | No | No | No |
| Protein binding | 98% | 95% | 95% | 45% | 98% | 99% |
| Half-life (hours) | 0.5-1.2 | 1.1-1.7 | 2-3 | 2 | 14-17 | 2-3 |
| Liver metabolism (% absorbed dose) | 95% | 70% | < 87% | 50% | 98% | extent unknown |
| Active metabolites | No | Yes | Yes | Yes | Yes | Yes |
| Source: Adapted from reference 7. | ||||||
Clinical efficacy
Previous statin reviews have compared lovastatin with pravastatin and vs. simvastatin, and simvastatin vs. pravastatin in patients with primary hypercholesterolemia and TG < 340-400 mg/dL. To summarize, lovastatin was shown to be equivalent to pravastatin in lowering LDL-C, and simvastatin was shown to be twice as potent as lovastatin and pravastatin in lowering LDL-C on a milligram per milligram basis.7
Fluvastatin
A double-blind, parallel, controlled, multicenter trial randomized 348 patients to fluvastatin 20 mg at bedtime or lovastatin 20 mg with the evening meal. A mean of more than 30% LDL-C reduction from baseline was achieved by 13% of the fluvastatin group and by 42% of the lovastatin group. LDL-C was decreased 18% from baseline by fluvastatin and 27% by lovastatin (p < 0.001). There were no statistically significant differences in percent increase in HDL-C (3.4% by fluvastatin, 4.5% by lovastatin). Based on this study, lovastatin appears to be about 30% more effective than fluvastatin in lowering LDL-C but equipotent in lowering TG.8
Atorvastatin: Efficacy in primary hypercholesterolemia
Nawrocki and colleagues randomized 81 patients with primary hypercholesterolemia (LDL-C between 165 mg/dL and 225 mg/dL, TG < 300 mg/dL) to placebo or atorvastatin 2.5, 5, 10, 20, 40, or 80 mg daily for six weeks. The adjusted mean percent change in LDL-C was a 7.6% increase for placebo and 25%, 29%, 41%, 44.3%, 49.7%, and 61% decreases in atorvastatin patients, respectively. Approximately 90% of maximum LDL-C reduction was achieved in two weeks. Percent decrease in TG was 0.7% for placebo and 24.6%, 14.2%, 33.2%, 24.9%, and 27.2% for the atorvastatin doses, respectively. HDL-C increased 3.4% to 12.1%, which is simi -lar to the other statins. Atorvastatin was well tolerated with no statistically significant differences in the incidence of side effects compared to placebo. No patient withdrew due to adverse effects or had clinically significant creatine phosphokinase (CPK) elevations. Only one patient taking the 40 mg dose had increased liver enzymes (three to four times the upper limit of normal).9
Efficacy in primary hypertriglyceridemia
Bakker-Arkema and colleagues randomized 56 patients with primary hypertriglyceridemia (TG > 350 mg/dL, mean LDL-C of 118.7 mg/dL) to either placebo or atorvastatin 5, 20, or 80 mg per day for four weeks. The adjusted mean percent reductions in TG levels were 8.9%, 26.5%, 32.4%, and 45.8%, respectively. Maximum TG reduction occurred in two weeks. Mean LDL-C reductions were 1.4%, 16.7%, 33.2%, and 41.4%, respectively. Mean HDL-C increases were between 9% and 12% for atorvastatin. Compared to placebo, no statistically significant differences in adverse effects were observed and no patient withdrew due to adverse effects.10
Comparative studies
In an eight-week, multicenter trial, Jones and colleagues randomized 534 patients with primary hypercholesterolemia (LDL-C 160 mg/dL, TG 400 mg/dL) to one of 15 treatment arms: atorvastatin 10, 20, 40, or 80 mg/day; simvastatin 10, 20, or 40 mg/day; pravastatin 10, 20, or 40 mg/day; lovastatin 20, 40, or 80 mg/day; or fluvastatin 20 or 40 mg/day.
