Abstract 3698: Impact of the MTP-Inhibitor, AEGR-733, as Monotherapy and in Combination with Ezetimibe on Lipid Subfractions as Measured by NMR Spectroscopy
The development of new methods for measuring subclasses of lipoprotein particles, such as proton nuclear magnetic resonance spectroscopy (NMRS), can provide additional insight on a drug’s impact on lipid metabolism. Recent research is also indicating that the number of LDL particles (LDL-P) may be a better indicator of CHD risk than the traditional LDL-C value. Microsomal triglyceride transfer protein inhibitors (MTP-Is) represent a potential new mechanism for the reduction in LDL-C and TGs. In a recently completed phase 2 clinical trial, we studied 5–10 mg doses of the MTP-I AEGR-733 alone and in combination with ezetimibe (EZE). A total of 85 patients were randomized to one of three arms: AEGR-733 alone, EZE 10 mg alone or AEGR-733 + EZE 10 mg. Those patients randomized to AEGR-733 started at 5 mg, titrated to 7.5 mg and then 10 mg at 4 week intervals for a total of 12 weeks of treatment. At 12 weeks, AEGR-733 10 mg gave a 30% reduction in LDL-C as compared to 20% for EZE 10 mg. The combination resulted in a 46% reduction in LDL-C. Patients treated with AEGR-733 also saw modest reductions in TGs, HDL-C and Lp(a). NMRS analysis of lipid subfractions was carried out at baseline and weeks 4, 8 and 12. Data were analyzed among all patients as well as within the subgroups with baseline TGs above/below 150 mg/dl. At week 12, patients receiving AEGR-733 saw significantly greater reductions in LDL-P (−29%) than patients on EZE 10 mg (−10%); p<0.001. The combination resulted in even greater reductions in LDL-P (−34%). AEGR-733 had more pronounced results on small LDL-P, particularly in patients with TGs > 150 mg/dl, whereas EZEs LDL-P effects were similar between large and small particles and patient subgroups. AEGR-733 resulted in a modest decrease in HDL-P similar to the effects in HDL-C. Among the HDL subfractions, reduction with AEGR-733 was seen only with small HDL-P whereas an increase in large HDL-P was seen with all 3 treatment groups. A mechanism that reduces VLDL/LDL production may result in greater reductions in LDL-C and LDL-P than cholesterol absorption inhibition and may represent an avenue for robust improvement in CHD risk. AEGR-733s effects on HDL-P require continued elucidation in regards to mechanism and impact, if any, on CHD risk.