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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?
Methods:
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.
Results:
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.
Conclusions:
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.
Perspective:
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.
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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