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LETTERS TO THE EDITOR
Year : 2018  |  Volume : 22  |  Issue : 2  |  Page : 296-297

REVEAL study: Reveals the limitations of cholesteryl ester transfer protein inhibition


Medical Affairs & Clinical Research, Ipca Laboratories Limited, Mumbai, Maharashtra, India

Date of Web Publication14-May-2018

Correspondence Address:
Anil Pareek
Ipca Laboratories Limited, 142-AB, Kandivli Industrial Estate, Kandivli West, Mumbai - 400 067, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijem.IJEM_17_18

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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



Sir,

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.[1] 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%.[2]

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 [3] and evacetrapib [4] were stopped after around 2 years due to unexpected cardiovascular hazards or apparent lack of efficacy. Recently, published REVEAL study [1] 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.[5] 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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.  Back to cited text no. 1
    
2.
Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: An analysis of FOURIER, SPIRE, and the cholesterol treatment trialists collaboration. Eur Heart J 2017; [Epub ahead of print].  Back to cited text no. 2
    
3.
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.  Back to cited text no. 3
    
4.
Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KA, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933-42.  Back to cited text no. 4
    
5.
Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest 1996;97:2917-23.  Back to cited text no. 5
    




 

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