Update of HDL in atherosclerotic cardiovascular disease / Nuevos conceptos de las HDL en la enfermedad cardiovascular aterosclerótica

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the “HDL quality over quantity” hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors. (AU)

Estudios epidemiológicos respaldan una asociación inversa entre los niveles de colesterol de lipoproteínas de alta densidad (c-HDL) y la enfermedad cardiovascular aterosclerótica (ECVA), identificando el c-HDL como un importante factor de riesgo cardiovascular y postulando diversas funciones vasculares y cardioprotectoras de las HDL más allá de su capacidad para promover el transporte reverso del colesterol. Sin embargo, el fracaso de varios ensayos clínicos dirigidos a aumentar el c-HDL en pacientes con enfermedad cardiovascular manifiesta, puso en duda el concepto que incrementar la carga de c-HDL fuera una estrategia eficaz para potenciar sus propiedades protectoras. Paralelamente, numerosos estudios han evidenciado que las HDL son partículas complejas y heterogéneas cuya composición es esencial para mantener sus funciones protectoras, lo que refuerza la hipótesis de que «la calidad de las HDL prima sobre la cantidad». En el siguiente manuscrito revisamos el estado del arte sobre los últimos avances en torno a las funciones de las HDL en la ECVA, nos adentramos en los avances recientes en la comprensión de la complejidad de la composición de las partículas de HDL, incluidas las proteínas, los lípidos y otros componentes transportados por las HDL, y revisamos los resultados clínicos tras la administración de inductores del c-HDL, especialmente los inhibidores de la proteína transportadora del colesterol esterificado (CETP). (AU)

Update of HDL in atherosclerotic cardiovascular disease.

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the "HDL quality over quantity" hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors.

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.

Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl-1) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly (P < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients.

The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis.

BACKGROUND: Despite the increasing prevalence of type 2 diabetes mellitus (T2DM), limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPis) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycaemic measures. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and Cochrane databases (all articles until 4 March, 2021) for randomised controlled trials (RCT) ≥1-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycaemic measures [haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)]. A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Four RCTs (n = 75 102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPis were found to significantly decrease the risk of new-onset diabetes by 16% (RR: 0.84; 95% CI: 0.78, 0.91; P < 0.001), with low between-trial heterogeneity (I2 = 4.1%). Glycaemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. CONCLUSION: Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.

Development of an effective liposomal cholesterol ester transfer protein (CETP) vaccine for protecting against atherosclerosis in rabbit model.

Clinical trials of cholesterol ester transfer protein (CETP) peptide vaccine were stopped after disappointing results in humans due to the inadequacy of adjuvant aluminum hydroxide in stimulating the immune response against the self-antigen of CETP. To increase the efficacy of the CETP vaccine, we developed a novel liposomal form of tetanus toxoid-CETP (TT-CETP) peptide (Lip CETP) with well-characterized properties and high encapsulation efficiency. The vaccine efficacy against atherosclerosis was evaluated in rabbits challenged with a high cholesterol diet. Rabbits were immunized with Lip-CETP or liposome containing CETP with CpG ODN (Lip CETP/CpG). Control groups received empty liposomes or buffer. Anti-TT-CETP specific antibodies in serum were determined and gene expression of cytokine IFN-γ and IL-4 were measured in blood peripheral mononuclear cells. Therapeutic response was evaluated by titration of plasma lipoproteins during the study and pathologic analysis of aorta atherosclerotic lesions at the end. Lip-CETP/CpG elicited strong anti-TT-CETP antibodies and a higher IFN-γ level than the buffer. IL-4 was lower than the buffer in all vaccinated groups. Plasma lipoproteins showed no significant difference in the studied groups. Atherosclerosis thickness grade of the aorta was lower than the buffer group (p < 0.001) in rabbits vaccinated with Lip-CETP but not with Lip-CETP/CpG. In conclusion, Lip-CETP showed a strong atheroprotective effect.

Dyslipidemia induced inflammatory status, platelet activation and endothelial dysfunction in rabbits: Protective role of 10-Dehydrogingerdione.

