Durable and safe lipid-modifying effects of anacetrapib
Lipids, Safety Parameters, and Drug Concentrations After an Additional 2 Years of Treatment With Anacetrapib in the DEFINE Study
Literature - Gotto AM et al., J Cardiovasc Pharmacol Ther. 2014 - J Cardiovasc Pharmacol Ther. 2014 Apr 14Gotto AM Jr, Kher U, Chatterjee MS, et al., the DEFINE Investigators
J Cardiovasc Pharmacol Ther. 2014 Apr 14
Background
Cholesteryl ester transfer protein (CETP) inhibitors experimental agents that raise HDL-cholesterol by inhibiting the transfer of cholesteryl esters and triglycerides between HDL and apolipoprotein B-containing lipoproteins [1]. Anacetrapib is such a CETP-inhibitor under development, evaluated in the 76-week phase III DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) study. Blood pressure, electrolytes and other safety parameters were no different between the anacetrapib and the placebo treatment groups [2]. Patients receiving anacetrapib 100 mg/day showed a placebo-adjusted 39.8% reduction in LDL-c (primary endpoint) and an 138.1% increase in HDL-c. This paper describes a 2–year extension of the DEFINE study, to further evaluate safety, lipid effects and anacetrapib drug concentrations. Patients were off the drug for at least 12 weeks, up to 24 weeks, before continuing the assigned study treatment.Main results
- Treatment with anacetrapib during an extra 2 years was generally well tolerated. No differences in the occurrence of drug-related or serious adverse events were observed between anacetrapib and placebo. No clinically relevant elevations of electrolytes or liver or muscle enzymes were seen with anacetrapib in comparison with placebo. No statistically significant increases of categorical blood pressure were seen. Fasting plasma glucose was decreased with anacetrapib vs. placebo (-5.2%), while in patients with diabetes, change in HbA1c from baseline was 0.03% vs. 0.2% in anacetrapib vs. placebo.
- After 2 years, a sustained effect of treatment with anacetrapib on the lipid profile was seen, with a placebo-adjusted mean percent reduction of 39.9% for Friedewald-calculated LDL-c, and an increase of 153.5% for HDL-c. Non-HDL-c was on average reduced by 30.9%, and apolipoprotein B by 16.3%, while apolipoprotein A-I was increased with 44.5%, with anacetrapib vs. placebo.
- Residual mean plasma concentration of anacetrapib at the start of the extension study was 219 nmol/L. In the extension study, plasma anacetrapib levels increased, to reach a plateau at the 40th extension week (659 nmol/L).
Conclusion
The effects of treatment with anacetrapib on LDL-c and HDL-c were similar in the 104-week extension period to the 76-week DEFINE base study. No clinically relevant adverse effects were associated with extended use of anacetrapib.A steady state plasma concentration of about 640 nmol/L was reached around week 40. The time line towards this steady state is difficult to predict from this study data, since patients started the extension period with significant residual drug levels of the base study. However, these data show that anacetrapib did not continue to accumulate in the plasma after 40 weeks of treatment in the 2 –years extension study.
Find this article on Pubmed
References
1. Barter PJ, Brewer HB Jr, Chapman MJ, et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23(2):160-167.
2. Cannon CP, Shah S, Dansky HM, et al. Determining the efficacy and tolerability investigators. safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;
363(25):2406-2415.