Managed care initiatives to reduce cardiovascular disease (CVD) risk have, to date, focused almost exclusively on statins, which are primarily low-density lipoprotein cholesterol-lowering agents and have limited effects on triglycerides and high-density lipoprotein (HDL) cholesterol at commonly used doses. Significant residual CVD risk (ie, risk of recurrent CVD events) remains after treatment with statins and may stem, at least partially, from low HDL cholesterol and/or elevated triglycerides. Consequently, national treatment guidelines suggest that combination therapy may be necessary to address multiple lipid targets and adding niacin or a fibrate to a statin is a strategy to be considered. Recent clinical trial evidence has demonstrated the efficacy of niacin/statin and fenofibric acid/statin combination therapies in treating multiple lipid abnormalities.
(Am J Manag Care. 2009;15:S65-S73)
In the treatment of cardiovascular disease (CVD), national guidelines and many healthcare professionals focus on low-density lipoprotein (LDL) cholesterol. However, rather than viewing LDL cholesterol level as a therapeutic end point, healthcare professionals should consider modification of atherothrombosis and prevention of CVD events as the goal of any lipid-altering therapy or preventive strategy. Treatments for mature CVD, including mechanical revascularization, should be considered palliative therapies that help treat an episode in what is a chronic disease process. Many patients who undergo these interventions are going to have additional or repeat procedures related to the progression of coronary artery disease (CAD) or peripheral arterial disease. Consequently, it is important to recognize that for these patients to decrease their risk of recurrent events, they need to utilize every aggressive, preventive treatment strategy available. This may include addressing several non-LDL cholesterol lipid parameters.1 Approximately 28% of adults in the United States have high LDL cholesterol and a third or more have high triglycerides (TGs) and/or low high-density lipoprotein (HDL) cholesterol. Almost 50% of adults have at least 1 lipid abnormality.2
One of the most effective classes of medications for preventing cardiovascular events is hydroxylmethylglutaryl-coenzyme A reductase inhibitors, or statins. However, examination of statin clinical trial data reveals that a significant number of patients being treated continue to experience cardiovascular events. In the 4S (Scandinavian Simvastatin Survival Study) trial, which studied patients with very high LDL cholesterol levels and known coronary heart disease (CHD), a significant risk reduction was observed with statin treatment. Although the relative risk of a major cardiovascular event decreased by approximately one third, the results from 4S also indicate that over the study's duration almost 20% of statin-treated patients had a cardiovascular event.3 Indeed, data collected from several major statin trials have consistently revealed the existence of significant residual cardiovascular risk even after large reductions of LDL cholesterol ().3-8 Additional trials have included high-risk patients with CHD or diabetes mellitus who were treated with intensive LDL-lowering statin therapy. In the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) study, 4162 patients with acute coronary syndromes (ACS) were treated with either pravastatin 40 mg or atorvastatin 80 mg.9 Clinical events were further reduced in the high-dose atorvastatin group compared with the pravastatin group; however, during the 2-year trial, 22.4% of the individuals treated with high-dose atorvastatin still suffered a major CVD event despite achieving mean LDL cholesterol levels of 62 mg/dL.9 Similar results were observed in the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) and TNT (Treating to New Targets) studies, which further demonstrated that significant residual CVD risk remains in patients even after intensive statin therapy that achieves LDL cholesterol goals well below 100 mg/dL.9-12 It is interesting to note that evidence suggests only modest benefits are provided by lowering LDL cholesterol from 100 to 70 mg/dL, and some investigators believe cogent data supporting the use of higher statin drug dosages and their greater costs and possible toxicity are limited.13 To continue to reduce the incidence of cardiovascular events, it is apparent that additional factors need to be addressed.
