Home / Resources / Articles / 138% Rise in HDL Cholesterol with New Cholesterol Lowering Drug

138% Rise in HDL Cholesterol with New Cholesterol Lowering Drug

Dec 10, 2010
 

CETP inhibitor anacetrapib shows major effects on LDL and HDL-cholesterol levels without the adverse safety profile that plagued its predecessor….

Dr. Christopher Cannon (Brigham and Women’s Hospital, Boston, MA), showed that anacetrapib significantly decreased LDL-cholesterol levels by 36% and increased HDL-cholesterol levels by 138% when compared with placebo. Importantly, there was no increase in systolic blood pressure, an off-target effect that troubled torcetrapib, an earlier CETP inhibitor that was later pulled from clinical testing after a large morbidity and mortality trial revealed an increased risk of mortality and cardiovascular events.

 

Cannon told the media during a morning press conference that, “I think the very exciting thing is that we’re entering an era where we have medications that raise HDL cholesterol.” “We know from epidemiological studies that it’s good to have high HDL cholesterol, but [in terms of] current medications, we have just one that raises HDL, that’s niacin, and we have to push that to a high dose where there are a lot of side effects…. It’s been a very difficult lipid parameter to affect.”

While investigators were impressed with the “striking” increase in HDL-cholesterol levels, they were also equally pleased with a pre-specified safety analysis showing anacetrapib was not associated with an increased risk of death or cardiovascular events. Over the course of the 76-week study, known as Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE), cardiovascular events (a composite of death from cardiovascular causes, MI, hospitalization for unstable angina, or stroke) occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients treated with placebo (2.6%), a nonsignificant difference.

Presenting the results of the study during the late-breaking clinical-trials session at the American Heart Association 2010 Scientific Sessions, Cannon said the safety and adverse-event data provide reassurance that the inhibition of CETP, when not accompanied by the off-target effects linked with torcetrapib, does not appear to cause adverse cardiovascular events

In the DEFINE trial, investigators randomized 1623 patients to treatment with anacetrapib 100 mg or to placebo. Patients included in the trial had known coronary heart disease or were at high risk for coronary heart disease and had a baseline LDL-cholesterol level between 50 mg/dL and 100 mg/dL while taking a statin medication and an HDL-cholesterol level <60 mg/dL. The primary end point of the study was the change in LDL-cholesterol levels at 24 weeks, which investigators chose because it is a surrogate marker that is strongly correlated with cardiovascular events, and the safety and side-effect profile at 76 weeks. The change in HDL-cholesterol level was a secondary end point.

LDL-cholesterol levels decreased from 81 mg/dL at baseline to 45 mg/dL after 24 weeks of treatment with anacetrapib, a statistically significant difference compared with placebo. HDL-cholesterol levels increased from 40.5 mg/dL at baseline to 101 mg/dL at 24 weeks and to 102 mg/dL at 76 weeks, also a statistically significant difference.

DEFINE: Changes in lipid parameters in the anacetrapib-treated patients

Variable
Baseline
Week 24
Week 76

LDL cholesterol (mg/dL)

81.2
44.7
48.9

HDL cholesterol (mg/dL)

40.5
101.2
102.3

Non-HDL cholesterol (mg/dL)

109.7
69.7
73.0

Apolipoprotein B (mg/dL)

88.4
70.1
69.6

Apolipoprotein A1 (mg/dL)

142.5
208.0
203.0

Total cholesterol (mg/dL)

150.3
170.8
175.2

Lipoprotein(a) (mmol/L)

26.8
14.8
16.4
 

There was no observed change in blood pressure, electrolytes, or aldosterone levels among the anacetrapib-treated patients. As noted, mortality and cardiovascular events were not significantly different in the two treatment arms, and there was a trend toward a reduction in revascularization, mainly PCI, among patients treated with the CETP inhibitor.

New England Journal of Medicine, November 17, 2010