What medications are used to treat high cholesterol?

Overview

The guidelines also recommend high-intensity statins for primary prevention among adults (age 40 – 75) with moderately high cholesterol (LDL-C levels 70 mg/dL to 189 mg/dL) if they are at high (>20%) 10-year risk of ASCVD. Moderate-intensity statins are recommended for adults (age 40 – 75) at intermediate (≥7.5% and <20%) 10-year ASCVD risk for myocardial infarction (MI) or stroke. The 10-year risk of MI or stroke can be estimated using the Pooled Cohort Equation (PCE) that factors in cholesterol levels, age, smoking status, blood pressure levels, and race to predict ASCVD risk.

Younger adults (age <40 years) should consider statins if their LDL-C level is ≥160 mg/dL and there is a family history of premature ASCVD.¹ Older adults (age >75 years) with high cholesterol may also be candidates for statin therapy, but strong evidence of risk and benefits in this age group is lacking.

Other drugs have also been shown to reduce LDL-cholesterol (LDL-C) including bile acid sequestrants, ezetimibe, and PKSK9 inhibitors. These drugs may be recommended in addition to statins, under certain circumstances. 

Statins

Statins lower LDL-C. High-intensity statins have been shown to lower LDL-C by 50% and moderate-intensity statins can lower LDL-C by 30% to 49%. The cardiovascular benefit that is achieved in an individual depends on how much the cholesterol levels decline in response to statins.^2,3 For secondary prevention, Baigent et al. compared data from individuals with ASCVD taking more intensive statin regimens with those taking standard statin regimens (n=39,612).⁴ Compared with less intensive regimens, more intensive regimens resulted in a 15% (95% confidence interval [CI] [11–18%], p<0.0001) further reduction in major vascular events, including MI and stroke.

To estimate the positive effect of statin use in primary prevention, Chou et al. conducted a systematic review of 19 clinical trials to evaluate the effect of statin therapy in reducing the risk of cardiovascular events among individuals without pre-existing ASCVD.⁵ Compared to placebo or no statin therapy, statin therapy was associated with reduced risk of cardiovascular outcomes (risk ratio 0.70, 95% CI [0.63 – 0.78]) with greater absolute benefits in patients at greater baseline risk.

Ezetimibe

Ezetimibe is a non-statin medicine that has been shown to further reduce LDL-C levels by 13% to 20% when added to a statin regimen.^1,4 It is recommended for use in high-risk adults with pre-existing ASCVD for secondary prevention, in combination with statins. It may be considered under other circumstances when maximally tolerated statin therapy is insufficient to lower LDL-C levels by 50%.¹ 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.⁶ After a median follow-up of six years, those taking combination therapy had a small but statistically significant reduction in cardiovascular events. 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% CI [0.89 – 0.99] p=0.016).

For primary prevention in intermediate-risk adults, ezetimibe can also be considered as an add-on to a moderate-intensity statin, if high-intensity statins are advisable, but not tolerated, according to the 2018 ACC/AHA cholesterol guidelines.¹

Bile Acid Sequestrants

Bile acid sequestrants have been shown to further reduce LDL-C by 15% to 30% when added to a statin regimen, but can cause increases in triglycerides in some patients.^1,7 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 Bile acid-sequestrants can also be considered for use in intermediate-risk adults for primary prevention of ASCVD added to moderate-intensity statin therapy, when high-intensity statins are advisable, but not tolerated.¹

PCSK9-inhibitors

Medications that inhibit protein convertase subtilisin-kexin type 9 (PCSK9-inhibitors) have been shown to further reduce LDL-C (43% to 63%) in short term-studies,^8,9 but their long-term safety and efficacy have not been demonstrated.¹ According to the 2018 AHA/ACC cholesterol guidelines, they may be considered as an add-on to maximally tolerated statin and ezetimibe therapy in people with heterozygous familial hypercholesteremia or very high baseline LDL-C when other treatment has not been successful in reaching LDL-C goals.¹

Other Non-Statins

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.^10,11 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.¹² Neither of these treatment strategies is recommended by the 2018 AHA/ACC cholesterol guidelines.

References

1. 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.
2. 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.
3. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380 (9841): 581-590.
4. 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.
5. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016; 316 (19): 2008-2024.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.