Beyond statins: The role of ezetimibe in targeting residual cardiovascular risk

ACS patients who are not at LDL-c treatment goal despite statin therapy, currently have two options; increasing statin dose or receiving combination therapy. More cholesterol-lowering drugs are available beyond statins, including ezetimibe, which can be used in combinational setting to further reduce residual CV risk. Statins and ezetimibe both affect the bulk metabolism of cholesterol in the body. While statins reduce cholesterol synthesis in the liver, ezetimibe blocks cholesterol absorption in the gut and thereby enhances the excretion of cholesterol. Combining these drugs introduces a double cholesterol-affecting hit and is therefore attractive to use.

“The double hit affects cholesterol metabolism in the whole body and is attractive in terms of the complementarity of action”

The benefit of this combination therapy is evidenced by the IMPROVE-IT study, which revealed an extra reduction of approximately 20% when using ezetimibe on top of statins. This study also showed a subsequent 6-8% reduction of CV disease, MI and stroke endpoints2. A Mendelian randomisation trial confirmed the conclusions of the IMPROVE-IT study, as the combination of a reduced gastrointestinal absorption and suppressed synthesis of LDL-c due to genetic variants in HMGR and NPC1L1, also lowered coronary heart disease risk8.

The IMPROVE-IT trial further demonstrated that ezetimibe did not only affect the frequency of first events but also of a secondary, third and fourth event. Such a trend had also been observed with statins, which Packard illustrated with data from the WOSCOPS trial. In the WOSCOPS trial pravastatin treatment for only 5 years resulted in a benefit that persisted for at least 20 years9. Another conclusion deduced from the IMPROVE-IT trial was that also this trial fitted with the observation that every 1 mmol/L reduction of LDL-c translates into a 22% decrease of risk. This insight corroborates the concept of further LDL-c lowering beyond statins in different clinical situations.

Packard also underlined the possibility of statin dose-lowering when using ezetimibe. This enables minimisation of statin-related adverse events that individuals can experience and may be worried about, while still maximising the benefit.

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