Beyond LDL Cholesterol: Low HDL Cholesterol and Elevated TGs Increase CVD Risk
Residual cardiovascular risk is likely multifactorial. Recent evidence suggests the important contribution to CVD risk of lipid parameters other than LDL cholesterol, such as high TGs and low HDL cholesterol.1 In an analysis of data from the Coronary Primary Prevention Trial, the Multiple Risk Factor Intervention Trial, the Lipid Research Clinics Prevalence Mortality Follow-up Study, and the Framingham Heart Study, for every 1-mg/dL (0.026 mmol/L) increase in plasma HDL cholesterol in the populations studied, there was a decrease in CHD risk of approximately 2% in men and 3% in women independent of other risk factors, including plasma LDL cholesterol.14 According to NHANES II (Third National Health and Nutrition Examination Survey), more than one third of the overall US adult population has low HDL cholesterol.15 Thirty-five percent of adult men and 39% of adult women were reported to have HDL cholesterol below 40 mg/dL and 50 mg/dL, respectively.15 The NCEP ATP II (National Cholesterol Education Program Adult Treatment Panel III ) guidelines report that low HDL cholesterol is a significant, independent risk factor for CHD. Often, low HDL cholesterol is correlated with elevations of serum TG and remnant lipoproteins, and is strongly and inversely associated with CHD risk.16
There are a number of different mechanisms through which HDL cholesterol may exert its antiatherogenic effects. The penetration and retention in the arterial wall of atherogenic apolipoprotein B-containing lipoproteins, including LDL cholesterol and very low-density lipoprotein (VLDL) cholesterol, may initiate and promote atherosclerosis.17 A variety of studies show HDL cholesterol may promote the efflux of cholesterol from foam cells in atherosclerotic lesions through reverse cholesterol transport.18 In addition, HDL cholesterol may inhibit atherogenesis through antioxidant and anti-inflammatory properties16,18,19 and reduce cardiovascular events via antithrombotic and vasodilatory activities, and endothelial repair.19,20
Importantly, as shown by data from the Framingham Heart Study, even in the presence of very low LDL cholesterol, low HDL cholesterol is still a potent risk factor. As HDL cholesterol decreases, it contributes significantly to CHD risk at all levels of LDL cholesterol and, even when LDL cholesterol levels are optimal (<100 mg/dL), the lower the HDL cholesterol level, the higher the risk of CHD.21 Even when LDL cholesterol levels are controlled with intensive statin therapy, the heightened risk of CHD conferred by low HDL cholesterol remains. In the TNT investigation of high-dose statin therapy, individuals with acceptable LDL cholesterol levels (<70 mg/dL) had a significant, increased 5-year risk of CHD events that was directly related to HDL cholesterol levels ().22 Patients in the highest HDL cholesterol quintile (Q5 ≥55 mg/dL) had a lower risk for major cardiovascular events than did patients in the lowest HDL cholesterol quintile (Q1 <37 mg/dL; hazard ratio [HR] vs Q5, 0.61; 95% confidence interval [CI], 0.38-0.97; P = .03).22
Although LDL cholesterol is recognized as the most important atherogenic lipoprotein, elevations in TG levels can be considered a marker for atherogenic VLDL remnant lipoproteins. Because VLDL cholesterol is the most readily available measure of atherogenic remnant lipoproteins, it may be combined with LDL cholesterol to improve CVD risk prediction as major components of non-HDL cholesterol. When serum TG levels are elevated, the non-HDL cholesterol measure better represents the concentration of all atherogenic lipoproteins than does LDL cholesterol.16 Non-HDL cholesterol incorporates all atherogenic lipoproteins, including LDL cholesterol, VLDL cholesterol, lipoprotein(a) (Lp[a]), and intermediate-density lipoprotein (IDL) cholesterol. Non-HDL cholesterol, according to the NCEP ATP II guidelines, is a secondary target of therapy after LDL cholesterol goals have been reached and when TG levels are ≥200 mg/dL.16
A recently published meta-analysis by Sarwar et al included 29 Western prospective studies (262,525 participants; 10,158 CHD cases) to investigate the association between TGs and CHD risk.23 The meta-analysis revealed an adjusted odds ratio of 1.72 (95% CI, 1.56-1.90) in patients in the highest third of TG values compared with those patients in the lowest third of TG values.23 An earlier study by Genest et al reported that in both men and women with premature CAD, the most significant risk factor is low HDL cholesterol, although these individuals often exhibit high TG levels as well.24 Although this study had small numbers of patients with premature CAD (n = 87 men; n = 15 women), TGs were significantly higher and HDL cholesterol was significantly lower compared with patients from the Framingham Offspring Study who were free of CHD at baseline.24 Furthermore, in the 8-year follow-up of 4639 middle-aged men with no history of myocardial infarction or stroke in the PROCAM (Prospective Cardiovascular Münster) study, elevated levels of TGs emerged as a significant, independent predictor for CHD events. There was a 6-fold increased CHD risk in patients with TGs >200 mg/dL and LDL cholesterol to HDL cholesterol ratio >5.0. According to the PROCAM data, high TGs put middle-aged men at increased risk for CHD regardless of their HDL cholesterol or LDL cholesterol levels.25
