There have been issues with the first two CETP inhibitors, torcetrapib and dalcetrapib.
The difference in the washout of anacetrapib vs. evacetrapib following discontinuation of treatment suggests that the distribution and/or elimination characteristics of these two CETP inhibitors are fundamentally different.
The two CETP inhibitors that are currently most advanced in development, anacetrapib and evacetrapib, have so far shown no adverse safety signal in phase II trials, and have beneficial effects in raising HDL cholesterol, as well as lowering triglycerides and atherogenic lipoproteins including LDL cholesterol and lipoprotein(a) [ 85, 86].
A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G A, 0.5%), was found in men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL-cholesterol levels (+10% for D442G) [ 40].
Of the eight loci reported by Petersen et al., we identified five (LIPC, CETP, FADS1, GCKR, APOA1) in association with NMR intensities at single chemical shift positions (NMR bins) in our genome-wide approach.
Three other CETP inhibitors are currently in clinical trials, i.e. dalcetrapib, anacetrapib and evacetrapib.
Of these there were 11 eligible trials of niacin, 20 of fibrates, and eight of CETP inhibitors.
Values of the transfer of the four lipids, CETP serum concentration, LCAT activity and serum concentration of unesterified cholesterol were plotted against the several parameters measured here.
Five of the seven loci (LIPC, CETP, FADS1, GCKR, APOA1) are also known lipid risk loci, and all have previously been identified in GWAS with metabolic traits.
For example, a NMR study showed that eight loci (LIPC, CETP, PLTP, FADS1, -2, and -3, SORT1, GCKR, APOB, APOA1) were associated with specific lipid subfractions (for example, chylomicrons, low-density lipoprotein (LDL), HDL), whereas only four loci (CETP, SORT1, GCKR, APOA1) were associated with serum total lipids [ 43].
However, in the GWAS with ratios of chemical shift pairs (NMR ratios), we observe a strong increase in the strength of association for four loci (LIPC, CETP, FADS1, GCKR), resulting in P values that are between 9 and 89 orders of magnitude lower than the values reported by Petersen et al. for the associations with lipid subclasses (Table 2).
