Preventive cardiologySafety and Tolerability of Dalcetrapib†
Section snippets
Methods
Five double-blind, randomized, placebo-controlled phase II trials of dalcetrapib were conducted in patients with dyslipidemia, CHD, or CHD risk equivalents. Inclusion criteria are listed in Table 1. Exclusion criteria were body mass index ≥35 kg/m2 (≥40 kg/m2 for the 12-week study); uncontrolled hypertension; diabetes (except for 2 studies in which it was considered a CHD risk equivalent); clinically significant arterial, hepatic, renal, cardiac, or cerebral disease; hepatic transaminase >1.5
Results
In the 4-week studies, a total of 546 of 551 randomized patients received ≥1 dose of study medication (safety population), and 546 patients were included in the efficacy (intent-to-treat) population (Figure 1). In the 12-week study, 292 patients were randomized (safety population), and 287 patients were in the efficacy population (Figure 1). For the phase IIa studies, patients in the dalcetrapib 300 and 900 mg groups were of greater (p <0.05) mean age and body mass index and had greater (p
Discussion
In this analysis, dalcetrapib effectively increased levels of HDL cholesterol and apolipoprotein A-I. The pooled and 12-week data presented support the findings of the 2 previously published individual trials5, 6 (included in this analysis). Dalcetrapib reduced CETP activity and increased CETP mass. Although comparisons with torcetrapib are limited because of study differences, a phase I study reported CETP decreases of up to 53% with torcetrapib.10 A comparative in vitro study has reported
Acknowledgment
We thank the investigators, study staff members, and patients who participated in these studies. Editorial assistance was provided to the authors by Teresa Haigh and Emma Marshman (Prime Healthcare). Portions of these data were presented at the 2008 Annual Scientific Session of the American College of Cardiology, Chicago, Illinois, and the European Atherosclerosis Society Congress 2008, Istanbul, Turkey.
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2017, Current Opinion in PharmacologyCitation Excerpt :Since CETP transports cholesteryl esters from HDL to VLDL or LDL in exchange for triglycerides, increased CETP activity is considered as a major determinant of low HDL-C. Several CETP inhibitors have been tested, including anacetrapib, evacetrapib, and dalcetrapib. These studies have shown that in patients already receiving statin therapy, the three CETP inhibitors increase HDL levels by approximately 140%, 80% and 30%, respectively [43–45], but similar to the niacin trial, treatment failed to reduce cardiovascular events [46]. These findings raised questions about whether medically increasing HDL-C has anti-atherogenic properties and whether simply measuring circulating HDL-C levels is enough to predict the risk of cardiovascular events.
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This study was supported by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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Conflicts of interest: Dr. Stein has received grants for studies of lipid-modifying agents, has received consulting fees and honoraria for professional input regarding agents to modify lipid profile, and/or has delivered lectures for the American Association for Clinical Chemistry, Washington, District of Columbia; Abbott Laboratories, Abbott Park, Illinois; AstraZeneca, Wilmington, Delaware; the United States Food and Drug Administration, Washington, District of Columbia; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Isis Pharmaceuticals, Inc., Carlsbad, California; Merck & Co., Whitehouse Station, New Jersey; the National Lipid Association, Jacksonville, Florida; Novartis International AG, Basel Switzerland; Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey; Daiichi Sankyo Co., Ltd., Tokyo, Japan; Schering-Plough Corporation, Kenilworth, New Jersey; Takeda Pharmaceutical Company Ltd., Osaka, Japan; and Wyeth, Madison, New Jersey. Dr. Stroes has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd. and Novartis International AG. Dr. Steiner has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd.; Solvay, Brussels, Belgium; Ethypharm S.A., Saint-Cloud, France; and Merck Frosst Canada Ltd. (Kirkland, Quebec, Canada)/Schering-Plough Corporation. Dr. Buckley has received research grants from AstraZeneca; Merck Sharp & Dohme, Dublin, Ireland; and Pfizer, Inc., New York, New York. Dr. Buckley has received honoraria and consulting fees and/or delivered lectures for AstraZeneca; Bristol-Myers Squibb, New York, New York; F. Hoffmann-La Roche Ltd.; Novartis International AG; Pfizer, Inc.; and Sanofi-Aventis, Paris, France. Dr. Capponi has received consulting fees and honoraria from F. Hoffmann-La Roche Ltd. Dr. Burgess is an employee of Hoffmann-La Roche Inc., Nutley, New Jersey. Drs. Niesor and Kallend are employees of F. Hoffmann-La Roche Ltd. Dr. Kastelein has received research grants, honoraria, or consulting fees for professional input and/or has delivered lectures for Pfizer, Inc.; Merck Sharp & Dohme; F. Hoffmann-La Roche Ltd.; Novartis International AG; Isis Pharmaceuticals, Inc.; Kowa Pharmaceutical Company Ltd., Nagoya, Japan; Schering-Plough Corporation; and AstraZeneca.