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![• CETP inhibitors provide remarkable elevations in
HDL cholesterol up to around 140% and drop the
serum concentrations of the entire spectrum of
atherogenic lipoprotein including VLDL
remnants, LDL, and even lipoprotein(a).[11]
• The HDL is functional, activates cholesterol
transport, capable of extracting cholesterol
from loaded cells, and is engaging the
transporters in all membranes
UP-APICON-2015,Noida](https://image.slidesharecdn.com/cetpinhibitor-151109031550-lva1-app6892/75/CETP-inhibitors-Future-in-lipid-management-12-2048.jpg)
![• In Asia -- in populations in the Kochi Prefecture of
Japan, in South Korea, and in parts of China --
loss-of-function polymorphisms in CETP are
actually associated with reduced risk for
cardiovascular events.[2]
• However, in western studies such as PREVEND,
REGRESS and Framingham low CETP activity in all
of those studies correlates with increased risk for
cardiovascular events.
UP-APICON-2015,Noida](https://image.slidesharecdn.com/cetpinhibitor-151109031550-lva1-app6892/75/CETP-inhibitors-Future-in-lipid-management-13-2048.jpg)
Uploaded byVeerendra Singh
CETP inhibitors Future in lipid management
1) CETP inhibitors are a new class of drugs that potently raise HDL cholesterol levels while lowering LDL and other atherogenic lipoproteins. 2) The first CETP inhibitor, torcetrapib, was associated with increased cardiovascular and mortality risks in clinical trials due to off-target effects and was not approved. 3) Ongoing trials with the CETP inhibitors evacetrapib and anacetrapib aim to determine if effective CETP inhibition can reduce cardiovascular events through modifying lipoprotein levels without safety issues.
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CETP inhibitors Future in lipid management
- 1. CETP Inhibitors Where willthey fit in practice ? Dr. Veerendra Singh MD (Medicine) Fellow UP Diabetes Association Vice President UPDA
- 2. The goal ofmy talk today is to assess • The clinical implications of safety and efficacy profiles of cholesteryl ester transfer protein (CETP) inhibitors • To suggest a potential place in therapy for CETP inhibitors UP-APICON-2015,Noida
- 3. What we know -CVD major burden - LDL-C causally related with CVD - LDL-C goals: the lower the better - Statins : corner stone in therapy UP-APICON-2015,Noida
- 4. Potential for further riskreduction = Reduction in MACE statin vs placebo (%) 0 further LDL-C lowering? and or Additional Rx? -100 -30 -50 How well do we do?
- 5. 93- D n Lipoproteins and CoronaryHeart isease 302,430 participants in 68 studies The Emerging Risk Factors Collaboration. JAMA. 2009;302:19 2000.
- 6. • Although statinsreduce LDL cholesterol and concomitantly decrease cardiovascular morbidity and mortality by up to 40%, substantial residual cardiovascular risk remains. • Subnormal levels of HDL cholesterol constitute a major, independent cardiovascular risk factor. Attention has, therefore, shifted towards novel strategies for raising HDL cholesterol as a preventive therapy for cardiovascular disease. UP-APICON-2015,Noida
- 7. Atheroprotective functions ofHDL Anti-infectious activity Anti-thrombotic activity Anti-proteolytic activity Reverse cholesterol transport/cellular cholesterol efflux Anti- inflammatory activity Immune system Anti-oxidative activity Anti-apoptotic activity HDL Vasodilatory activity/ endothelial repair
- 8. Infusion of RecombinantApo AI Milano/Phospholipid complexes over 5 weeks produced significant regression of coronary atherosclerosis as estimated on the basis of atheroma volume by IVUS in patients with acute coronary syndromes. Nissen et al., JAMA, 2003, 290 : 2292-2300 These findings suggest that elevation of HDL/Apo AI may enhance cholesterol efflux from plaque tissue and may therefore be a critical component of atherosclerotic plaque regression Impact of HDL on Plaque Evolution : Experimental Evidence for Plaque Regression