A recent analysis of data from the PROVE IT-TIMI 22 trial examined a combination of LDL cholesterol and TG levels on CVD risk in ACS patients.12 During the 2-year follow-up, significantly fewer CHD events occurred in patients who had LDL cholesterol <70 mg/dL than in patients who had LDL cholesterol ≥70 mg/dL (HR, 0.81; P = .015). Similarly, significantly fewer events occurred in patients with TGs <150 mg/dL than in those patients with TGs ≥150 mg/dL, as revealed through univariate analysis (HR, 0.73; 95% CI , 0.62-0.87; P <.001). A Cox proportional hazards model was utilized to further examine the relationship between achieved LDL cholesterol and TGs at the day 30 time point and risk of recurrent CHD events. Compared with patients who had LDL cholesterol ≥70 mg/dL and TGs ≥150 mg/dL, lower CHD risk was observed with low on-treatment TGs (<150 mg/dL) and LDL cholesterol (<70 mg/dL) (HR , 0.72; 95% CI, 0.54-0.94; P = .017).12 Patients with TGs <150 mg/dL, even if they had LDL cholesterol >70 mg/dL, exhibited CHD event rates 15% lower than those patients who had low LDL cholesterol but high TGs. Among patients receiving statin therapy after ACS, on-treatment TGs <150 mg/dL were associated with a lower risk of recurrent CHD events independent of the level of LDL cholesterol. Therefore, achieving both lower LDL cholesterol and TG levels may be an important therapeutic strategy in patients with ACS.12
When considering lipid parameters beyond LDL cholesterol, non-HDL cholesterol (ie, total cholesterol - HDL cholesterol) is a better estimate of the total atherogenic burden and is easily calculated from nonfasting lipid values. Non-HDL cholesterol represents atherogenic VLDL remnant lipoproteins, including LDL cholesterol, VLDL cholesterol, IDL cholesterol, and Lp(a).16 Data from the Framingham Heart Study suggest that non-HDL cholesterol is a stronger predictor of CHD risk than is LDL cholesterol.26 Overall, the association with CHD incidence was stronger for non-HDL cholesterol than for LDL cholesterol at all levels of non-HDL cholesterol, regardless of whether TG levels were <200 or ≥200 mg/dL.26
National Guideline Recommendations for Treating Beyond LDL Cholesterol
Several national guidelines address the treatment of high TGs and non-HDL cholesterol and low HDL cholesterol. Therapeutic lifestyle changes, as noted in the NCEP ATP III recommendations, remain very important and include diet, exercise, and smoking cessation. The NCEP ATP II guidelines target elevated LDL cholesterol as the primary therapeutic intervention to decrease CVD risk.16 Because elevated non-HDL cholesterol levels in patients with hypertriglyceridemia (eg, TGs ≥200 mg/dL) impart increased risk for cardiovascular events even after the LDL cholesterol goal has been reached, non-HDL cholesterol is considered to be a secondary therapeutic target that may provide additional CHD risk reduction.27,28 The 2004 update to the 2001 NCEP ATP II guidelines emphasized the increasing evidence for the benefits of combination therapy, as compared with monotherapy, by recommending the possibility of adding a fibrate or niacin to LDL-lowering therapy in high-risk patients with elevated TGs or low HDL cholesterol levels.27
In 2007 the American Diabetes Association (ADA) and the American Heart Association (AHA) collaborated on a joint statement recommending LDL cholesterol remain the primary target of lipid-modifying therapy. The ADA/AHA guidelines further recommend an LDL cholesterol goal <100 mg/dL in patients with diabetes mellitus.29 The ADA and the AHA have also individually released guidelines for CVD prevention that include therapies targeting multiple lipid fractions. According to the 2008 ADA guidelines, the primary goal in patients with diabetes mellitus is an LDL cholesterol level <100 mg/dL in individuals without overt CVD, although a lower LDL cholesterol goal (<70 mg/dL) is an option in individuals with overt CVD.30 In addition, the ADA suggests a TG goal <150 mg/dL and HDL cholesterol goals >40 mg/dL in men and >50 mg/dL in women.30 For patients with TGs between 200 and 499 mg/dL, the AHA recommends a non-HDL cholesterol goal <130 mg/dL.29 Interestingly, the AHA advocates efforts to raise HDL cholesterol levels but does not specifically designate therapeutic goals. The ADA/AHA joint statement suggests that a combination of statins with fibrates or niacin may be necessary to achieve multiple lipid targets.29
Similar recommendations for lipid values and treatments were published in the 2006 AHA/American College of Cardiology Secondary Prevention Guidelines for patients with coronary and other atherosclerotic vascular disease.31 This update provides target levels for TGs and non-HDL cholesterol. The guidelines recommend that if TGs are between 200 and 499 mg/dL, the non-HDL cholesterol goal should be <130 mg/dL. Moreover, it is reasonable to consider reducing non-HDL cholesterol <100 mg/dL when a patient is at sufficiently high risk for cardiovascular events. The therapeutic options to reduce non-HDL cholesterol are more intensive LDL cholesterol lowering or the addition of niacin or a fibrate to reduce TGs and increase HDL cholesterol after LDL-lowering therapy has been initiated.31
Combination Therapies for Residual CVD Risk Reduction
Recently, several clinical end point and arteriographic investigations were compared for efficacy in reducing cardiovascular events ().32 Across a variety of trials, combination therapies produced an average clinical event relative risk reduction of 71.6%, an average number needed to treat (NNT) of 9.6, and an average NNT per year of 3.4.32 These data reveal significantly enhanced efficacy for reducing clinical events with the combination of LDL cholesterol-lowering plus HDL cholesterol-raising pharmacologic therapy compared with LDL cholesterol-lowering therapy alone.
