Statins have been shown to reduce the risk of all-cause mortality, stroke, and myocardial infarction (MI). Pooled analysis also indicates a decreased risk of composite CV outcomes. Relative risk ranged from 0.67 to 0.92 with consistent absolute risk differences.²

However, despite the efficacy and the widespread use of statins, patients are often not adherent to therapy and may discontinue these agents due to statin-associated muscle symptoms (SAMs) or fear of other adverse drug effects, resulting in poor patient outcomes.³

When should non-statin therapies be considered?

Since 2018, guidelines recommend the use of non-statin therapies such as ezetimibe, bile acid sequestrants/resins, and proprotein convertase subtilisin/kexin type 9 as secondary prevention treatment options for patients with a very high risk of CVD events, for patients with statin intolerances, or for patients in whom a statin alone does not lower LDL-C sufficiently (<1.8mmol/l).³

In South Africa, ezetimibe is indicated for patients who cannot control their cholesterol levels by diet alone. Ezetimibe adds to the cholesterol-lowering effect of statins and is the only drug within the class of selective cholesterol absorption inhibitors.^3,4

Ezetimibe inhibits the absorption of cholesterol by targeting a sterol transporter called Niemann-Pick C1-Like 1, which is localised at the brush border cells of the small intestine and involved in the uptake of cholesterol. Inhibition of this transporter decreases the delivery of cholesterol into the mesenteric veins, hence to the liver, and ultimately increases the clearance of cholesterol from the blood.³

Ezetimibe as monotherapy

Monotherapy with ezetimibe has demonstrated a mean percentage reduction in LDL-C from baseline when compared to placebo. Knopp et al showed ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, HDL-C, and lipoprotein. Furthermore, ezetimibe lowered triglyceride levels.⁵

A meta-analysis by Pandor et al, showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL-C of -18.58%, compared with placebo. Significant changes were also found in total cholesterol (-13.46%), HDL-C (3%), and triglyceride levels (-8.06%).⁶

Ezetimibe combination therapy

For patients who do not tolerate statins, fenofibrate may be added to ezetimibe. Studies show that patients who are treated with fenofibrate monotherapy or in combination with ezetimibe achieved mean changes in LDL-C of −24.2% (combination therapy), −16.0% (fenofibrate), and −17.4% (ezetimibe).³

The addition of ezetimibe to a statin has been proven to result in additional LDL-C reductions, compared to monotherapy with either medication. Specific incremental reductions from baseline levels were 14%, 12%, 14%, and 15% for ezetimibe administered with simvastatin, atorvastatin, pravastatin, and lovastatin, respectively, compared to statin monotherapy.^3,7-10

The additional LDL-C lowering effects seen with ezetimibe in combination with low-dose statin therapy was shown to be equivalent to the LDL-C lowering effects of a high-dose statin. This finding may be beneficial for patients experiencing SAMs with moderate or high-intensity statin doses.^3,7-10

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is considered the landmark study of ezetimibe on CV outcomes. IMPROVE-IT evaluated the effect of ezetimibe combined with simvastatin, as compared with that of simvastatin alone, in stable patients (n= 18 144) who had had an acute coronary syndrome and whose LDL-C levels were within guideline recommendations.^3,11

The primary endpoint was a composite of CV death, non-fatal MI, unstable angina requiring rehospitalisation, coronary revascularisation (≥30 days after randomisation), or nonfatal stroke. At the time of hospitalisation for the index event, the mean LDL-C level was 2.4mmol/l in each group. The median follow-up was six years.¹¹

The median average LDL-C level during the study was 1.4mmol/l in the simvastatin–ezetimibe group, compared to 1.8mmol/l in the simvastatin-monotherapy group, representing a 24% further lowering of LDL-C when ezetimibe was combined with simvastatin than when simvastatin was administered alone.¹¹

The rates of death from CV causes and from any cause were similar in the two groups. The risk of any MI was significantly lower with simvastatin–ezetimibe than with simvastatin monotherapy (1.7%), as was the risk of ischaemic stroke (0.7%).¹¹

There was a non-significantly higher risk of haemorrhagic stroke with simvastatin–ezetimibe than with simvastatin monotherapy (0.2%), although the number of hemorrhagic strokes was low.¹¹

The rate of major vascular events (a composite of death from coronary heart disease, MI, stroke, or coronary revascularisation ≥30 days or more after randomisation) was also significantly lower in the simvastatin–ezetimibe group.¹¹

Conclusion

Statins are the cornerstone of primary CVD prevention in patients living with hypercholesterolaemia, offering proven reductions in all-cause mortality, stroke, and MI. Nevertheless, non-adherence and discontinuation due to side effects hinder optimal outcomes. Enter ezetimibe, a promising adjunctive therapy. Its inhibition of cholesterol absorption via Niemann-Pick C1-Like 1 transporter presents a novel mechanism. Ezetimibe monotherapy consistently showcases LDL-C reductions alongside improved lipid profiles. Combination therapy with statins amplifies the benefits, offering LDL-C lowering comparable to high-dose statins, as illustrated by IMPROVE-IT. These findings underscore ezetimibe's role as an essential tool in addressing hypercholesterolaemia and mitigating CVD risk, especially in statin-intolerant patients.

References

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2. US Preventive Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults. US Preventive Services Task Force Recommendation Statement. JAMA, 2022.
3. Bardolia C, Amin NS, Turgeon J. Emerging Non-statin Treatment Options for Lowering Low-Density Lipoprotein Cholesterol. Front Cardiovasc Med, 2021.
4. Professional Information. Tryzetor. [Internet]. Available at: https://www.mydynamics.co.za/wp-content/uploads/2022/05/Tryzetor-Plus-A2681-1.pdf
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