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| |  DALM: Novel Agent, JTT-705, Shows Promise in Increasing High-Density Lipoprotein Levels in Combination With Pravastatin By Chris Berrie VENICE, ITALY -- October 27, 2004 -- A novel cholesteryl ester transfer protein (CETP) inhibitor, JTT-705, appears to increase levels of high-density lipoprotein cholesterol (HDL-C) when combined with pravastatin, and is safe and well tolerated, according to a 4-week, randomised, double-blind, placebo-controlled study. Jan Albert Kuivenhoven, PhD, group leader, department of vascular medicine, Academic Medical Centre, Amsterdam, The Netherlands, presented the study here on October 26th at the XV International Symposium on Drugs Affecting Lipid Metabolism. A previous study showed that the investigational agent raises HDL-C levels when used as monotherapy (Circulation. May 7, 2002;105(18):2159-65). To determine the efficacy of JTT-705 when combined with statin therapy, Dr. Kuivenhoven and colleagues conducted a study in 152 patients with low-density lipoprotein cholesterol (LDL-C) levels above 160 mg/dL, HDL-C below 60 mg/dL, and triglyceride levels below 400 mg/dL. On a continuous background of pravastatin 40 mg/day, 52 patients were randomised to 4 weeks of placebo, 53 to JTT-705 at 300 mg/day, and 47 to 600 mg/day. There were no significant differences in background demographic characteristics or baseline CETP parameters (activity, concentration) and full lipid profiles in the 3 treatment groups. After 4 weeks, the 600-mg group demonstrated a significant decrease from baseline in CETB activity (30%, P <.001) that was mirrored by a significant increase from baseline in HDL-C levels (28%, P <.001). This was also accompanied by a lower, but significant, decrease from baseline in LDL-C levels (5%, P <.03). Looking at the additional lipid parameters, in the higher-dose JTT-705 group there was a dramatic increase in CETP levels over baseline (102.6%) and over pravastatin monotherapy (2.4%). Dr. Kuivenhoven indicated that the mechanism for this effect remains unclear. While triglycerides, total cholesterol, and apolipoprotein (apo) B levels were essentially similar across the treatment groups, the higher JTT-705 treatment achieved a significant increase in apo A-I levels (13.6%, P <.001) and HDL2 and HDL3 (48.3%, P <.001; 18.9%, P <.001, respectively), which were not seen with pravastatin monotherapy. Consideration across the full range of key clinical and laboratory liver, kidney, muscle, and gastrointestinal safety data did not raise any notable safety concerns or show any significant adverse effects, Dr. Kuivenhoven said. "This 4-week administration of the combination of JTT-705 on top of pravastatin 40 mg results in significant dose-dependent increases in HDL-C and apo A-I plasma levels and a moderate but significant additional reduction of LDL-C," Dr. Kuivenhoven said. This combination was also well tolerated up to 4 weeks. Dr. Kuivenhoven stressed that although these data hold promise for this combination therapy, many questions remain unanswered to date. "In this recent human study, a 4-week JTT-705 regimen was shown to be very effective in reducing CETP activity in a dose-dependent fashion, by about 40% at the highest concentration, with a concomitant 30% increase in HDL-C seen," he said. As JTT-705 demonstrates this modulatory activity towards HDL-C, should it prove to be used in the clinic, this is more than likely to be in combination with an evidence-based LDL-C modulator, he added. Thus, a new study has been designed with the primary objective of evaluating the safety and efficacy of the use of JTT-705 in combination with pravastatin.
[Study title: Inhibition of Cholesteryl Ester Transfer Protein by JTT-705 in Combination With Pravastatin in Type 2 Dyslipidemia. Abstract 537]
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