Statins have gained increasing favor in the treatment of dyslipidemia as data supporting their efficacy have emerged. Whereas the NCEP ATP I guidelines featured strong support for resins and niacin as first-line therapy, statins were not included as “major drugs” and fibrates were not recommended for mixed hyperlipidemia until the release of ATP II in 1993.
11 Now, robust data support the use of these agents and combination regimens in the treatment of dyslipidemia, warranting a brief review.
In the Heart Protection Study (HPS), the risk of major vascular events with simvastatin 40 mg/d was significantly lower than that with placebo.
15 Compared with patients taking simvastatin, the larger percentage of patients in the placebo group who had a major vascular event (including nonfatal myocardial infarction [MI], coronary death, revascularization, or stroke) was evident by year one, and the differences continued to grow as the study progressed.
15 The cumulative difference per 1,000 patients who benefited from simvastatin and avoided a major vascular event increased each year, reaching 60±18 patients by year six.
15 The relative risk (RR) of any major vascular events with simvastatin was 24% (P <0.0001) in this analysis.
15
JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) enrolled 17,802 patients with no history of coronary artery disease (CAD) (men aged ≥50 y; women aged ≥60 y; LDL-C <130 mg/dL; hs-CRP levels ≥2.0 mg/L; baseline LDL-C = 108 mg/dL, HDL-C = 49 mg/dL) randomized to either rosuvastatin or placebo.
16 Treatment with rosuvastatin resulted in a significantly lower (P <0.05) rate of any stroke; any MI; stroke, MI, or death; and any death per 100 patient-years than that for placebo.
16 These findings led the researchers to conclude that the statin reduces mortality in primary prevention, with patients at highest risk experiencing the greatest benefit from rosuvastatin therapy.
16
Four statin monotherapy trials—West of Scotland (WOSCOPS primary prevention), Scandinavian Simvastatin Survival Study (4S), CARE, and the HPS—demonstrated that pravastatin (WOSCOPS and CARE) or simvastatin (4S and the HPS) alone only reduced cardiovascular events by 25% to 35%.
17 This is typical of statin monotherapy trials, which primarily demonstrate reduced LDL-R-C and LDL-C particle number with treatment.
The previously discussed HPS was heralded for showing that clinicians can achieve a 25% risk reduction with simvastatin monotherapy if a patient's baseline LDL-C is 90 to 100 mg/dL. However, it also seems that even if simvastatin reduced a patient's LDL-C to 60 to 70 mg/dL in the HPS, statin monotherapy cannot achieve the order of risk reduction demonstrated in combination therapy trials. In fact, the combination therapy trials FATS (1986-1990 niacin + colestipol and niacin + lovastatin), FATS Ten Year (1990-2000 niacin 2.5 g/d, colestipol 20 g/d, lovastatin 40 mg/d), and HATS (simvastatin + niacin) demonstrated that combination therapy with niacin and a statin resulted in event reductions of 80% to 95%.
17
Similarly, Grundy et al conducted a US-based multicenter, randomized, double-blind, active-controlled, 18-week study to determine if combination therapy with simvastatin plus fenofibrate was more effective than simvastatin alone in reducing elevated triglyceride (TG) levels, thus improving the lipoprotein pattern in patients with combined hyperlipidemia compared with simvastatin monotherapy.
18
From baseline to week 12, median TG levels decreased 43% in the combination therapy group and 20.1% in the simvastatin monotherapy group (treatment difference, -23.6%; P <0.001).
18 Mean LDL-C levels decreased by 31.2% and 25.8% (treatment difference, -5.4%; P <0.001) and mean HDL-C levels increased by 18.6% and 9.7% (treatment difference, 8.8%; P <0.001) in the combination therapy and monotherapy groups, respectively.
18
The researchers concluded that combination therapy with simvastatin 20 mg and fenofibrate 160 mg in patients with combined hyperlipidemia resulted in additional improvement in all lipoprotein parameters measured compared with simvastatin 20 mg monotherapy, proving this combination therapy to be beneficial in managing combined hyperlipidemia.
18
The combination of simvastatin and the cholesterol absorption-inhibitor ezetimibe likewise has demonstrated improvements in lipid parameters over statin monotherapy.
19,20 Davidson et al reported that patients who received combination therapy with 10 mg ezetimibe and 10 mg simvastatin had the same improvement in lipid parameters as patients who received eight times the dose of simvastatin alone (80 mg).
19
Because the magnitude of incremental LDL-C reduction with a combination of ezetimibe and a starting dose of a statin is similar to that seen with three-step statin titration, and because statin titration is associated with increased incidence of adverse events, the combination of ezetimibe and a statin represents a useful option for achieving targeted LDL-C levels in a greater proportion of individuals (
Figure 2).
20 Ezetimibe does not alter the pharmacokinetics and bioavailability of statins, and the safety and tolerability profile of the combination of ezetimibe and a statin is comparable to that of statin alone.
20
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study also evaluated the addition of ezetimibe to statin monotherapy, this time compared with extended-release niacin plus a statin.
21 However, in this case, the trial was stopped prematurely due to a precisely defined prespecified interim analysis showing niacin to be superior to ezetimibe.
21
Specifically, as compared with ezetimibe, niacin had greater efficacy regarding a change in mean carotid intima-media thickness by a margin of 0.014 mm (IMT) over 14 months (P=0.003), leading to significant reduction of both mean (P=0.001) and maximal carotid IMT (P 0.001 for all comparisons).
21 Although these results demonstrate superior efficacy of extended-release niacin over ezetimibe in preventing the progression of carotid atherosclerosis, they give little guidance regarding ezetimibe's effectiveness, given that no placebo arm was included in the study. Furthermore, some clinicians advise taking caution when interpreting the findings of ARBITER 6-HALTS since it was a small, short-duration, surrogate-end-point study that was prematurely stopped (40% of patients did not undergo the final IMT measurement at 14 months).
22
In an editorial accompanying the ARBITER 6-HALTS data, Blumenthal and Michos cite the existence of substantial evidence supporting the use of adjunctive therapy with a fibrate, niacin, a bile-acid sequestrant, n-3 fatty-acid supplements or ezetimibe if lipid goals cannot be met with a statin alone; however, these recent data suggest niacin should be the first-line choice after statin monotherapy.
23 Still, some clinicians question the validity of a surrogate end-point (IMT) in determining the true clinical benefit of therapy and state that the magnitude of difference between extended-release niacin and ezetimibe may have been exaggerated because the trial was stopped early.
22,23