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CETP inhibitors: TA-8995 reduces LDL cholesterol and increases cholesterol efflux

Phase 2b TULIP study results with CETP inhibitor, TA-8995, a drug in the field of dyslipidemia, were published in the Lancet. The peer-reviewed article is entitled Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia ( TULIP ): a randomised, double-blind, placebo-controlled phase 2 trial.

The TULIP ( TA-8995: its Use in patients with mild dysLIPidaemia ) study was conducted in specialized cardiovascular Centres across Denmark and the Netherlands. A total of 364 individuals with dyslipidaemia were randomised into nine cohorts: placebo, TA-8995 as monotherapy at different doses, or in combination with different statins.
The study investigated the effects of TA-8995 on a wide range of established cardiovascular disease ( CVD ) biomarkers over a three month dosing period.

The results showed potent effects on the primary endpoint, which was a composite of change from baseline in LDL cholesterol and HDL cholesterol.
5 mg of TA-8995 reduced LDL-C by 45% and increased HDL-C by 161%. 10 mg of TA-8995 in combination with statin therapy reduced LDL-C by an additional 48%.
With this combination therapy nearly all patients achieved the most stringent LDL cholesterol target of less than 1.8 mmol/L.
In addition, TA-8995 boosted cholesterol efflux significantly.

Finally, TA-8995 was safe and well tolerated without any drug accumulation as has been reported with other CETP inhibitors.

Cholesterol efflux represents the capacity of plasma to remove toxic cholesterol from the plaque in the coronary arteries. It has recently been established that cholesterol efflux is a strong and inverse, independent risk factor for cardiovascular events.
At the 5 mg dose, TA-8995 increases this capacity by over 40%, when compared to placebo.

Dyslipidemia is a generally asymptomatic disease in which serum lipid levels deviate from the normal level. It is considered to be a modifiable risk factor for cardiovascular disease due the direct relation with atherosclerosis.

The Cholesteryl Ester Transfer Protein ( CETP ) facilitates the transfer of cholesterol from HDL to other lipoproteins including LDL, in exchange for triglycerides. The CETP mediated transfer of cholesterol into LDL particles results into maturation of those LDL particles to more atherogenic LDL particles, which contribute to macrophage foam cell, and eventually plaque formation.
Large Mendelian Randomization studies, epidemiological as well as preclinical studies have provided evidence for the notion that CETP activity is inversely related to cardiovascular mortality and reduced activity of CETP by pharmaceutical means or by naturally occurring mutations in the CETP gene results in increased HDL and decreased LDL levels.
This provides a rationale for inhibition of CETP activity as a therapeutic intervention in dyslipidemic conditions characterized by either low HDL or high LDL cholesterol. ( Xagena )

Source: Dezima, 2015