|LETTERS TO THE EDITOR
|Year : 2018 | Volume
| Issue : 2 | Page : 296-297
REVEAL study: Reveals the limitations of cholesteryl ester transfer protein inhibition
Anil Pareek, Indranil Purkait, Anu Grover, Ravi Tejraj Mehta
Medical Affairs & Clinical Research, Ipca Laboratories Limited, Mumbai, Maharashtra, India
|Date of Web Publication||14-May-2018|
Ipca Laboratories Limited, 142-AB, Kandivli Industrial Estate, Kandivli West, Mumbai - 400 067, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Pareek A, Purkait I, Grover A, Mehta RT. REVEAL study: Reveals the limitations of cholesteryl ester transfer protein inhibition. Indian J Endocr Metab 2018;22:296-7
|How to cite this URL:|
Pareek A, Purkait I, Grover A, Mehta RT. REVEAL study: Reveals the limitations of cholesteryl ester transfer protein inhibition. Indian J Endocr Metab [serial online] 2018 [cited 2018 Aug 14];22:296-7. Available from: http://www.ijem.in/text.asp?2018/22/2/296/232368
Anacetrapib is a potent inhibitor of cholesteryl ester transfer protein (CETP), which doubles high-density lipoprotein (HDL) cholesterol and lowers low-density lipoprotein (LDL) cholesterol. Epidemiologic studies have shown inverse associations between HDL cholesterol levels and cardiovascular (CV) outcomes. Ference et al. showed that with every 1 mmol/L reduction in the LDL cholesterol levels, the risk of coronary events and ischemic stroke reduces by approximately 20%.
Pharmacologic inhibition of CETP has the potential to substantially increase HDL cholesterol levels, along with reductions in non-HDL portion. Due to this dual effect, it was postulated that CETP inhibitors may result in significant CV risk reduction and thus have generated considerable research interest in the past few years. Previous trials of CETP inhibitors, i.e., torcetrapib  and evacetrapib  were stopped after around 2 years due to unexpected cardiovascular hazards or apparent lack of efficacy. Recently, published REVEAL study  assessed the efficacy and safety of anacetrapib, a potent CETP inhibitor among patients with established occlusive vascular disease. The drug when added to effective doses of atorvastatin showed 9% reduction in CV events. Detailed examination of the study reveals the following:
- Substantial HDL elevation (104% proportional difference) and LDL reduction (41% proportional difference) by anacetrapib did not get translated into proportional CV benefits
- There is a direct correlation of LDL reduction to risk reduction, proven in numerous studies, but this is not exhibited in this study. Similar observations were seen with other CETP inhibitors; evacetrapib and torcetrapib which showed 31.1% and 24.9% LDL reduction, respectively, with no clinical benefits. This aspect needs more research
- The study showed benefits only in participants with higher baseline LDL (>66 mg/dL), with no benefits seen in first 2 years
- The subgroup analysis revealed that patients on low dose statins benefitted more. The drug is not found as effective in females and patients with prior cerebrovascular disease, PAD and HF. This narrows the clinical utility of the drug.
It can be concluded that CETP inhibition as a therapeutic target is doubtful. Previous observational study in Japanese-American men (Honolulu Heart Program) with mutation in the CETP gene showed increased Coronary Heart Disease (adjusted RR of 1.68) despite increased HDL levels. This finding suggests that not only HDL concentration but also the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the antiatherogenicity of the HDL fraction.
The REVEAL study showed a good safety profile of anacetrapib. One possible therapeutic utility of the molecule can be in patients who are unable to tolerate statins, so the drug can offer some hope in this population group. This will require an outcome study which is unlikely to be carried out.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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