The SEACOAST (Safety and Efficacy of Fixed Dose Niacin ER and Simvastatin Combination Therapy) trial, a 24-week randomized clinical trial, compared simvastatin monotherapy with a combination of extended-release niacin (niacin ER)/simvastatin in patients with mixed dyslipidemia.33,34 Following a simvastatin run-in phase, during which patients received simvastatin 20 or 40 mg for at least 2 weeks, patients were assigned to either simvastatin low-dose (SEACOAST I) or simvastatin high-dose (SEACOAST II) groups. In SEACOAST I, the treatment groups were simvastatin 20 mg, niacin ER/simvastatin 1000 mg/20 mg, and niacin ER/simvastatin 2000 mg/20 mg.34 In SEACOAST II , which included more intensive lipid-modifying therapy during both the run-in phase and the 24-week trial phase, the treatment groups were simvastatin 80 mg, niacin ER /simvastatin 1000 mg/40 mg, and niacin ER/simvastatin 2000 mg/40 mg. The primary end point in SEACOAST was the median percent change in non-HDL cholesterol during the period from baseline to week 24.33,34
In SEACOAST I, the niacin ER/simvastatin 1000 mg/20 mg and 2000 mg/20 mg combination therapies produced significant, dose-related improvements in non-HDL cholesterol, HDL cholesterol, TGs, and Lp(a) compared with simvastatin 20-mg monotherapy.34 As shown in , a 22.5% reduction in non-HDL cholesterol was observed with high-dose niacin ER/simvastatin as compared with the 7.4% reduction seen with simvastatin 20-mg monotherapy. Although there was a dose-related response in LDL cholesterol levels, there were no significant differences in LDL cholesterol between these groups; simvastatin alone resulted in a 7.1% decrease in LDL cholesterol, whereas high-dose niacin ER/simvastatin produced a 14.2% reduction. The results of SEACOAST I also showed a 24.9% increase in HDL cholesterol associated with high-dose niacin ER/simvastatin and a substantial reduction in TGs that reached 38% in the high-dose group. Finally, a significant 25% reduction in Lp(a) was observed with the high-dose niacin ER /simvastatin treatment, whereas little change in Lp(a) was observed with simvastatin monotherapy. A similar pattern of results was observed in SEACOAST II, as shown in . A 17.1% reduction in the primary end point of non-HDL cholesterol was seen with the high-dose niacin ER/simvastatin 2000-mg/40-mg combination therapy as compared with a 10.1% reduction with simvastatin 80-mg monotherapy, although this difference was not statistically significant. Decreases in LDL cholesterol were observed to be comparable (-11.6% high-dose niacin ER/simvastatin 2000 mg/40 mg vs -12.7% simvastatin 80 mg) across all treatment groups. Both niacin ER/simvastatin 1000 mg/40 mg and 2000-mg/40-mg combination therapies resulted in significant, dose-related improvements in HDL cholesterol, Lp(a), and TGs, compared with simvastatin 80-mg therapy.33 Across these lipid parameters, simvastatin 80-mg monotherapy had essentially no effect beyond that conferred by the simvastatin 40-mg dose administered during the run-in phase.
