Treatment of dyslipidemia – is here still place for CETP-inhibitors?

Česká verzia

Authors: Ján Murín; Miroslav Pernický; Soňa Kiňová
Authors place of work: I. interná klinika LF UK a UN Bratislava, Slovenská republika
Published in the journal: Vnitř Lék 2016; 62(10): 789-794
Category: Reviews

Summary

In the treatment of dyslipidemias about 5–6 years back a new class of drugs emerged, CETP (cholesteryl ester transfer protein)-inhibitors. Their benefit was due to an increase of HDL-cholesterol (HDL-C) serum levels. This treatment mode was supported by epidemiological and clinical studies, as people with high serum HDL-C levels suffered less from cardiovascular (CV) events. Three studies with CETP inhibitors (ILLUMINATE with torcetrapib, dal-OUTCOMES with dalcetrapib and ACCELERATE with evacetrapib) were unfortunately negative, and torcetrapib was even harmful to patients due to an increase of aldosterone serum levels. Treatment with dalcetrapib was safe, but without benefit. Similar it was with evacetrapib. There is still running also a study with anacetrapib (REVEAL), but a benefit is here not expected. Evacetrapib and anacetrapib in comparison to dalcetrapib can reduce serum LDL-cholesterol (LDL-C) much more, and similar results were found also in another CETP-inhibitor TA-8995 (TULIP study). Authors try to explain why there is no benefit with CETP-inhibitors (dysfunctional HDL particle, another effective mechanism than reverse cholesterol transport). A genetic analysis in dalcetrapib studies (dal-OUTCOMES and dal-PLAQUE-2) showed, that a cardiovascular benefit from this treatment is concentrated only to a subgroup of patients with a genotype AA in the gene ADCY9 on 16^th chromosome. In the population there are about 20% of people with this AA genotype. A clinical study DAL-301 will test this data in a near future. Framingham Offspring study showed that the association of“ HDL-C serum level – CV risk in the future” is greatly influenced by serum levels of LDL-C and triglycerides (if these are increased, than the CV future prediction with HDL-C levels is lost). HDL particles are complex and we do not know which subtype of HDL particles is for cardiovascular prognosis important. The research here continues.

Key words:
acute coronary syndrome – CETP-inhibitors – dalcetrapib – dysfunctional HDL particles – dyslipidemia – HDL-cholesterol – pharmacogenomics of ADCY9 gene

Zdroje

1. Murín J, Kiňová S. Komentár k Odporúčaniam Európskej kardiologickej spoločnosti a Európskej diabetologickej spoločnosti o prístupe k diabetikovi s kardiovaskulárnym ochorením. Cardiol Lett 2014; 23(4): 253–258.

2. Aguiar C, Alegria E, Bonadonna RC et al. A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: A report from an expert consensus meeting on the role of fenofibrate – statin combination therapy. Atherosclerosis Supplements 2015; 19: 1–12. Dostupné z DOI: <http://dx.doi.org/10.1016/S1567–5688(15)30001–5>.

3. Arsenault BJ, Boekholdt SM, Tardif JC et al. De-risking the clinical development of cholesteryl ester transfer protein inhibitors: how much is good enough ? Eur Heart J 2012; 33(13): 1548–1550. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehr408>.

4. Barter PJ, Caulfield M, Eriksson M et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357(21): 2109–2122.

5. Rhainds D, Arsenault BJ, Brodeur MR et al. An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels. Future Cardiol 2012; 8(4): 513–531. Dostupné z DOI: <http://dx.doi.org/10.2217/fca.12.25>.

6. Schwartz GG, Olsson AG, Abt M et al. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367(22): 2089–2099. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1206797>.

7. Stiles S. Lilly Pulls Plug on its CETP Inhibitor Evacetrapib. Medscape 2015 October 12. Dostupné z WWW: Dostupné z WWW: http://www.medscape.com/viewarticle/852516.

8. Nicholls SJ, Lincoff A, Barter P et al. [Late-Breaking Clinical Trials II]. The ACCELERATE trial: impact of the CETP inhibitor evacetrapib on cardiovascular outcome. Presented at the 65th Annual Scientific Session and Expo of the ACC. April 2–4, 2016. Chicago.

9. Kastelein JJ, Besseling J, Shah S et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolemia (REALIZE): A randomized, double-blind, placebo-controlled phase 3 study. Lancet 2015; 385(9983): 2153–2161. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(14)62115–2>. Abstract.

10. ClinicalTrials. gov Identifier: NCT01252953. REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL). Dostupné z WWW: https://clinicaltrials.gov/ct2/show/NCT01252953

11. dal-OUTCOMES: Wrestling with why the CETP Inhibitor Failed to Reduce Outcomes. Medscape 2012 November 05. Dostupné z WWW: http://www.medscape.com/viewarticle/773974.

12. Hovingh GK, Kastelein JJP, van Deventer SJH et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidemia (TULIP): A randomized, double-blind, placebo-controlled phase 2 trial. Lancet 2015; 386(9992): 452–460. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(15)60158–1>.

13. Keene D, Price C, Shun-Shin MJ et al. Effect on cardiovascular risk of high-density lipoprotein targeted treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomized, controlled trials including 117 411 patients. BMJ 2014; 349: g4379. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.g4379>.

14. Zanoni P, Khetarpal SA, Larach DB et al. Rare variabl in scavenger receptor VI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351(6278): 1166–1171. Dostupné z DOI: <http://dx.doi.org/10.1126/science.aad3517>.

15. Brunton L, Chabner B, Knollman BC (eds). Goodman and Gilman´s the Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill: New York 2011. ISBN 978–0071624428.

16. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008; 51(23): 2199–2211. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jacc.2008.03.016>.

17. Tardif JC, Rhéaume E, Perreault LP et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet 2015; 8(2): 372–382. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCGENETICS.114.000663>.

18. Bartlett J, Predazzi IM, Williams SM et al. Is isolated low high-density lipoprotein cholesterol a cardiovascular disease risk factor? New insights from the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes 2016; 9(3): 206–212. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCOUTCOMES.115.002436>.

19. Banach M, Rysz J, Rizzo M et al. Investigating dysfunctional HDL in selected groups of patients at high risk of cardiovascular events (DYS-HDL study): Protocol and organization. Atherosclerosis 2014; 235: e171-e172.