There is strong evidence that elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of heart disease and stroke, and that the risk rises as blood concentrations of cholesterol increase.1,2 Several classes of drugs have been shown to lower LDL-C including HMG-CoA reductase inhibitors (statins), ezetimibe, PCSK9-inhibitors, and bile acid sequestrants.3 Residual cardiovascular risk remains even after LDL-C reduction, and the use of fibrates has been shown to lower that risk in patients with atherogenic dyslipidemia, a condition that refers to elevated triglycerides (>150 mg/dL), small-dense low-density lipoprotein, and low levels of high-density lipoprotein cholesterol (<40 mg/dL for men and <50 mg/dL for women).4,5
2018 American Heart Association/American College of Cardiology (ACA/AHA) Guideline on the Management of Blood Cholesterol strongly recommends a heart-healthy lifestyle for all individuals to lower the risk of cardiovascular disease.6 The guideline also strongly recommends lipid-lowering drugs, specifically statins, to reduce cholesterol levels for anyone who has preexisting disease of the heart or blood vessels as they are known to have a higher risk of having a future heart attack or stroke than those who do not.7,8
Statins are also recommended for people with high cholesterol (LDL-C 190 mg/dL or higher) or a high atherosclerotic cardiovascular disease (ASCVD) risk. Randomized controlled trials and meta-analyses have demonstrated the beneficial effects of statin therapy on the prevention and treatment of ASCVD.9,10 More intensive statin therapy has been shown to further reduce the incidence of heart attack and stroke when compared with less intensive regimens of statin therapy.11,12 Other drugs that have also been shown to reduce LDL-cholesterol (LDL-C) including ezetimibe and PCSK9 inhibitors, may be recommended in addition to statins, under certain circumstances.6,12
For people with clinical ASCVD considered to be at very high risk, a secondary goal is to lower LDL-C levels below 70 mg/dL.6 These include people who have had multiple major ASCVD events or who have multiple high-risk conditions. If high-intensity statin therapy is inadequate to reach this goal, non-statin therapy, specifically ezetimibe, is recommended. If that regimen is still inadequate, it is reasonable, according to the 2018 guidelines, to consider PCSK9 inhibitor therapy, after a clinician-patient discussion of net benefit, safety, and cost.
The addition of non-statin drugs to further lower LDL-C is based on recent evidence of their effectiveness in further lowering risk in patients with clinical ASCVD. Cannon et al. conducted a randomized double-blind trial of patients hospitalized with acute coronary syndrome with LDL-C levels between 50 and 125 mg/dL (n=18,144).15 They followed patients for a median of 6 years and compared outcomes (composite of cardiovascular deaths, nonfatal myocardial infarction, unstable angina, coronary revascularization, or nonfatal stroke) between patients taking simvastatin 40 mg and ezetimibe 10 mg with patients taking simvastatin 40 mg and placebo. Median LDL-C levels achieved in the simvastatin-ezetimibe group was 53.7 mg/dL compared to 69.5 mg/dL in the simvastatin-placebo group (p<0.001). The adverse cardiovascular event rate in the 6 years of follow-up in the simvastatin-ezetimibe was 32.7% compared to 34.7% in the simvastatin-placebo group (HR 0.936, 95% CI [0.89 – 0.99], p=0.016), a small, but statistically significant effect size.