Atorvastatin (10, 20, and 40 mg) produced greater reductions in LDL-C (38%, 46%, and 51% reductions, respectively) and total cholesterol than milligram-equivalent doses of the other statins (p < 0.01). However, the reduction in LDL-C (54%) with atorvastatin 80 mg was not statistically greater than lovastatin 40 mg BID (48% reduction). All statins were well tolerated, and no patient experienced significant increases in serum transaminases, although the study may not have lasted long enough to see those results because this usually occurs with two to five months of treatment.11
Wierzbicki and colleagues randomized 54 patients with familial hypercholesterolemia to atorvastatin 80 mg, simvastatin 40 mg plus fenofibrate 200 mg, or simvastatin 40 mg plus choles tyra mine 32 g/day. Compliance with simvastatin plus cholestyramine therapy was variable, but all regimens achieved improvements in the lipid profile compared to pre-treatment values. LDL-C decreased by 45%, 42%, and 36% in the atorvastatin, simvastatin plus fenofibrate, and simvastatin plus cholestyramine treatment groups, respectively. The atorvastatin group had a comparable incidence of side effects, and the most commonly observed adverse effects were rash and myalgias (six patients) and gastrointestinal (GI) disturbance (three patients); two patients discontinued therapy due to debilitating myalgias or severe diarrhea. Atorvastatin also caused a significant increase in transaminase levels in three patients, but this was not statistically significant compared to other regimens. The major adverse effect in the simvastatin-cholestyramine group was severe GI disturbances, and myalgia was reported in 11.2% of the simvastatin-fenofibrate group.12
Cerivastatin
Stein pooled data from randomized, double-blind studies for more than 2,700 patients with primary hypercholesterolemia. Cerivastatin 0.3 mg daily was well tolerated and demonstrated a 30% decrease in LDL-C, a 22.9% decrease in total cholesterol, and an 8% increase in HDL-C. Decreases in TG were dependent on baseline levels; 0.3 mg cerivastatin produced decreases in TG levels up to 25% with baseline TG > 250 mg/dL. There were no significant differences between adverse event profiles in the cerivastatin (at any dose), lovastatin, simvastatin, or placebo groups. In all groups, headache and GI disturbances were the most common adverse events.13
In unpublished data by Insull and colleagues, 939 patients with primary hypercholesterolemia (mean LDL-C 193 to 202 mg/dL, mean TG 164 to 175 mg/dL) were randomized to receive cerivastatin 0.05, 0.1, 0.2, or 0.3 mg per day, lovastatin 40 mg per day, or placebo for 24 weeks. LDL-C decreased 28% with cerivastatin 0.3 mg per day, 33% with lovastatin, and increased 2% with placebo. Triglycerides decreased 13% and HDL-C increased 10% with cerivastatin 0.3 mg per day.14
High-dose simvastatin
Davidson and colleagues sequentially randomized 156 patients with primary hypercholesterolemia (LDL-C > 160 mg/dL, TG < 350 mg/dL) to receive simvastatin 40, 80, or 160 mg per day for a period of six weeks. Median LDL-C reductions achieved were 41%, 47%, and 53% respectively; median TG reductions were 21%, 23%, and 33% respectively; and median HDL-C increases were 6%, 7%, and 8%, respectively. In contrast to the atorvastatin studies, 6.4% of patients withdrew due to adverse effects (one 40 mg, three 80 mg, and five 160 mg patients). One case of myopathy occurred in a patient taking 160 mg per day. A significant increase in liver enzymes also occurred with the 160 mg dose. Although there was a trend toward a greater incidence of adverse effects associated with higher doses, there were no statistically significant between-treatment differences in the incidence of adverse effects.15
In 1997, 80 mg and 160 mg gel extrusion nodule (GEM) formulations were developed. The rationale for the GEM formulation is to slow delivery of the drug to the intestines and thereby reduce drug plasma levels without compromising delivery to the site of action, the liver. In an 1,800-patient phase III trial comparing the 80 mg conventional tablet, 80 mg GEM tablet, and 160 mg GEM tablet, one arm was closed due to the occurrence of rhabdomyolysis requiring hospitalization in three of 400 patients taking the 160 mg GEM tablet.16 As a result, only the 80 mg GEM tablet was approved by the FDA.
To determine the efficacy and safety of simvastatin 80 mg/day, Stein and colleagues conducted a randomized, multicenter, double-blind, para -llel group study with 523 hypercholesterolemia patients. Patients were randomly assigned to receive 40 mg or 80 mg daily for 24 weeks.
