# Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug Development
## 3 Hyperlipidemic Rabbit Models for the Development of Drugs
### CETP Inhibitors  
Epidemiological studies have demonstrated that lower plasma HDL-C is associated with increased coronary heart disease (CHD) risk [92]. Therefore, for a long time, it has been hypothesized that elevated plasma HDL-C levels may be beneficial to cardiovascular functions. CETP is a plasma protein that facilitates the transport of cholesteryl ester and triglycerides between the lipoproteins. It collects triglycerides from VLDL or LDL and exchanges them for cholesteryl ester from HDL, and vice versa. CETP inhibitors prevent the transfer of cholesteryl ester and increases plasma HDL-C levels; therefore, their use is intended to reduce the risk of atherosclerosis by improving blood lipid levels [93]. Until now, several CETP inhibitors have been developed. Interestingly, CETP only exists in humans and a few laboratory animals, such as rabbits, guinea pigs, and hamsters, whereas mice and rats do not have CETP [9]. To study the functions of CETP and its inhibitors, rabbits are often used. The effects of CETP inhibitors in rabbits are summarized in Table 4. Many studies showed that administration with these CETP inhibitors effectively increased plasma HDL-C in rabbit models [94; 95; 96; 97; 98; 99]. Dalctrapib administration mildly reduced plasma TC levels in cholesterol-fed rabbits [96; 97]. Furthermore, dialectrib, torcetrapib, and K-312 showed an atheoprotective effect in cholesterol-fed rabbits [96; 98; 99]. Our laboratory also demonstrated that genetic ablation of the CETP gene in rabbits led to increased plasma HDL-C and lowered plasma TC levels, and it protected against diet-induced atherosclerosis [100]. In the early clinical trials, four CETP inhibitors, namely torcetrapib, dialectrapib, anacetrapib, and evacetrapib, could significantly elevate plasma HDL-C levels. Although clinical trials with three other inhibitors failed to show any beneficial effect for CHD, anacetrapib decreased the incidence of CHD [101]. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Rabbit**} & \multirow{2}{*}{**Drug**} & \multicolumn{3}{c}{**Plasma Lipids**} & \multirow{2}{*}{**Atherosclerosis**} & \multirow{2}{*}{**Atherosclerosis Reference**} \\ \cline{3-3} \cline{5-6}  & & **HDL-C** & & & \\ \hline \multicolumn{6}{c}{Normal standard diet} \\ \hline \multirow{2}{*}{JW (male)} & Dalcetrapib (300 mg/kg) & 2.1-fold \(\uparrow\)\({}^{*}\) & 4\% \(\uparrow\) & 73\% \(\uparrow\)\({}^{*}\) & - & [PERSON] [94] \\  & for 7 days & (7 days) & (7 days) & (7 days) & & \\ \hline \multirow{2}{*}{NZW (male)} & Dalcetrapib (300 mg/kg) & 3.3-fold \(\uparrow\)\({}^{*}\) & 7\% \(\uparrow\) & 86\% \(\uparrow\)\({}^{*}\) & \multirow{2}{*}{-} & \multirow{2}{*}{[PERSON] [95]} \\  & Anacetrapib (30 mg/kg) & 2.7-fold \(\uparrow\)\({}^{*}\) & 21\% \(\uparrow\) & 72\% \(\uparrow\)\({}^{*}\) & & \\ \cline{1-1}  & for 2 weeks & (2 weeks) & (2 weeks) & (2 weeks) & & \\ \hline \multicolumn{6}{c}{High-cholesterol diet} \\ \hline \multirow{2}{*}{JW (male)} & Dalcetrapib & 2.0-fold \(\uparrow\)\({}^{*}\) & \multirow{2}{*}{-} & 24\% \(\downarrow\) & 70\% \(\downarrow\)\({}^{*}\) & Okamoto [96] \\  & (\(\approx\)225 mB/kg) & (6 months) & & (6 months) & (Aortic arch, gross lesion) & Okamoto [96] \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Effects of cholesteryl ester transfer protein (CETP) inhibitors in rabbit models.