Another CETP inhibitor: clinical data with evacetrapib bodes well

Evacetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor, either alone or in combination with a range of commonly used statins at usual clinical doses, substantially increased HDL cholesterol and also lowered LDL cholesterol in patients with dyslipidemia, according to a study published in JAMA. Evacetrapib monotherapy produced a dose-related increase in HDL cholesterol to 128.8% and a corresponding dose-related decrease in LDL cholesterol to 35.9%. The data were simultaneously presented at a clinical trial hotline session of the American Heart Association Scientific Sessions.

Nicholls SJ, Brewer B, Kastelein JJP et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol. JAMA 2011;306:2099-109.

Editorial. JAMA. 2011;306]:2153-5.

There is clear recognition that a low plasma level of HDL cholesterol is an important cardiovascular risk factor, even among patients achieving low LDL cholesterol on intensive statin therapy.1,2 Niacin is currently the most effective agent for raising HDL cholesterol (by 20-25% at recommended dosage). However, evidence from population studies predicts that a greater increase in HDL cholesterol levels may translate to improved clinical outcomes. Therefore, investigation of new agents with the potential for greater increases in HDL cholesterol has been the ‘holy grail’ for reducing cardiovascular disease events.

Considerable interest has focused on the CETP inhibitors. CETP plays a key role in reverse cholesterol transport, the process by which cholesterol is transported from peripheral tissues to the liver for excretion, as well as in remodelling of HDL. Inhibition of CETP offers the potential to shift the balance of plasma cholesterol in favour of the protective HDL fraction and substantially raise plasma levels of HDL cholesterol.

The termination of the first in class CETP inhibitor, torcetrapib, due to excess mortality and major cardiovascular events in ILLUMINATE3 led to much controversy regarding the role of CETP inhibition. It is now thought that off-target adverse effects of torcetrapib unrelated to CETP inhibition were responsible for harm caused by this agent.4,5 Newer CETP inhibitors, dalcetrapib and anacetrapib, have shown a favourable safety profile with no evidence of the safety issues associated with torcetrapib.6,7 Furthermore, in dal-PLAQUE, there were encouraging multimodality imaging data to suggest that dalcetrapib decreases plaque inflammation in the carotid arteries and may have the potential to reduce the adverse remodelling of the arteries associated with plaque progression.8

Against this setting, the emergence of another CETP inhibitor – evacetrapib – fuels interest in this therapeutic class. As previously reported in CETPi Forum, evacetrapib raised HDL cholesterol and lowered LDL cholesterol without any obvious effects on blood pressure, or synthesis of aldosterone or cortisol in an animal model.9

This trial included 398 patients (mean age 58 years, 56% women) with elevated LDL cholesterol or low HDL cholesterol levels recruited by centres throughout the USA and Europe. Most patients were recruited on the basis of elevated LDL cholesterol, as indicated by the baseline lipid profile; mean LDL cholesterol was 144.3 mg/dL (3.73 mmol/L) and mean HDL cholesterol was 55.1 mg/dL (1.42 mmol/L). This was a 10-arm study. Patients were randomly allocated to placebo (n=38); evacetrapib monotherapy 30 mg/d (n=40), 100 mg/d (n=39), or 500 mg/d (n=42); or usual clinical doses of commonly used statins (n=239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. The primary outcomes were the percent changes in HDL and LDL cholesterol levels from baseline (start of the trial) to 12 weeks.

Evacetrapib monotherapy produced dose-dependent increases in HDL-cholesterol levels ranging from 53.6% to 128.8% (absolute increases of 30 to 66 mg/dL [0.78 to 1.71 mmol/L]) vs. a decrease of 3% on placebo. Treatment was also associated with dose-dependent decreases in LDL cholesterol ranging from 13.6% to -35.9% (absolute changes of -20.5 to -51.4 mg/dL [0.53 to 1.33 mmol/L]) vs. a decrease of 3.9% on placebo. Interestingly, the increase in HDL cholesterol was higher in patients with lower levels of HDL cholesterol (p<0.001) or elevated triglycerides (p=0.005) at baseline. Dose-dependent increases in apolipoprotein A-I paralleled those of HDL cholesterol. There was less LDL cholesterol lowering with evacetrapib monotherapy in patients with higher LDL cholesterol levels.

In combination with statin, evacetrapib significantly raised HDL cholesterol (p<0.001) and produced greater decreases in LDL cholesterol (p<0.001) than statin monotherapy (Table 1). The lipid effects were generally consistent across the statins tested.

Table 1. Change in HDL and LDL cholesterol, mg/dL (%), with evacetrapib 100 mg/day plus statin vs. statin alone.

Statin

Evacetrapib + statin

Relative change (%)

With atorvastatin 20 mg/d

 

 

 

HDL-C

+1.3 (1.4%)

+42.1 (79.9%)

­78.5%

LDL-C

-49.5 (-33.6%)

-70.5 (-47.6%)

¯13.9%

With simvastatin 40 mg/d

 

 

 

HDL-C

+2.9 (7.3%)

+45.1 (86.6%)

­79.3%

LDL-C

-51.3 (-34.9%)

-67.1 (-46.1%)

¯11.2%

With rosuvastatin 10 mg/d

 

 

 

HDL-C

+2.7 (5.5%)

+50.5 (94.0%)

­88.5%

LDL-C

-57.7 (-38.8%)

-75.8 (-52.3%)

¯13.5%

Evacetrapib, either alone or in combination with a statin, was well tolerated, with no adverse effects on blood pressure, aldosterone or cortisol levels, or renal, liver or muscle safety parameters.

Another promising addition to the CETP inhibitors in development

According to HDL Forum Editor Professor Philip Barter, Director, Heart Research Institute, Sydney, Australia: ‘These interesting early data indicate that evacetrapib is a potent CETP inhibitor with a lipid-modifying profile similar to that of anacetrapib. The effects on HDL and LDL cholesterol, in combination with a range of commonly used statins, are potentially clinically relevant.’

Of particular interest are data showing greater HDL cholesterol raising in patients with low HDL cholesterol and/or elevated triglycerides at baseline. This dyslipidemic profile has been shown to be associated with increased cardiovascular risk, even among patients achieving LDL cholesterol goals.2,10

The emerging data with a range of CETP inhibitors may herald promise for this therapeutic class. However, we need to temper our enthusiasm by bearing in mind that we still do not have answers for two key questions:

  • Does CETP inhibition translate to reduction in cardiovascular events?
  • Does the extent of HDL raising with CETP inhibition matter?

For that, we need to wait for the completion of large ongoing cardiovascular clinical outcomes studies using dalcetrapib and anacetrapib.

References

1. Gordon DJ, Probstfield JL, Garrison RJ et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.

2. Barter P, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.

3. Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22

4. Hu X, Dietz JD, Xia C et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 2009;150:2211-9.

5. Forrest MJ, Bloomfield D, Briscoe RJ et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-73

6. Stein EA, Stroes ES, Steiner G et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91.

7. Cannon CP, Shah S, Dansky HM et al. The DEFINE Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15.

8. Fayad ZA, Mani V, Woodward M et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised trial. Lancet 2011; published on-line Sept 12, doi:10.1016/S0140-6736(11)61383-4.

9. Cao G, Beyer TP, Zhang Y et al. Evacetrapib is a novel, potent and selective inhibitor of cholesteryl ester transfer protein that elevates high-density lipoprotein cholesterol without inducing aldosterone or increasing blood pressure. J Lipid Res 2011;published online ahead of print. Doi:10.1194/jlr.M018069.

10. Chapman MJ, Ginsberg HN, Amarenco P et al; European Atherosclerosis Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61

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