Significant differences occurred between the two groups in regards to decreases in total cholesterol (29% vs. 35% reductions in the 40 mg and 80 mg groups, respectively), LDL-C (38% vs. 46% reductions, respectively), apolipoprotein B (34% and 40% reductions, respectively), and TG (17% and 25% reductions, respectively). HDL-C increases (6% and 6.1% respectively) were not significantly different.
No patients experienced serious drug-related adverse events, and there were no significant differences between the groups in any drug-related clinical adverse experience. In the 40 mg and 80 mg groups, 0 and two (0.6%) patients, respectively, met criteria for myopathy. Three (1.4%) and six (1.9%) patients in the 40 mg and 80 mg groups, respectively, developed increases greater than three times the upper limit of normal in hepatic transaminases.17
Drug interactions
The most important statin drug-drug interactions involve the increased risk of myopathy and rhabdomyolysis associated with concurrent administration of statins with cyclosporine, niacin, gemfibrozil, or CYP3A4 inhibitors such as erythromycin and the azole antifungals. Risk vs. benefit of these combinations must be weighed carefully. Patients should be advised of the symptoms and instructed to stop the statin is those symptoms occur.
Adverse reactions
Of the four major classes of lipid-lowering agents (statins, bile acid sequestraints, fibric acids, and niacin), the statins were the best tolerated due to a much lower incidence of adverse effects.18 The most common adverse effects are GI disturbances, headache, and sleep disturbances. Rare but serious dose-related adverse effects include increased CPK levels with or without muscle symptoms and increased hepatic transaminase levels.
Administration and dosage
See table, above, for an outline of FDA-approved administration and dosage of the statins.
Cost
In choosing a statin, cost to both the institutions and the patients must be considered. While statins are the most effective class of cholesterol-lowering drugs, they are also often the most expensive. Acquisition cost, drug formularies, and the individual patient's method of payment are important factors to consider. Refer to the tables on pp. 5-6 for information regarding the average wholesale prices (AWP) and wholesale acquisition costs (WAC) following all rebates for the statins.
Conclusions and recommendations
The ability to decrease morbidity and mortality appears to be a class effect directly related to the ability of the statins to effectively lower LDL-C. All statins appear to have similar types and incidences of adverse effects, most of which are dose-related. Therefore, cost-effectiveness of the individual agents is a major consideration in choosing a statin.
When evaluating the available literature and comparing LDL-C reductions on a milligram per milligram basis, it appears that:
• lovastatin and pravastatin are roughly equivalent in efficacy;
• lovastatin and pravastatin are approximately 30% more effective than fluvastatin;
• cervistatin is roughly equivalent in efficacy to 20 mg of lovastatin or pravastatin;
• simvastatin is approximately twice as effective as lovastatin and pravastatin;
• atorvastatin is approximately 30% more effective than simvastatin;
• atorvastatin 80 mg has shown the greatest percent reduction in LDL-C.
In terms of TG reduction:
• A 10% to 15% TG reduction can generally be achieved with cerivastatin 0.3 mg, fluvastatin 20 to 80 mg, lovastatin 20 to 40 mg, pravastatin 10 to 20 mg, and simvastatin 5 to 10 mg
• An approximate 20% reduction in TG can generally be achieved with lovastatin 80 mg, pravastatin 40 mg, simvastatin 29 and 40 mg, and atorvastatin 10 mg.
• Greater than 20% reduction in TG can generally be achieved with pravastatin 40 mg, simvastatin 80 mg, and atorvastatin 20 to 40 mg
• Greater than 30% reduction in TG can generally be achieved with atorvastatin 80 mg.
• Greater reduction in TG tends to occur in patients with a higher baseline TG level
In terms of adverse effects, the statins are very similar (the incidence of adverse effects increases with the dose).
o Primary hypercholesterolemia (elevated LDL-C, TG < 200 mg/dL)
If < 30% reduction in LDL-C is needed, any of the statins will likely be effective. If 30% to 40% LDL-C reduction is needed, lovastatin, pravastatin, simvastatin, or atorvastatin would all likely be effective; however, because of the greater inconvenience associated with lovastatin (must be given with food, doses > 40 mg/day must be divided into BID dosing), pravastatin, simvastatin, or atorvastatin would likely be preferred because these agents can all be administered without regard to meals and would only require once daily dosing even at the maximum dose.
