CETP inhibitor explained

Use:	None as of 2017
Biological Target:	Cholesterylester transfer protein

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.
• 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]

Others:

• 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] Merck halted the development of the drug in 2017, concluding it wasn't sufficiently effective to be a competitive product.^{[9] [10]}
• Obicetrapib (TA-8995, AMG-899): Phase II results were reported in 2015 and Phase III trials beginning in 2023.^[11]

Mechanism

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

CETP inhibitors inhibit cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or 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]

Notes and References

1. Tall AR . CETP inhibitors to increase HDL cholesterol levels . The New England Journal of Medicine . 356 . 13 . 1364–1366 . March 2007 . 17387130 . 10.1056/NEJMe078029 .
2. Joy TR, Hegele RA . The failure of torcetrapib: what have we learned? . British Journal of Pharmacology . 154 . 7 . 1379–1381 . August 2008 . 18536741 . 2492099 . 10.1038/bjp.2008.248 .
3. Rennings AJ, Stalenhoef A . JTT-705: is there still future for a CETP inhibitor after torcetrapib? . Expert Opinion on Investigational Drugs . 17 . 10 . 1589–1597 . October 2008 . 18808319 . 10.1517/13543784.17.10.1589 . 5781222 .
4. Carmen Drahl . The Cholesterol Bet . Chemical & Engineering News . 90 . 8 . 13–20 . February 2012 . 10.1021/cen-09008-cover .
5. Filippatos TD, Kei A, Elisaf MS . Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias? . Diseases . 5 . 4 . 21 . September 2017 . 28961179 . 5750532 . 10.3390/diseases5040021 . free .
6. Larry Husten. Roche Terminates Development Of CETP Inhibitor Dalcetrapib. Forbes. May 2012.
7. News: Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease . Oct 12, 2015.
8. Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, Collins R, Wiviott SD, Cannon CP, Braunwald E, Sammons E, Landray MJ . 6 . Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease . The New England Journal of Medicine . 377 . 13 . 1217–1227 . September 2017 . 28847206 . 10.1056/NEJMoa1706444 . free .
9. Web site: Merck Provides Update on Anacetrapib Development Program . October 11, 2017 . Merck.com . January 4, 2018.
10. December 4, 2017 . Notable drug failures in 2017 . . 95 . 48.
11. Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J, Saleheen D, Rader DJ, Brewer HB, Barter PJ . 6 . Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial . Lancet . 386 . 9992 . 452–460 . August 2015 . 26047975 . 10.1016/S0140-6736(15)60158-1 . free . 1887/117246 . 7540974 .
12. Barkowski RS, Frishman WH . HDL metabolism and CETP inhibition . Cardiology in Review . 16 . 3 . 154–162 . May 2018 . 18414186 . 10.1097/CRD.0b013e31816a3b60 . 25024920 .
13. Keene D, Price C, Shun-Shin MJ, Francis DP . Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients . BMJ . 349 . g4379 . July 2014 . 25038074 . 4103514 . 10.1136/bmj.g4379 .
14. Tardif JC, Rhéaume E, Lemieux Perreault LP, Grégoire JC, Feroz Zada Y, Asselin G, Provost S, Barhdadi A, Rhainds D, L'Allier PL, Ibrahim R, Upmanyu R, Niesor EJ, Benghozi R, Suchankova G, Laghrissi-Thode F, Guertin MC, Olsson AG, Mongrain I, Schwartz GG, Dubé MP . 6 . Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib . Circulation: Cardiovascular Genetics . 8 . 2 . 372–382 . April 2015 . 25583994 . 10.1161/CIRCGENETICS.114.000663 . free .
15. Web site: Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS - Full Text View - ClinicalTrials.gov. clinicaltrials.gov. 2016-12-02.