Why do I have to take more than one medicine to lower my cholesterol?

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

^References

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