The enzyme acyl–coenzyme A:cholesterol transferase ( ACAT ) is responsible for the esterification of cholesterol in a variety of tissues.
Inhibition of ACAT1 is intended to make more free cholesterol available for reverse cholesterol transport that theoretically could reduce lipid accumulation within atherosclerotic lesions.
Previous animal models have shown that ACAT inhibition was capable of reducing atheroma volume, presumably by preventing the accumulation of cholesterol within macrophages and thereby inhibiting foam-cell formation.

In the ACTIVATE trial, 534 patients with symptomatic coronary artery disease and coronary angiography with >20% stenosis were enrolled at 52 US hospitals.

All patients received recommended therapy, including statins if indicated.

Intravascular ultrasound using a 40-MHz transducer and a motorized pullback at 0.5 mm/s through a target segment of >30 mm in length of a single “target” coronary artery was performed at baseline; it was repeated after 18 months to measure the progression of atherosclerosis.

Patients were randomized to receive the ACAT inhibitor Pactimibe ( 100 mg/d ) or placebo for 18 months of treatment.
Approximately 60 patients in each study arm did not return for repeat intravascular ultrasound of the target vessel.

Baseline characteristics between the 2 study arms were similar. The average baseline low-density lipoprotein ( LDL ) cholesterol levels were 95 mg/dL in both treatment arms.

The primary efficacy parameter was change in percent atheroma volume.

Both treatment groups showed a statistically significant progression although the increase in percent atheroma volume was slightly greater in the Pactimibe group compared with the placebo group ( 0.69% vs 0.59%, respectively, P = .77 ).

However, both the secondary efficacy parameters ( change in atheroma volume in the total artery and then in the most diseased segment ) showed proatherogenic effects with Pactimibe treatment.
Normalized total atheroma volume showed regression in the placebo group, and no regression in the Pactimibe group.
The change in the atheroma volume in the most diseased 10-mm subsegment showed similar results.

Adverse cardiovascular outcomes neither increased nor decreased with Pactimibe therapy.

“ For patients with coronary disease, treatment with an ACAT inhibitor showed no benefit for the primary efficacy parameter ( percent atheroma volume ) and adverse effects for 2 major secondary efficacy measures. The results of this study suggest that ACAT inhibition is not an effective strategy for limitation of atherosclerosis and may be proatherogenic.

Source: American Heart Journal, 2006


XagenaMedicine2006