- 9. HDL therapy Rader DJand Hovingh GK, Lancet 2014;384:618-25
- 10. CETP inhibition HDL LDL / VLDL Liver Bile CE LDL-R FC F C LCAT CETP C ESR-B1 Xinhibition Free Cholesterol (FC) in Extrahepatic tissues The more CETP is working, the more it reduces HDL-C
- 11. • High CETPactivity, typical of metabolic diseases enriches the triglyceride content of HDL particles. Triglyceride-rich HDL are hydrolysed by hepatic lipase, with shedding of apoAI and elimination from the circulation by the kidney. . • CETP inhibitors could theoretically correct not only the core lipid composition of HDL (cholesteryl ester:triglyceride ratio) but also HDL functional defects. UP-APICON-2015,Noida
- 12. • CETP inhibitorsprovide remarkable elevations in HDL cholesterol up to around 140% and drop the serum concentrations of the entire spectrum of atherogenic lipoprotein including VLDL remnants, LDL, and even lipoprotein(a).[11] • The HDL is functional, activates cholesterol transport, capable of extracting cholesterol from loaded cells, and is engaging the transporters in all membranes UP-APICON-2015,Noida
- 13. • In Asia-- in populations in the Kochi Prefecture of Japan, in South Korea, and in parts of China -- loss-of-function polymorphisms in CETP are actually associated with reduced risk for cardiovascular events.[2] • However, in western studies such as PREVEND, REGRESS and Framingham low CETP activity in all of those studies correlates with increased risk for cardiovascular events. UP-APICON-2015,Noida
- 14. Torcetrapib was thefirst CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial— ”Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE)”. UP-APICON-2015,Noida
- 15. DL- L- n- - (- 3) - Torcetrapib:ILLUMINATE Trial Torcetrapib/ Atorvastatin Group (Post Ru In) 140 127 115 112 112 112120 TG 9% 27,+1 *100 82.980.979.7 H C77.5 71.880 +72.1% (34.7) † 60 48.6 LD C 58.2 58.359.7 59.3 24.9% (28.5) † 40 20 0 Baseline 1 3 Study Month 6 12 Barter et al, NEJM 2007;357:2109 Lipids(mg/dL)
- 16. But Inhibiting CETP withTorcitrapib in humans did not reduce atherosclerosis in three human imaging trials and a large scale cilincal end point trial (ILLUMINATE) torcitrapib increased both cardiovascular and non cardiovascular events and mortality UP-APICON-2015,Noida
- 17. Torcetrapib treatment resultedin significantly increased aldosterone levels, altered serum electrolytes and elevated blood pressure, indicating an off-target mechanism of torcetrapib related toxic effects
- 18. s ff- e s( d at Y e e e n However Torcetrapib had seriou o target adverse effects (unrelated to CETP) that responsible outcome in MAY have been for the adverse the ILLUMINATE trial
- 19. b al S . Ngl d. 89- 9 Dalcetrapib OUTCOMES was investigated in the d - and found to have no safety issues but also no effect on CV events Schwartz et al En J Me 2012; 367:20 209 .
- 20. Lipid effects withdalcetrapib -5 0 5 10 15 20 25 30 35 HDL-C LDL-C ApoA-I D 24 weeks D 48 weeks Placebo * D 48 weeks vs. placebo Stein EA et al. Eur Heart J 2010;31(4):480-8 %changefrombaseline *p<0.0001 *p<0.01 *p=0.002 D Dalcetrapib 900 mg/da
- 21.
- 24. b al- n y b DL- Thereason for the failure of dalcetrapib in del- may is a OUTCOMES is not have been because weak inhibitor and had C known but dalcetrapib no effect on LDL-
- 25. 25 Up to 33%reduction in LDL Up to 130%% reduction in HDL
- 26. Percent change frombaseline in HDL and LDL cholesterol with statin plus evacetrapib Controversies in dyslipidaemia management: Atherosclerosis Volume 221, Issue 2 2012 321 - 324 Evacetrapibe
- 27.