If > 40% LDL-C reduction needed, atorvastatin will generally be the only effective statin, as the others usually do not achieve this amount of LDL-C reduction. Although combination therapy has been shown to be safe and effective in providing this amount of LDL-C reduction, using atorvastatin alone will likely be less expensive than using other statins in combination with a bile acid sequestrant or niacin. Single-drug therapy would also likely enhance compliance, have a lower incidence of side effects, and have less potential for drug interactions.
o Primary hypertriglyceridemia (TG > 200 mg/dL)
For patients with mildly elevated TG, higher doses of simvastatin (40 and 80 mg) and atorvastatin (40 to 80 mg), in combination with lifestyle modifications (decreased intake of fat, cholesterol, concentrated sweets, and alcohol, combined with increased aerobic exercise and subsequent weight loss) may be a good option as the reduction achieved with higher doses may lower TG by as much as 20% to 30%. However, for patients with moderate to severe elevations in TG levels (> 400 mg/dL), the drug of first choice still is gemfibrozil, as the statins are generally insufficiently effective at controlling TG elevations of this severity.
o Mixed dyslipidemia (elevated LDL-C, TG > 200 mg/dL)
Starting doses of atorvastatin or higher doses of pravastatin or simvastatin, combined with lifestyle modifications, may result in adequate control of both cholesterol and triglycerides. For patients not adequately controlled, higher doses of atorvastatin and/or addition of gemfibrozil or niacin to the statin regimen may be considered, weighing the potential risks, benefits, and costs associated with combination treatment vs. higher doses of atorvastatin.
References
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2. West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Eng J Med 1995; 333:1,301-1,307.
3. Castelli WP. Epidemiology of triglycerides: A view from Framingham. Am J Cardiol 1992; 70:3J-9H.
4. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Preven tion Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988; 233:405-418.
5. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: Implications for treatment. Circulation 1992; 85:37-45.
6. Bakker-Arkema R, Davidson M, Goldstein R, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor in patients with hypertriglyceridemia. JAMA 1996; 275:128-133.
7. Kellick K, Burns K, McAndrew E, et al. Focus on atorvastatin: An HMG-CoA reductase inhibitor for lowering both elevated LDL cholesterol and triglycerides in hypercholesterolemic patients. Formulary 1997; 323:352-363.
8. Hsu I, Spinler S, Johnson E. Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmcother 1995; 29:743-59.
9. Nawrocki J, Weiss S, Davidson M, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Aterioscler Thromb Vasc Biol 15:678-82.
10. Bakker, Arkema R, Rayyad R, Davidson M, et al. One-year study comparing the safety and efficacy of atorvastatin to that of lovastatin. Presented at the 66th Congress of the European Atherosclerosis Society. July 1996.
11. Jones P, Kafonek S, Laurora, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin and fluvastatin in patients with hypercholesterolemia (the CURVES study) Am J Cardiol 1998; 81:582-587.
12. Wierzbicki AS, Lumb PJ, Semra TY, et al. High-dose atorvastatin therapy in severe heterozygous familial hyperchosterolemia. OJ Med 1998; 91:219-294.
13. Stein E. Cerivastatin in primary hyperlipidemia: A multicenter analysis of efficacy and safety. Am J Cardiol 1998; 82-40J-46J.
14. Insull W, Stein E, Whalen E, et al. Cerivastatin, a new potent HMG-CoA reductase inhibitor: Efficacy and tolerability in primary hypercholesterolemia. J Am Coll Cardiol 1997; 29 (supplA):46A.
15. Davidson M, Stein E, Dujovne C, et al. The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day. J Am Coll Cardiol 1997; 79:38-42.
16. F-D-C Reports. The Pink Sheet. 1997; May:T&G-7.
17. Stein EA, Davidson MH, Dobbs A, et al. Efficacy and safety of simvastatin 80mg//day in hypercholesterolemic patients. Am J Cardiol 1998; 82:311-316.
18. Andrade S, Walker A, Gottleib L, et al. Discontinu ation of antihyperlipidemic drugs: Do rates reported in clinical trials reflect rates in primary care settings? N Eng J Med 1995; 332:1125-31.
• Stephanie Shamsie, PharmD, BCPS, Lesley Dolan, PharmD, Department of Pharmacy Services, Scott & White Hospital, Department of Pharmacy Services, 2401 South 31st St., Temple, TX 76508. Telephone: (254) 724-2111.
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