In SEACOAST, treatment with niacin ER/simvastatin for 24 weeks was well-tolerated with no unanticipated adverse effects. Only flushing was significantly more frequent with niacin ER/simvastatin combination therapy as compared with simvastatin monotherapy, and there was no evidence of increased risk of hepatoxicity or myopathy with niacin ER/simvastatin therapy. Overall, these data support the use of niacin ER/simvastatin combination therapy in a broad population of dyslipidemic patients to help them reach and maintain multiple lipid goals.33,34
Fibrates, similar to niacin, have been added to statin therapy to address multiple lipid abnormalities. Recently, a new formulation of fenofibrate (fenofibric acid) has been investigated in combination with rosuvastatin in patients with mixed dyslipidemia. This 12-week, randomized, double-blind, active-controlled trial compared the efficacy of fenofibric acid 135-mg monotherapy, rosuvastatin 10-mg monotherapy, and fenofibric acid/rosuvastatin 135-mg/10-mg combination therapy in patients with mixed dyslipidemia. Combination therapy with fenofibric acid/rosuvastatin () resulted in a significantly greater reduction in LDL cholesterol compared with fenofibric acid monotherapy (P <.001). Combination therapy with fenofibric acid/rosuvastatin resulted in significantly greater increases in HDL cholesterol and reductions in TGs compared with rosuvastatin 10-mg monotherapy (P <.001).35 In addition to its beneficial effects on various lipid parameters, fenofibric acid/rosuvastatin combination therapy resulted in a substantial shift in the percentage of patients with large, less atherogenic LDL particles from 13.3% at baseline to 51.8% following 12 weeks of therapy. Conversely, rosuvastatin monotherapy produced a more modest shift, with only 18.2% of patients expressing large, less atherogenic LDL particles as compared with 6.8% at baseline.36 Fenofibric acid/rosuvastatin combination therapy also resulted in significantly greater improvements in the ratios of total cholesterol to HDL cholesterol, non-HDL cholesterol to HDL cholesterol, apolipoprotein B to apolipoprotein A-I, and TG to HDL cholesterol compared with fenofibric acid monotherapy or rosuvastatin monotherapy.37 Importantly, fenofibric acid/rosuvastatin combination therapy was well-tolerated; no hepatic, renal, or muscle safety signals were identified.35
Several lipid parameters, such as LDL cholesterol, TGs, HDL cholesterol, and atherogenic remnant lipoproteins, are strongly associated with atherosclerosis and heightened CVD risk. The primary therapeutic target is LDL cholesterol, and lipid-lowering therapy with statins has proved to be highly beneficial for reducing cardiovascular event rates. However, significant cardiovascular risk remains in patients treated even with intensive statin therapy to reduce LDL cholesterol. As a result, there has been an increased focus on elevated TGs and low HDL cholesterol and their significant contributions to cardiovascular risk even when LDL cholesterol levels are well-controlled. Treatment guidelines recommend that combination therapy may be necessary to achieve multiple lipid goals, including non-HDL cholesterol, HDL cholesterol, and TGs.
When considering all of the evidence addressing various lipid fractions and CVD risk, lipid management in specific patients should not be limited to statin monotherapy. Rather, achieving multiple lipid goals and reducing CVD risk should utilize statins and additional therapeutic agents to target lipid parameters other than LDL cholesterol when necessary. The benefits conferred by raising HDL cholesterol with niacin appear additive to LDL cholesterol lowering with statins. This combination addresses several atherogenic lipid abnormalities, slows the progression of atherosclerosis, and reduces residual CVD risk. Niacin/statin combination therapy has an excellent safety profile and may be needed to optimally reduce CVD risk in high-risk patients. Similarly, recent reports indicate that combination therapy of fenofibric acid with rosuvastatin also appears to safely and effectively correct several atherogenic lipid abnormalities. Consequently, several options exist for combination lipid therapy that may be necessary to optimally address multiple lipid abnormalities and improve patient outcomes.
Author Affiliation: From Pennsylvania State College of Medicine, Penn State Heart and Vascular Institute, Hershey, PA.
Funding Source: This work was supported by an educational grant from Solvay Pharmaceuticals and Abbott.
Author Disclosure: Honoraria: Abbott, Merck-Schering-Plough, Pfizer.
Authorship Information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; supervision.
Address correspondence to: Peter Alagona Jr, MD, FACC, The Milton S. Hershey Medical Center, Pennsylvania State Heart and Vascular Institute, H047, 500 University Dr, Hershey, PA 17033. E-mail: firstname.lastname@example.org.
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