The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on the Management of Blood Cholesterol recommends lipid-lowering statins for adults with high cholesterol.1 Other drugs have also been shown to reduce cholesterol including bile acid sequestrants, ezetimibe, and PCSK9 inhibitors, and may be recommended in addition to statins, under certain circumstances.
Lowering low-density lipoprotein cholesterol (LDL-C) levels by 40 mg/dL has been shown to reduce heart and blood vessel related events, such as myocardial infarction (MI), coronary deaths, strokes, and coronary revascularizations by 20% to 25% for each year statins are taken.2,3 High-intensity statins have been shown to lower LDL-C by 50% from baseline and moderate-intensity statins can lower LDL-C by 30% to 49%.1 Some individuals, particularly those who are unable to tolerate high-intensity statins or do not achieve hoped for reductions in LDL-C with statins, may benefit from the addition of non-statin medication.
Ezetimibe is a non-statin that decreases cholesterol absorption in the small intestine and has been shown to reduce LDL-C levels by 13% to 20%.1,4 Cannon et al. compared statin therapy alone (simvastatin 40 mg plus placebo) with simvastatin 40 mg plus ezetimibe 10 mg in 18,144 patients recently diagnosed with acute coronary syndrome.4 After a median follow-up of six years, those taking combination therapy had a small, but statistically significant, further reduction in cardiovascular . The event rate was 32.7% in the simvastatin–ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (hazard ratio 0.936, 95% confidence interval [CI], [0.89 – 0.99], p=0.). Bohula et al. used an atherothrombotic risk score (based on the presence or absence of specific risk factors) to stratify patients by risk of recurrent coronary events after acute coronary syndrome and then measured response to the addition of ezetimibe to statin therapy.5 High-risk patients (n=4,393) had a 6.3% absolute risk reduction (95% CI [2.9% – 9.7%]) in ASCVD events at seven, while low-risk patients (n=8,032) did not appear to derive a benefit from the addition of ezetimibe to statin therapy.
The addition of ezetimibe is a reasonable consideration if maximally tolerated statin therapy has not resulted in a 50% reduction in LDL-C or an LDL-C below 100 mg/dL, in individuals with hypercholesterolemia for primary prevention of ASCVD.1 It is also reasonable in individuals with pre-existing ASCVD and at high-risk of recurrent events to consider the addition of ezetimibe if the LDL-C is 70 mg/dL or higher on a maximally tolerated statin regimen. It may be reasonable to add ezetimibe to maximally tolerated statin therapy in individuals with diabetes who are at very high-risk of ASCVD events, if necessary, to reduce the LDL-C levels by 50%, but effectiveness of this approach has not been well-established.
Bile Acid Sequestrants
Bile acid sequestrants have been shown to reduce LDL-C by 15% to 30% but can cause increases in triglycerides in some patients.1,6 The effect of this lowering on ASCVD outcomes has not been studied in randomized controlled studies. Adding bile acid sequestrants to maximally tolerated statin and ezetimibe therapy can be considered in patients with severe hypercholesterolemia without hypertriglyceridemia, to achieve LDL-C treatment goals.1
Medications that inhibit protein convertase subtilisin-kexin type 9 (PCSK9-inhibitors) have been shown to significantly reduce LDL-C (43% to 63%) in short term-studies,7,8 but their long-term safety and efficacy have not been demonstrated. In addition, the 2018 AHA/ACA guidelines caution that cost-effectiveness of PCSK9-inhibitors is low given 2018 prices. They may be reasonable as add-on to maximally tolerated statin and ezetimibe therapy in people with heterozygous familial hypercholesteremia or a very high baseline LDL-C (≥220 mg/dL) when other treatment has not been successful in reaching LDL-C goals.
Fibrates have been shown to lower triglycerides, raise high-density lipoprotein, and may be effective in preventing ASCVD events. Further study is needed to evaluate these effects.9,10 Niacin raises high-density lipoprotein levels and has been studied for its potential effect in reducing ASCVD events and mortality. A recent systematic review of randomized controlled trials determined that niacin does not lead to significant reductions in all cause-mortality or recurrent ASCVD events.11 Neither of these treatment strategies is recommended by the 2018 AHA/ACC guidelines.
- 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.
- 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.
- Cannon C, Blazing M, Giugliano R, Al E. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372 (25): 2387-2397.
- Bohula E, Morrow D, Guigliano R, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol 2017; 69 (8): 911-921.
- Huijgen R, Abbink EJ, Bruckert E, et al. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther 2010; 32 (4): 615-625.
- 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).
- 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.
- Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015;(10): CD009580.
- Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-Gonzalez I, Briel M. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database Syst Rev 2016; 11 : CD009753.
- Garg A, Sharma A, Krishnamoorthy P, et al. Role of niacin in current clinical practice: a systematic review. Am J Med 2017; 130 (2): 173-187.