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Pfizer's early CETP inhibitor torcetrapib failed due to an off-target molecule design that stimulated aldosterone secretion in the adrenal glands. This toxic effect raised blood pressure and increased mortality, leading to the trial's termination in 2006.
Obicetrapib is a highly potent CETP inhibitor that lowers LDL by up to 45% as a monotherapy. The ongoing global Prevail trial will assess cardiovascular outcomes in 9,500 patients on maximum-tolerated statins over a minimum follow-up of 2.5 years.
Obicetrapib reduces small LDL particles by 90% and lowers Lp(a) by approximately 50%. Davidson emphasizes that unlike statins, which can slightly increase diabetes risk, CETP inhibitors systematically lower the risk of developing diabetes.
In the Broadway trial, homozygous APOE4 carriers treated with obicetrapib saw over 20% reduction in the Alzheimer's biomarker p-tau 217 compared to placebo. The drug also improved other key neurodegenerative markers, including NfL and GFAP.
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