Cholesterol Ester Transfer Protein Inhibition by TA-8995 in Mild Dyslipidemia | Journal Scan

Study Questions:

What is the safety, tolerability, and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA-8995 in patients with mild dyslipidemia?


TULIP was a randomized, double-blind, placebo-controlled, parallel-group phase 2 trial, in patients aged 18-75 years from 17 sites in the Netherlands and Denmark with fasting low-density lipoprotein cholesterol (LDL-C) levels between 97 mg/dl and 170 mg/dl, high-density lipoprotein cholesterol (HDL-C) levels between 30 mg/dl and 68 mg/dl, and triglyceride levels <396 mg/dl after washout of lipid-lowering treatments. Patients were randomly allocated (1:1) to receive one of nine treatments: a once a day dose of 1 mg, 2.5 mg, 5 mg, or 10 mg TA-8995 or matching placebo; 10 mg TA-8995 plus 20 mg atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone. Primary outcome was percentage change in LDL-C and HDL-C from baseline at week 12, analyzed by intention to treat.


Between August 15, 2013, and January 10, 2014, 364 patients were enrolled. At week 12, LDL-C levels were reduced by 27.4% with the 1 mg dose, 32.7% in patients given the 2.5 mg dose, 45.3% in those given the 5 mg dose, and 45.3% in those given the 10 mg dose (p < 0.0001). LDL-C levels were reduced by 68.2% in patients given 10 mg TA-8995 plus atorvastatin, and by 63.3% in patients given rosuvastatin plus 10 mg TA-8995 (p < 0.0001). A daily dose of 1 mg TA-8995 increased HDL-C levels by 75.8%, 2.5 mg by 124.3%, 5 mg by 157.1%, and 10 mg dose by 179.0% (p < 0.0001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin, HDL-C levels increased by 152.1%, and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin, by 157.5%. There were no serious adverse events or signs of liver or muscle toxic effects.


TA-8995, a novel CETP inhibitor, is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidemia. A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events.


Initial attempts to show cardioprotective effects of CETP inhibition with torcetrapib (increased aldosterone and blood pressure) and dalcetrapib in human beings failed despite the marked decrease in LDL-C and increase in HDL-C. There is speculation that the cholesterol-rich HDL particles may be dysfunctional and thus accelerate atherosclerosis and events despite the marked lowering of LDL-C.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Aldosterone, Anticholesteremic Agents, Apolipoproteins, Atherosclerosis, Cardiovascular Diseases, Cholesterol Ester Transfer Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Double-Blind Method, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intention to Treat Analysis, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Primary Prevention, Sterol Esterase, Sulfhydryl Compounds, Triglycerides

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