Objective-The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib 414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study. Methods and Results-Five groups of 8 subjects each were randomized to placebo (nϭ2) or torcetrapib (nϭ6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50ϭ43 nM) was as expected based on in vitro potency (IC50 Ϸ50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL. studies, the inverse correlation between high-density lipoprotein (HDL) levels and premature coronary heart disease (CHD) has been strengthened. A 1% decrease in HDL cholesterol (HDL-C) has been associated with a 1% to 2% increase in risk for CHD, 3 and lipid intervention trials have demonstrated that increases in HDL-C 4 and its main apoprotein, A-I, 5 contribute to reduced CHD, even in the absence of any change in low-density lipoprotein cholesterol (LDL-C). 6 However, current therapies for raising HDL are limited. The fibrates and statins produce only modest elevations in HDL, and the use of niacin, although somewhat more effective, has been hampered by side effects. 7 In a recent study, the combination of lovastatin and extended-release niacin (Advicor) was able to increase HDL levels by 20% to 32%, 8 but withdrawal rates for incidents of flushing and other adverse events were relatively high. Conclusions-TheseThe marked increase in HDL associated with human deficiency of cholesteryl ester transfer protein (CETP) 9 has See page 387 and cover suggested CETP inhibition as a means of elevating HDL. Expression of CETP in transgenic mice under different metabolic settings has produced mixed results regarding its atherogenicity, whereas inhibition of endogenous CETP in rabbits has more consistently been antiatherogenic. 10 With regard to human CETP mutations and the associated reduction in CETP levels, recent analysis of prospective data from the Honolulu Heart Study 10 is consistent with the results of a previous study of Japanese subjects 11 in concluding that CETP deficiency is protective when associated with HDL-C levels Ն60 mg/dL.The results for a phase 2 study testing the synthetic CETP inhibitor JTT-705 in subjects with mild hyperlipidemia have been reported. 12 At 900 mg daily, JTT-705 led to ...

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Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.