- 28. Just because anintervention raises HDL-C, we cannot ASSUME that MI risk will be lowered
- 29. HDL intervention; failures Torcetrapib,Dalcetrapib, Niacin
- 30. HDL intervention; failures Torcetrapib,Dalcetrapib, Niacin
- 31. HDL intervention; failures Torcetrapib,Dalcetrapib, Niacin
- 32. HDL intervention; failures Torcetrapib,Dalcetrapib, Niacin
- 33. T b The results withtorcetrapib and dalcitratib have not adequately tested the hypothesis that effective inhibition of CETP reduces CV risk
- 34. The hypothesis iscurrently being tested in two large, clinical outcome trials
- 35. id n e L- w- n REVEALtrial Randomized Evaluationof the Effects ofAnacetrapib through Lip - modification Anacetrapib 100 mg30,000 patients aged > 50 with with occlusive arterial disease Atorvastati to achiev target LD C Sites in NorthAmerica, Europe and Asia 4 year follo up Primary End Point Coronary death, myocardial infarction coronary revascularization Planned completion in 2017 or Placebo
- 36. E of yl b gh- b0 V h, , y sc or 3 w- n nd sia 16- ACCELERAT trial Assessmentof Clinical Effects Cholester EsterTransferProtein Inhibition with EvacetrapibI Patientsat a High Risk for VascularOutcomes Evacetrapi 13 mg Treatment with a12,000 patients at high CV risk statin for at 30 days least Sites in NorthAmerica, Europe and Asia- Pacific countries year follo up Primary End Point Planned in 20 completion 2017 CV death MI stroke, coronary revascularisation hospitalization for UA Placebo
- 37. TA8995: A new potentCETP inhibitor
- 38. N=42 placebo +placebo N=42 TA-8995 1mg + placebo N=42 TA-8995 2.5mg + placebo N=42 TA-8995 10mg+ Atorvastatin 20mg N=42 placebo +Atorvastatin 20mg N=42 TA-8995 10mg + placebo N=42 TA-8995 5mg + placebo N=42 placebo + Rosuvastatin 10mg N=42 TA-8995 10mg + Rosuvastatin 10mg Washout/run in treatment 12 weeks FU TULIP Design - mild dyslipidemia - no CVD - LDL-C 2.5- 4.5 mmol/L - HDL-C 0.8-1.8 mmol/L - TG <4.5 mmol/L
- 39. 0% 100% 76% 122% 180% 50% 200% HDL-C %changeat 12 weeks Placebo TA-8995 (mg/day) 1 2.5 5 10 150% 2% 166%
- 40. 0% -20% -27% -34% -47% -47% -40% LDL-C %changeat 12 weeks -60% Placebo TA-8995 (mg/day) 1 2.5 5 10
- 41. M s f TA8995 isa potent inhibitor of CETP• • Major reduction in atherogenic lipoproteins and major increase in HDLs at low dose o TA8995 • Treatment with TA8995 enhances the ability to of serum to promote the efflux of cholesterol from macrophages • TA8995 has an excellent safety profile • TA8995 is rapidly removed from the body after cessation of therapy
- 42. • KEY POINTS •Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent agents for raising HDL cholesterol • Torcetrapib, the first CETP inhibitor to enter a large-scale, prospective, placebo- controlled interventional trial (ILLUMINATE), was associated with excess cardiovascular and noncardiovascular mortality in the active-treatment group • Torcetrapib treatment resulted in significantly increased aldosterone levels, altered serum electrolytes indicative of mineralocorticoid excess, and elevated blood pressure, indicating an off-target mechanism of torcetrapib related toxic effects involving activation of mineralocorticoid receptors by aldosterone with subsequent induction of hypertension • Other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation that tends to discount a class effect • Potential adverse effects of CETP inhibition cannot, however, be excluded; CETP inhibition could result in the generation of HDL particles that have deficient antiatherogenic activities and a deleterious impact on reverse cholesterol transport and steroid metabolism
- 43. CETP inhibitors area very exciting new drug class. They remain in development. They are not yet approved for use. Everyone is awaiting the results of heart outcomes trials with REVEAL and ACCELERATE, but in the meantime they are definitely drugs very worthy of discussion and further understanding. UP-APICON-2015,Noida
- 44. Trials, trials, trials,and nothing but trials will tell us whether - HDL based therapy and - further LDL-C lowering, reduces risk for CVD....
- 45. Don’t give upon HDL, researchers plead At a session on the subject, Dr Alan Tall (Columbia University, New York) summarized the situation: Hughs S, Jun, 2012 "The HDL hypothesis is certainly under attack. And there have been a lot of setbacks. But we mustn't throw the baby out with the bathwater. I think we need a new, modified HDL hypothesis."
- 46. An interesting roadahead of us...
- 47.