What is the role of CETP inhibition therapy in the treatment of low HDL cholesterol (hypoalphalipoproteinemia)?

Updated: May 21, 2021
  • Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI; Chief Editor: George T Griffing, MD  more...
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Answer

CETP mediates the transfer of cholesteryl ester for TGs from HDL to VLDL and LDL. It may be proatherogenic if the VLDL-LDL cholesteryl ester is taken up by arterial macrophages. Blocking CETP prevents the transfer of cholesterol from HDL2 to the apo B–containing lipoproteins, and therefore, the HDL concentration in terms of cholesterol rises.

Two pharmacologic inhibitors of CETP have undergone phase 3 clinical trials: torcetrapib and JTT-705. The 2 drugs differ in chemical structure. With torcetrapib, the CETP activity is inhibited by only about 50% to 60%, to avoid the fact that patients with complete CETP deficiency, mostly found in Japan, exhibit a paradoxically increased risk of CAD. The effect of torcetrapib is dose-dependent; for example, increasing the dose from 10 mg to 120 mg twice daily is associated with an almost 90% CETP inhibition and a greater rise in HDL. In addition, LDL is reduced by torcetrapib, by as much as 40%.

Torcetrapib was looked at in a phase 3 global study called the Investigation of Lipid level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE) trial. The study utilized 15,067 patients (mean age 61 years; 78% male, 93% white) with CHD or CHD risk equivalent (type 2 diabetes). [42] Patients received either torcetrapib and atorvastatin or atorvastatin alone.

At 12 months follow-up, patients who received torcetrapib demonstrated a mean increase of 72.1% in HDL cholesterol and a mean decrease of 24.9% in LDL cholesterol, as well as a mean decrease of 9% in TGs compared with baseline (all P< .001 vs atorvastatin-only patients). Beginning early in the trial, however, the 2 patient groups diverged with regard to the study's primary endpoint, a composite of first major cardiovascular events (CHD death, nonfatal myocardial infarction, stroke, and hospitalization for unstable angina).

By the study's termination, the torcetrapib group demonstrated a 25% elevation in risk over the patients who received only atorvastatin (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.09-1.44; P = .001). This included a greater risk of death from cardiovascular causes (49 in the torcetrapib group in comparison with 35 in the atorvastatin-only patients) and from noncardiovascular causes (40 in the torcetrapib group vs 20 in the atorvastatin-only patients). At 12 months follow-up, systolic blood pressure (SBP) in the torcetrapib patients had risen from baseline by a mean of 5.4 mm Hg, a significantly greater increase than that (0.9 mm Hg) found in the atorvastatin group (P< .001).

A significant (albeit small) change in serum electrolytes—a reduction in potassium and increases in sodium and serum bicarbonate—was also found in the torcetrapib patients. These changes may have indicated that mineralocorticoid excess accounted for the blood pressure increase.

A trial by Roche Pharmaceuticals using an agent similar to torcetrapib is underway. This drug reportedly does not raise blood pressure. The study's results should be available within a few years.


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