CETP inhibitor

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CETP inhibitor
Cholesterylester transfer protein
Legal status
In Wikidata

A CETP inhibitor is a member of a class of drugs that inhibit

cholesterylester transfer protein (CETP).[1][2][3][4] They are intended to reduce the risk of atherosclerosis (a cardiovascular disease) by improving blood lipid levels. At least three medications within this class have failed to demonstrate a beneficial effect.[5]

Types

These drugs have generally failed in clinical trials, either causing a marked increase in deaths (torcetrapib), or having no meaningful clinical improvement despite HDL increases (dalcetrapib, evacetrapib).

Failed:

  • Torcetrapib, failed in 2006 due to excess deaths in Phase III clinical trials.[citation needed]
  • Dalcetrapib, development halted in May 2012 when Phase III trials failed to show clinically meaningful efficacy.[6]
  • Evacetrapib, development discontinued in 2015 due to insufficient efficacy.[7]

Succeeded:

  • Anacetrapib. In 2017, the REVEAL trial based on more than 30,000 participants showed a modest benefit of the addition of anacetrapib to statin therapy.[8] Despite the successful trial, Merck halted the development of the drug.[9] Discontinued in 2017.[10]
  • Obicetrapib (TA-8995, AMG-899), Phase II results reported in 2015, Phase III trials beginning in 2023.[11]

Mechanism

Drugs in this class substantially increase HDL cholesterol, lower LDL cholesterol, and enhance reverse cholesterol transport.[citation needed]

CETP inhibitors inhibit

low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels.[12] CETP inhibitors do not reduce rates of mortality, heart attack, or stroke in patients already taking a statin.[13]

Pharmacogenomics

In 2015, a pharmacogenomic sub-study of the dal-OUTCOMES clinical trial on 5,749 individuals identified a genetic variant in the ADCY9 gene which modulates response to dalcetrapib. In patients with the rs1967309 'AA' genotype, there was a significant reduction in the rate of cardiovascular events in the dalcetrapib arm whereas non-carriers were at increased risk.[14] Beginning in 2015, the efficacy of dalcetrapib in the genetic sub-population was being investigated in the dal-GenE trial.[15][needs update]

Chemical structures

References

  1. PMID 17387130
    .
  2. PMID 18536741
    .
  3. S2CID 5781222
    .
  4. doi:10.1021/cen-09008-cover
    .
  5. PMID 28961179
    .
  6. ^ Larry Husten (May 2012). "Roche Terminates Development Of CETP Inhibitor Dalcetrapib". Forbes.
  7. ^ "Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease". Oct 12, 2015.
  8. PMID 28847206
    .
  9. ^ "Merck Provides Update on Anacetrapib Development Program". Merck.com. October 11, 2017. Retrieved January 4, 2018.
  10. ^ "Notable drug failures in 2017". Chemical & Engineering News. 95 (48). December 4, 2017.
  11. S2CID 7540974
    .
  12. S2CID 25024920
    .
  13. PMID 25038074
    .
  14. PMID 25583994
    .
  15. ^ "Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-12-02.
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