Ezetimibe is the most commonly used non-statin lipid-lowering drug. The decision to recommend ezetimibe as the first add-on to statin therapy was based on its availability as a generic drug, its proven safety, and the low incidence of side effects in studies in large numbers of high-risk patients.15–17
PCSK9 inhibitors have demonstrated effectiveness as LDL-lowering drugs.6,18,19 The addition of the PCSK9 inhibitor alirocumab to a maximally tolerated statin regimen was shown to reduce LDL-C levels by 50.6% ± 1.4% compared to 20.7% ± 1.9% for ezetimibe after 24 weeks of therapy (p<0.0001).18 Sabatine et al. followed 4,465 patients in an open-label randomized trial comparing the PCSK9 inhibitor evolocumab plus standard therapy versus standard therapy alone for a median of 11 months. After three months, the LDL-C level was reduced to 70 mg/dL or less in 73.6% of patients in the evolocumab group, as compared with 3.8% in the standard-therapy group. The rate of cardiovascular events at one year was 2.1% in the standard therapy group compared to 0.95% in the evolocumab group (HR 0.47,95% CI [0.28 – 0.78], p=0.003).19 Further study of longer duration is needed to evaluate the effect of PCSK9 inhibitors on the rate of cardiovascular events over the long term. The incidence of serious side effects was not significantly different between the two groups19 but long-term safety remains to be proven.20,21 In addition, the high cost of PCSK9 therapy warrants consideration as clinicians discuss its relative value in risk reduction.6
Fibrates have been shown to effectively treat hypertriglyceridemia and improve the lipid profile.5 They reduce triglyceride levels by 50% and increase HDL-C levels by 20% depending on the initial levels of dyslipidemia.22 Additional cardiovascular benefits may arise from improvements in carbohydrate metabolism, adipokines levels, thrombosis incidence, and reduced inflammation associated with the use of fibrates. Fibrates that are approved for use in the US include gemfibrozil and fenofibrate. 23–25 The 2018 AHA/ACC guidelines to manage blood cholesterol currently recommend fibrates to treat severe hypertriglyceridemia (>500 mg/dL) only after lifestyle interventions and statins have been attempted and secondary causes have been addressed.5 European guidelines recommend fenofibrate in high-risk patients with triglyceride levels >200 mg/dL despite statin therapy.26
Bile acid sequestrants, including colestipol, colesevelam, and cholestyramine, have been approved for use in the US to lower LDL-C.27–29 Bile acid sequestrants prevent bile acids in the intestine from being reabsorbed into circulation. This forces the body to use cholesterol in the blood to manufacture bile, reducing the amount of cholesterol in the blood. They may be recommended for people with very high LDL-C and low triglycerides, if maximally tolerated statins and ezetimibe have been insufficient to reach goals5 or when statins are not tolerated.30
- MacMahon S, Duffy S, Rodgers A, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: A meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370 (9602): 1829-1839.
- Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ 1991; 303 (6797): 276-282.
- Feingold KR, Grunfeld C. Cholesterol Lowering Drugs. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext [Internet]: MDText.Com, Inc.; 2000-. 2018 Dec 13. South Dartmouth (MA); 2018.
- Okopień B, Bułdak Ł, Bołdys A. Expert review of clinical pharmacology benefits and risks of the treatment with fibrates –– a comprehensive summary. Expert Rev Clin Pharmacol 2018; 11 (11): 1099-1112.
- Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011; 217 (2): 492-498.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol. J Am Coll Cardiol 2018.
- Piepoli MF, Corra U, Dendale P, et al. Challenges in secondary prevention after acute myocardial infarction: a call for action. Eur J Prev Cardiol 2016; 23 (18): 1994-2006.
- Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015; 36 (19): 1163-1170.
- Trialists CT. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493): 1267-1278.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388 (10059): 2532-2561.
- Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376 (9753): 1670-1681.
- Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 2018; 319 (15): 1566-1579.
- Wilson PWF, Polonsky TS, Miedema MD, Khera A, Kosinski AS, Kuvin JT. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2018;(2018).
- Alenghat FJ, Davis AM. Management of Blood Cholesterol. JAMA February 2019.
- Cannon C, Blazing M, Giugliano R. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372 (25): 2387-2397.
- Kashani A, Sallam T, Bheemreddy S, Mann DL, Wang Y, Foody JM. Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol 2008; 101 (11): 1606-1613.
- Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia : part 2. J Clin Lipidol 2015; 9 (6): S1-S122.e1.
- Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins : the ODYSSEY COMBO II randomized controlled trial. Eur Hear J 2015; 36 : 1186-1194.
- Sabatine M, Giugliano R, Wiviott S, Al E. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372 (16): 1500-09.
- Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol 2017; 69 (5): 471-482.
- Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017; 377 (7): 633-643.
- Okopień B, Buldak L, Bołdys A, Buldak L, Bo A. Fibrates in the management of atherogenic dyslipidemia. Expert Rev Cardiovasc Ther 2017; 15 (12): 913-921.
- Fenoglide (fenofibrate) [package insert]. San Diego, CA: Santarus, Inc; 2012.
- Triglide (fenofibrate) [package insert]. Florham Park NJ: Shionogi Inc; 2012.
- Lopid (gemfribrozil) [package insert]. New York, NY: Parke-Davis; 2008.
- Catapano A, Graham I, DeBacker G et al. 2016 ESC / EAS guidelines for the management of dyslipidaemias. Eur Hear J 2016; 37 (39): 2999-3058.
- Colestipol [package insert]. New York, NY: Pfizer Pharmaceuticals; 2014.
- Colesevelam [package insert]. Parsippany, NJ: Ascend Laboratories, LLC; 2018.
- Cholestyramine [package insert]. Pointe-Claire, Quebec: Odan Laboratories; 2016.
- Fischer S, Julius U. Management of patients with statin intolerance. Atheroscler Suppl 2017; 30 : 33-37.