The combination of statin and ezetimibe is safe, effective, and preferable

Abstract

In this issue of the Journal of Internal Medicine, Cha et al. from the Republic of Korea reported several important findings in the article entitled “Safety and efficacy of moderate-intensity statin with ezetimibe in elderly patients with atherosclerotic cardiovascular disease” [1]. The primary endpoint of the study was the incidence of statin-associated muscle symptoms (SAMSs) and the effect on low-density lipoprotein cholesterol (LDL-C) levels in elderly patients treated with high-intensity statin in monotherapy and those treated with moderate-intensity statin in combination with ezetimibe. Despite similar LDL level reductions in the two groups, a significantly lower frequency of SAMS was observed in that treated with the combination. In addition, there was a significant reduction in total cholesterol level, indicating a reduction of non-high-density lipoprotein cholesterol level (non-HDL-C), including “remnants.” Remnants have been shown to be highly atherogenic in patients with prediabetes, diabetes mellitus type 2, and kidney disease.

Muscular side effects of statins are seen in approximately 5% of the patients and are dose-dependent. The most severe side effect, rhabdomyolysis, is very rare (1/100,000) and has been proposed to be related to the development of auto-antibodies against HMG-CoA [2].

Statins have, in many studies, both in primary and secondary prevention settings, resulted in decreased morbidity and mortality in cardiovascular diseases [3]. Statins are currently prescribed to more than 10% of the population in many countries.

Statins inhibit the endogenous synthesis of cholesterol via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. They are most effective in patients with a high synthesis and low cholesterol absorption [4].

Ezetimibe blocks the uptake of cholesterol in the small intestine. The drug was discovered without a clear understanding of the molecular target of the drug. Later, it was found that the primary target of ezetimibe is the cholesterol transporter Niemann-Pick C1-Like 1 protein, expressed by intestinal enterocytes [5].

One of the first studies showing good results of combining statin with ezetimibe was the SHARP study, titled “Study of Heart and Renal Protection” [6]. The study resulted in a significant 17% reduction in major atherosclerotic events in patients with kidney disease treated with simvastatin plus ezetimibe compared to simvastatin/placebo. The previous study also reported a greater decrease in total cholesterol level compared to LDL-C, indicating a reduction in remnants.

A second study showing the positive effects of the combination of statin and ezetimibe was the IMPROVE-IT trial titled “Improved Reduction of Outcomes: Vytorin Efficacy International trial” [7]. The study included 18,144 patients with acute coronary syndromes who were randomized to treatment with a combination of ezetimibe/simvastatin or placebo/simvastatin. The primary efficacy endpoint was a composite of cardiovascular death, major coronary events (e.g., myocardial infarction), unstable angina requiring hospital admission, coronary revascularization occurring ≥30 days after randomization, or stroke. Diabetes was a prespecified subgroup. Due to a low incidence of the primary endpoint, the study took 7 years. The study also reported positive outcomes of the combined treatment, which was mainly seen in the group of patients with diabetes, where the number needed to be treated for prevention was as low as 24. In fact, this was the main reason for the overall positive results in the primary endpoint of the whole study. Moreover, in the IMPROVE-IT, the combination led to clear reductions in total cholesterol and non-HDL cholesterol levels.

In contrast to the presented study by Cha et al., statins in the latter studies were given in the same dosage in the combined treatment groups and the comparator group. Therefore, it is not a surprise that no difference was seen in muscular side effects between the treatment groups in those studies.

Osman et al. performed a study in healthy individuals treated with atorvastatin in comparison with those on atorvastatin in combination with ezetimibe. They reported a significant decrease in plasma cholesterol, cholesteryl esters, and triglycerides in remnants particles in the combination-treated group [8].

The results from the study by Cha et al. are very important when treating elderly patients, mainly due to the very low frequency of muscular side effects observed when using the combination, even though it provided the same effect on LDL cholesterol. In addition, the significant reduction in total cholesterol indicates a decrease in highly atherogenic “remnants.” This may have a significant impact on the incidence and outcome of cardiovascular diseases.

Thus, the combination of a moderate dosage of statin and ezetimibe is preferable to a high dosage of statin. The results indicate that the combination should be used in broader patient groups, especially in the elderly, where a high dosage of statins may cause more muscle problems.

The author declares the following: Lecturer, advisory board, and steering committee fees from Amgen, Sanofi, Novartis, Chiesi, TIMI, and Ultragenics.