Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the treatment of dyslipidemias about 5-6 years back a new class of drugs emerged, CETP (cholesteryl ester transfer protein)-inhibitors. Their benefit was due to an increase of HDL-cholesterol (HDL-C) serum levels. This treatment mode was supported by epidemiological and clinical studies, as people with high serum HDL-C levels suffered less from cardiovascular (CV) events. Three studies with CETP inhibitors (ILLUMINATE with torcetrapib, dal-OUTCOMES with dalcetrapib and ACCELERATE with evacetrapib) were unfortunately negative, and torcetrapib was even harmful to patients due to an increase of aldosterone serum levels. Treatment with dalcetrapib was safe, but without benefit. Similar it was with evacetrapib. There is still running also a study with anacetrapib (REVEAL), but a benefit is here not expected. Evacetrapib and anacetrapib in comparison to dalcetrapib can reduce serum LDL-cholesterol (LDL-C) much more, and similar results were found also in another CETP-inhibitor TA-8995 (TULIP study). Authors try to explain why there is no benefit with CETP-inhibitors (dysfunctional HDL particle, another effective mechanism than reverse cholesterol transport). A genetic analysis in dalcetrapib studies (dal-OUTCOMES and dal-PLAQUE-2) showed, that a cardiovascular benefit from this treatment is concentrated only to a subgroup of patients with a genotype AA in the gene ADCY9 on 16th chromosome. In the population there are about 20% of people with this AA genotype. A clinical study DAL-301 will test this data in a near future. Framingham Offspring study showed that the association of" HDL-C serum level - CV risk in the future" is greatly influenced by serum levels of LDL-C and triglycerides (if these are increased, than the CV future prediction with HDL-C levels is lost). HDL particles are complex and we do not know which subtype of HDL particles is for cardiovascular prognosis important. The research here continues.Key words: acute coronary syndrome - CETP-inhibitors - dalcetrapib - dysfunctional HDL particles - dyslipidemia - HDL-cholesterol - pharmacogenomics of ADCY9 gene.
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PMID:[Treatment of dyslipidemia - is here still place for CETP-inhibitors?] 2790 Aug 65

Dyslipidemia is associated with atherosclerosis and cardiovascular disease development, posing serious risks to human health. Cholesteryl ester transfer protein (CETP) is responsible for exchange of neutral lipids, such as cholesteryl ester and TG, between plasma high density lipoprotein (HDL) particles and Apolipoprotein B-100 (ApoB-100) containing lipoprotein particles. Genetic studies suggest that single-nucleotide polymorphism (SNPs) with loss of activity CETP is associated with increased HDL-C, reduced LDL-C, and cardiovascular risk. In animal studies, mostly in rabbits, which have similar CETP activity to humans, inhibition of CETP through antisense oligonucleotides reduced aortic arch atherosclerosis. Concerning this notion, inhibiting the CETP is considered as a promise approach to reduce cardiovascular events, and several CETP inhibitors have been recently studied as a cholesterol modifying agent to reduce cardiovascular mortality in high risk cardiovascular disease patients. However, in Phase III cardiovascular outcome trials, three CETP inhibitors, named Torcetrapib, Dalcetrapib, and Evacetrapib, did not provide expected cardiovascular benefits and failed to improve outcomes of patient with cardiovascular diseases (CVD). Although REVEAL trail has recently shown that Anacetrapib could reduce major coronary events, it was also shown to induce excessive lipid accumulation in adipose tissue; thereby, the further regulatory approval will not be sought. On the other hand, growing evidence indicated that the function of CETP inhibitors on modulating the cardiovascular events are determined by correlated single nucleotide polymorphism (SNP) in the ADCY9 gene. However, the underlying mechanisms whereby CETP inhibitors interact with the genotype are not yet elucidated, which could potentially be related to the genotype-dependent cholesterol efflux capacity of HDL particles. In the present review, we summarize the current understanding of the functions of CETP and the outcomes of the phase III randomized controlled trials of CETP inhibitors. In addition, we also put forward the implications from results of the trials which potentially suggest that the CETP inhibitors could be a promising precise therapeutic medicine for CVD based on genetic background.
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PMID:Cholesteryl ester transfer protein inhibitors in precision medicine. 3294 36