10-Dehydrogingerdione is a novel cholesteryl ester transfer protein (CETP) inhibitor of natural origin. Some synthetic CETP inhibitors have recently been reported to suppress proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, the present study aimed mainly to clarify the effect of 10-Dehydrogingerdione on cellular adhesion inflammatory molecules, platelet activation and endothelial dysfunction markers in addition to PCSK9 as compared to atorvastatin in dyslipidemic rabbits. Dyslipidemia was induced in 30 male rabbits, distributed in 3 equal groups through feeding dietary cholesterol (0.5% w/w) for 3 months. Two dyslipidemic groups were concurrently treated with either atorvastatin or 10-Dehydrogingerdione (10 mg/kg/ day, p.o) and dietary cholesterol. One additional group including 10 normal rabbits fed normal diet served as normal control (NC) group. Both 10-Dehydrogingerdione and atorvastatin significantly reduced serum CETP level and activity as well as PCSK9 and low density lipoprotein cholesterol (LDL-C) levels but increased high density lipoprotein cholesterol (HDL-C) levels as compared to dyslipidemic control (DC) rabbits (p < 0.001). Both treatments also induced a marked decrease in the interferon-gamma (IFN-γ), soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) levels, inflammatory cell infiltration, as well as atherogenic and coronary risk indexes in addition to aortic atheromatous changes and intima/media ratio, respectively as compared to the DC group (p < 0.001). The reduction in these markers showed a significant correlation with PCSK9 suppression and CETP inhibitory effect. Interestingly, 10-Dehydrogingerdione exerted a greater ameliorative potential regarding these biomarkers than atorvastatin. Our findings suggest that 10-Dehydrogingerdione is a promising PCSK9 inhibitor with a significant protective value against many atherosclerotic risk factors.

CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis.

Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.

Nonstatin therapies for management of dyslipidemia: a review.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia. METHODS: Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles. FINDINGS: Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials. IMPLICATIONS: Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.

Increasing HDL levels by inhibiting cholesteryl ester transfer protein activity in rabbits with hindlimb ischemia is associated with increased angiogenesis.

BACKGROUND: High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia. METHODS AND RESULTS: NZW rabbits were maintained for 6weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib. The left femoral artery was ligated after 2weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4weeks after femoral artery ligation. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib reduced CETP activity by 63±12% and 81±8.6%, increased plasma apoA-I levels by 1.3±0.1- and 1.4±0.1-fold, and increased plasma HDL-cholesterol levels by 1.4±0.1- and 1.7±0.2-fold, respectively. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib increased the number of collateral arteries by 60±16% and 84±27%, and arteriole wall area in the ischemic hindlimbs by 84±16% and 94±13%, respectively. Capillary density in the ischemic hindlimb adductor muscle increased from 1.1±0.2 (control) to 2.1±0.3 and 2.2±0.4 in the 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib-treated animals, respectively. Incubation of HDLs from des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells at apoA-I concentrations comparable with their plasma levels increased tubule network formation. These effects were abolished by knockdown of scavenger receptor-B1 (SR-B1) and PDZK1, and pharmacological inhibition of PI3K/Akt. CONCLUSION: Increasing HDL levels by inhibiting CETP activity is associated with increased collateral blood vessel formation in NZW rabbits with hindlimb ischemia in an SR-B1- and PI3K/Akt-dependent manner.

Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor for the treatment of atherosclerosis.

Anacetrapib, under development by Merck & Co Inc, is an inhibitor of the cholesterol ester transfer protein (CETP) for the treatment of atherosclerosis. By reversibly increasing the affinity of CETP for lipoprotein particles, anacetrapib inhibits CETP-mediated cholesterol exchange, resulting in elevated HDL-cholesterol levels and reductions in LDL-cholesterol levels. In phase I and II clinical trials, anacetrapib was well tolerated and, unlike the now discontinued CETP inhibitor torcetrapib, did not affect blood pressure and aldosterone levels. The impact of anacetrapib on lipoprotein parameters was superior to that of the CETP inhibitors torcetrapib and dalcetrapib. However, while anacetrapib displays promising anti-arteriosclerotic properties, the long-term safety and tolerability of the agent remains to be evaluated. Moreover, the concept that inhibiting CETP is atheroprotective is yet to be proven. The future of CETP inhibitors has also been affected by the failure of torcetrapib, which increased mortality in a phase III trial. Results from an ongoing phase III trial of anacetrapib will determine the likely future development of not only anacetrapib, but of the pharmacological class of CETP inhibitors.