In this study, combination therapy with ezetimibe had a stronger LDL-C lowering effect than an increased dose of rosuvastatin in patients with type 2 diabetes who maintained LDL-C levels higher than 80 mg/dL despite treatment with 2.5 mg/day of rosuvastatin. In addition, combination therapy led to further improvement of sdLDL-C, MDA-LDL, TG, and RLP-C, suggesting that the qualitative improvement of highly atherogenic lipoproteins was also greater.
Statins inhibit cholesterol synthesis in the liver, but this result in enhanced cholesterol absorption and that decreases the cholesterol-lowering effect. Thus, addition of ezetimibe, a cholesterol absorption inhibitor with a complementary action to statins, had a greater LDL-C-lowering effect. In addition, the percent reduction of LDL-C was −31% in the group that received ezetimibe, which was equal to the previously reported range in patients with dyslipidemia[6, 14]. Vaverkova et al. and Gianluca et al.[16, 17] reported that, similar to the results of the present study, the reduction of LDL-C with combined use of ezetimibe was higher among patients with type 2 diabetes compared to those with normal glucose tolerance. Cholesterol absorption from the small intestine is facilitated by the NPC1L1 transporter. In patients with diabetes, expression of NPC1L1 is enhanced, whereas there is reduced expression of ATP-binding cassette transporters (ABC) G5 and G8, which are involved in returning cholesterol from small intestinal epithelial cells to the small bowel lumen. Accordingly, patients with diabetes exhibit increased cholesterol absorption. Based on this background, it is considered likely that combination therapy with ezetimibe will have a more powerful effect in hypercholesterolemic patients with diabetes whose cholesterol absorption is enhanced, given that ezetimibe selectively inhibits cholesterol absorption from the intestine by binding to the NPC1L1 receptor.
In recent years, it has become clear that a decrease in the size of LDL particles is associated with the risk of coronary artery disease, and people who mainly have sdLDL-C, as opposed to those with normal-sized LDL, are known to show a three-fold higher incidence of CHD. On the other hand, it has been reported that patients with type 2 diabetes often have sdLDL-C, suggesting that not only maintaining a low blood level of LDL-C but also an increase in the size of LDL particles are essential for the prevention of atherosclerosis. In a previous study, ezetimibe combination therapy and statin monotherapy reportedly showed similar sdLDL-C-lowering effects. However, there has been no report about patients with type 2 diabetes mellitus who were already receiving statin therapy, and this is the first study to show that ezetimibe combination therapy has a greater sdLDL-C-improving effect than statin monotherapy in patients already using statins.
Oxidized LDL, including MDA-LDL, is a marker of oxidative stress, and has been reported to serve as a predictor of cardiovascular events. Oxidized LDL is closely related to progression of atherosclerosis, including the formation of foam cells, vascular endothelial dysfunction, and vascular inflammation. In coronary artery disease, diabetes mellitus, and metabolic syndrome, the level of oxidized LDL has been reported to be high, and it is thought to be closely involved in the pathology of diabetes as well as the progression of vascular complications. Regarding changes of MDA-LDL, only a few reports have compared statin monotherapy with ezetimibe combination therapy, and none of the previous studies targeted only patients with diabetes mellitus. In the present study, ezetimibe combination therapy showed a greater MDA-LDL-lowering effect than statin monotherapy, which was similar to the finding reported by Uemura et al., who studied patients with impaired glucose tolerance and coronary artery disease. The effectiveness of this combination therapy in patients with diabetes mellitus was thus emphasized.
Remnant lipoproteins accumulate in the vessel wall, and are involved in the onset and progression of atherosclerosis, such as foam cell formation, vascular endothelial dysfunction, promotion of vascular smooth muscle proliferation, and production of PAI-1. Remnant lipoprotein levels rise from the stage of abnormal glucose tolerance, and reportedly increase even without the presence of obvious dyslipidemia. In other words, in patients with diabetes mellitus, qualitative abnormalities of lipoproteins may be one of the reasons why the risk of cardiovascular events is so high. Some studies have compared statin monotherapy and ezetimibe combination therapy in patients with abnormal glucose tolerance and coronary artery disease[26, 30], but there has never been a study only targeting patients with diabetes mellitus. In the present study, the percent reduction of TG and atherosclerosis-inducing RLP-C, so-called “TG-rich lipoprotein”, was significantly higher in the combined group, suggesting that combination therapy with ezetimibe can be useful for suppressing the onset and progression of atherosclerosis by controlling remnant lipoproteins in diabetic patients.
In the present study, the levels of TG, sdLDL-C, RLP-C, and MDL-LDL were markedly improved in the group receiving concomitant treatment with ezetimibe. The mechanism by which ezetimibe decreases TG levels remains unclear, although this drug has been suggested to decrease TG levels by inhibiting cholesterol absorption, chylomicron production, fatty acid absorption via FATP4, and apoB-48 production in the small intestine[31–33]. Regarding the improvement of sdLDL-C and RLP-C, ezetimibe is considered to inhibit chylomicron production and thereby reduce the TG-rich lipoproteins, which means that this drug decreases the LDL-C level and normalizes the size of LDL particles and thereby decreases both sdLDL-C and RLP-C levels. Regarding the improvement of MDA-LDL, ezetimibe decreases the level of sdLDL-C, which is likely to be oxidized and degraded, and it inhibits the absorption of dietary oxysterol that is also likely to be oxidized and degraded.
It has been reported that ezetimibe improves insulin resistance in animals and humans. It has also been reported that ezetimibe improves insulin resistance in mice fed a high-fat diet, but not in mice fed a normal diet. This suggests that ezetimibe may normalize the high-fat diet-enhanced activity of SREBP-1c and thereby improve hepatic insulin resistance. Tsunoda et al. reported that ezetimibe improved insulin resistance in their patients with high insulin resistance (mean HOMA-IR: 5.3). In the present study, 44% of the subjects were taking pioglitazone and 36% were taking metformin before the start of the study, so their insulin resistance was improved (mean HOMA-IR:2.8) at the time of the study. Thus, it is considered that the effect of ezetimibe on insulin resistance might not have been evaluated properly.
This study had the following limitations. The first limitation was a relatively small sample size, and the observation period was also short. The second limitation is that the present study used surrogate markers for cardiovascular events to examine the effectiveness of statin monotherapy and ezetimibe combination therapy. The results of the currently ongoing IMPROVE-IT study targeting patients with acute coronary syndrome will help to determine which of these therapies can actually prevent atherosclerotic disease.