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Current status of CETP inhibitors in the treatment of hyperlipidemia: an update
Raktim Kumar Ghosh1, Samhati Mondal Ghosh
1Department of Pharmacology, Maulana Azad Medical College, New Delhi, India. dr.raktimghosh@gmail.com
Insights
Cholesteryl ester transfer protein (CETP) inhibitors aim to increase HDL-C for cardiovascular disease reduction. Lessons from torcetrapib
Area of Science:
- Pharmacology and Cardiovascular Medicine
Background:
- High-density lipoprotein cholesterol (HDL-C) inversely correlates with cardiovascular disease (CVD) risk.
- Reverse cholesterol transport (RCT) by HDL-C is a key anti-atherogenic mechanism.
- Cholesteryl ester transfer protein (CETP) is a critical regulator of RCT.
Purpose of the Study:
- To review the development of CETP inhibitors for managing hyperlipidemia and reducing cardiovascular risk.
- To discuss lessons learned from the failure of torcetrapib and the progress of other CETP inhibitors.
Main Methods:
- Review of preclinical and clinical data on CETP inhibitors.
- Analysis of the impact of torcetrapib, dalcetrapib, and anacetrapib on HDL-C levels and cardiovascular outcomes.
- Evaluation of safety profiles, including effects on blood pressure and aldosterone.
Main Results:
- Torcetrapib's phase 3 trial was halted due to increased mortality, later found to be molecule-specific.
- Dalcetrapib and anacetrapib showed good tolerability in early trials without adverse effects on blood pressure or aldosterone.
- CETP inhibition is a viable strategy for increasing HDL-C and potentially reducing cardiovascular risk.
Conclusions:
- Understanding torcetrapib's failure is crucial for the development of safer CETP inhibitors.
- Dalcetrapib and anacetrapib represent promising therapeutic options for hyperlipidemia and cardiovascular risk reduction.
- CETP inhibitors hold potential for managing dyslipidemia and mitigating cardiovascular events.
Introduction:
The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP).
Areas Covered:
Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels. In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.
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