Editorial
Obicetrapib: There is still Life in the CETP Inhibitor!
2024 年 31 巻 10 号 p. 1367-1369
詳細
2024 年 31 巻 10 号 p. 1367-1369
See article vol. 31: 1386-1397
In the prevention of atherosclerotic cardiovascular disease (ASCVD), the higher the blood low-density lipoprotein cholesterol (LDL-C) level, the worse, and the lower, the better. In other words, the LDL-C level is a causal marker. On the other hand, low blood high-density lipoprotein cholesterol (HDL-C) levels are often bad, but too high levels are not necessarily good. Also, treatment to increase HDL-C levels in patients already receiving LDL-C-lowering therapy does not necessarily reduce ASCVD. Consequently, HDL-C has been removed from its place of honor as “good cholesterol,” and HDL-C levels are now considered mere markers1).
Cholesteryl ester transfer protein (CETP) inhibitors seemed to have lost their image as the “ASCVD-preventive agents by increasing HDL.” However, there was still life in them! The results of clinical trials and Mendelian randomized analyses have focused attention on a strategy for CETP inhibitors to not only increase HDL but also to reduce apolipoprotein B (ApoB)-containing lipoproteins, which has led to their development as LDL-lowering agents. Since CETP transfers cholesteryl esters in HDL particles to apoB-containing lipoproteins and triglycerides in very low-density lipoprotein (VLDL) to LDL and HDL, its inhibition reduces the amount of cholesterol in apoB-containing lipoproteins.
In this issue of the Journal, Harada-Shiba et al. studied the efficacy, safety, and tolerability of a CETP inhibitor named obicetrapib in 102 Japanese subjects in a double-blind, randomized, controlled phase II trial2). The duration was 8 weeks and obicetrapib doses were 2.5, 5, and 10 mg/day, in a comparison with a placebo group. Pharmacokinetics were also examined in this study. All patients were already under statins treatment (atorvastatin 10 or 20 mg/day, or rosuvastatin 5 or 10 mg/day), making the study design more realistic. The results changed LDL-C, Apolipoprotein B (ApoB), Non-HDL-C, and HDL-C levels by -45.8%, -29.7%, -37.0%, and +159%, respectively, in the obicetrapib 10 mg/day group compared to the placebo group. Pharmacokinetic studies showed that obicetrapib disappears from the body 4 weeks after discontinuation. Obicetrapib is apparently less lipophilic than anacetrapib, which was discontinued because of its strong lipophilicity and delayed accumulation in adipose tissue, despite its success in reducing cardiovascular events3). Obicetrapib was originally developed in Japan, but phase II trials are being conducted overseas first4-6). Although Japanese have higher HDL-C levels than other racial groups, this study also demonstrated sufficient LDL-C, ApoB, and Non-HDL-C lowering effects, as well as a marked HDL-C increasing effect.
Interestingly, the drug has also been reported to reduce lipoprotein (a) (Lp(a)) levels by more than 40%. Unfortunately, the effect on Lp(a) was not examined in this study. The clinical significance in Japanese patients with low Lp(a) levels as well as in those with familial hypercholesterolemia (FH), who have high Lp(a) levels, is a topic for future study. In addition, the mechanism by which the drug lowers Lp(a) is unknown (Fig.1).
ASCVD: atherosclerotic cardiovascular disease, LDL-C: low-density lipoprotein cholesterol, ApoB: apolipoprotein B, Lp(a): lipoprotein (a), HDL-C: High-density lipoprotein cholesterol, ApoE: apolipoprotein E
Phase III trials evaluating the efficacy of obicetrapib in FH heterozygotes and patients with ASCVD are currently underway with Japanese participation7). If favorable results are obtained and it is decided to go ahead with its marketing as the first CETP inhibitor, it could provide a new option for patients who fail to reach LDL-C control targets, especially those with FH, diabetes, and ASCVD (Fig.1).
Although ezetimibe was not used in combination in this phase II study, the addition of ezetimibe to statin plus obicetrapib in the ROSE2 study further reduced LDL-C, non-HDL-C, and ApoB levels. This means that statins, ezetimibe, and CETP inhibitors all have different mechanisms of action in lowering LDL-C levels, and synergistic effects can be expected when used together. If obicetrapib has LDL-C-lowering effects that are not mediated by the LDL receptor, such as promotion of transintestinal cholesterol excretion (TICE), it may also be beneficial for patients with homozygous FH8).
As mentioned above, CETP inhibitors were originally developed as HDL-C increasing agents. These drugs also increase apolipoprotein E levels and there seem to be moves (Fig.1) to develop them as treatments for diseases other than ASCVD, such as Alzheimer’s disease, diabetes, and age-related macular degeneration as pathologies associated with HDL9). Obicetrapib may also hold promise as a treatment for schistosomiasis japonica10). By confirming the efficacy, safety, and tolerability of obicetrapib in Japanese patients, this study inspired the author of this Editorial Comment, who is an “HDL believer.”
Masatsune Ogura received lecture fees from Amgen, Ultragenyx Japan, and Kowa.
This work was supported by a grant from JSPS KAKENHI (21K08143).
