Cholesteryl Ester Transfer Protein Inhibitors Research Articles

P6193Dalcetrapib reduces incident diabetes in patients with recent acute coronary syndrome

Abstract Background Among patients with acute coronary syndrome (ACS) who do not have diabetes, incident diabetes is common and associated with an adverse prognosis. Some data suggest that high density lipoprotein (HDL) has favourable effects on beta cell function and that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes in conjunction with increased HDL cholesterol (HDL-C) concentration. Dalcetrapib is a CETP inhibitor under ongoing evaluation as a potential cardiovascular therapy. Purpose We compared the effect of treatment with dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome (ACS). Methods In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg or placebo daily, beginning 4–12 weeks after ACS. Absence of diabetes at baseline was based upon medical history, no use of diabetes medication, haemoglobin A1c <6.5%, and plasma glucose level <7 mmol/L (if measured under fasting conditions) or <11.1 mmol/L (if measured under non-fasting conditions). Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, use of a diabetes medication, HbA1c ≥6.5%, or two measurements of plasma glucose ≥7 mmol/L (fasting) or ≥11.1 mmol/L (non-fasting). The association of incident diabetes with baseline and on-treatment HDL-C was determined. Results At baseline, 10621 patients (67% of the trial cohort) did not have diabetes and formed the analysis cohort. Over median follow-up of 31 months, incident diabetes was identified in 392 of 5314 patients (7.4%) assigned to dalcetrapib and 505 of 5307 (9.5%) assigned to placebo (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.66–0.87; P<0.001). This corresponds to an absolute reduction in incident diabetes of 2.1%, and a need to treat 47 patients (for 31 months) to prevent 1 case of diabetes. Kaplan-Meier estimates of the cumulative incidence of diabetes are shown in the Figure. Across both treatment groups, incident diabetes was inversely associated with baseline HDL-C (OR 0.98 for 1 mg/dL increase in baseline HDL-C; 95% CI 0.97–0.98, P<0.001). In the dalcetrapib group, there was a further inverse association of incident diabetes with the change in HDL-C on assigned treatment (OR 0.98 for 1 mg/dL increase in HDL-C from baseline; 95% CI 0.97–0.99, P=0.002). Dalcetrapib was safe and generally well-tolerated in the trial. Conclusions In patients with recent ACS who do not have diabetes at baseline, incident diabetes is common. Dalcetrapib treatment reduced the relative risk of incident diabetes by 24% and the absolute risk by 2.1% over a median of 31 months. The reduction in incident diabetes with dalcetrapib was associated with increased HDL-C on treatment. Acknowledgement/Funding The dal-OUTCOMES trial was funded by F. Hoffmann LaRoche

P4606Comparing biomarker profiles in patients with stable atherosclerosis treated with anacetrapib versus placebo: a nested proteomic study from HPS3/TIMI 55-REVEAL

Abstract Background The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib improves cardiovascular outcomes in patients with stable atherosclerosis; however, the potential interaction of HDL-C-, LDL-C-, and non-lipid-mediated effects remains incompletely understood. Purpose The aim of this study was to identify biological pathways that are influenced by treatment with anacetrapib. Methods HPS3/TIMI 55-REVEAL was a randomized, double-blind, placebo-controlled trial of anacetrapib in patients with stable atherosclerotic cardiovascular disease. We performed a nested prospective biomarker study in 500 patients, analyzing 274 candidate biomarkers. We compared changes in biomarker levels between randomization and mid-study (∼2 years) in patients treated with anacetrapib vs. placebo using a stringent threshold for statistical significance. We evaluated associations between changes in selected biomarkers and changes in HDL-C and LDL-C from baseline to mid-study in each treatment group. Results Eleven biomarkers were significantly modified by anacetrapib vs. placebo (Figure). These proteins represent pathways implicated in inflammation, lipid metabolism, and hematopoiesis. Among anacetrapib-treated patients, changes in 5/11 biomarkers were not significantly correlated with changes in either serum HDL-C or serum LDL-C. Conclusion(s) In patients with stable atherosclerosis, treatment with anacetrapib results in changes in protein expression extending beyond lipid metabolism. Some of these changes appear to be independent of anacetrapib-mediated effects on HDL-C and LDL-C. Acknowledgement/Funding HPS3/TIMI 55-REVEAL was sponsored by Merck.

Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials.

The effect of therapeutic lowering of apolipoprotein B (apoB) on mortality and major adverse cardiovascular events is uncertain. It is also unclear whether these potential effects vary by different lipid-lowering strategies. A total of 29 randomized controlled trials were selected using PubMed, Cochrane Library and EMBASE through 2018. We selected trials of therapies which ultimately clear apolipoprotein B particles by upregulating low-density lipoprotein receptor (LDL-R) expression (statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants) or therapies which reduce apolipoprotein B independent of LDL-R (cholesteryl ester transfer protein inhibitor, fibrates, niacin, omega-3 fatty acids) with sample size of ≥1000 patients and follow-up of ≥1 year. The meta-regression and meta-analyses were constructed using a random effects model. In 332,912 patients, meta-regression analyses showed relative risks of 0.95 for all-cause mortality (95% confidence interval 0.92-0.99) and 0.93 (0.88-0.98) for cardiovascular mortality for every 10 mg/dL decrease in apolipoprotein B by all interventions combined. Reduction in all-cause mortality was limited to statins (0.92 (0.86-0.98)). For MACE, the relative risk per 10 mg/dL reduction in apolipoprotein B was 0.93 (0.90-0.97) for all therapies combined, with both statin (0.88 (0.83-0.93)) and non-statin therapies (0.96 (0.94-0.99)). which clear apolipoprotein B by upregulating LDL-R showing significant reductions; whereas interventions which lower apolipoprotein B independent of LDL-R did not demonstrate this effect (1.02 (0.81-1.30)). While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in apolipoprotein B, interventions which reduce apolipoprotein B independently of LDL-R were not associated with cardiovascular benefit.

Cholesteryl ester transfer protein: the physiological and molecular characteristics in the pathogenesis of atherosclerosis and Alzheimer’s disease

Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport, mediates the exchange of cholesteryl esters for triglycerides between high-density lipoproteinsand low-density lipoproteins/very low-density lipoproteins. Lipid transfer mechanism by CETP is unknown. Two main models have been proposed for the mechanism of action of CETP: shuttle and tunnel mechanisms. The variants of CETP gene affect activity and level of protein, thus they are associated with lipid profile and risk of many diseases. Some clinical studies reported that polymorphisms of CETP, including TaqIB and I405V, are associated with risk of atherosclerosis and/or Alzheimer’s disease. CETP plays important role an in the metabolism of cholesterol, thus is correlated with pathomechanism of coronary artery disease. Inhibition of CETP can be an effective strategy to improve the lipid profile and reduce risk of cardiovascular diseases. Therefore, new therapeutic strategies to reduce activity of CETP or decrease its level are developed. Effectiveness of following pharmacological methods of modulation of CETP activity was studied: anti-CETP vaccines, antisense oligonucleotide and small molecule inhibitors of CETP. This article presents an overview of the literature on the correlation between cardiovascular diseases and CETP protein/CETP gene. Furthermore, it discusses the impact of CETP on pathogenesis of Alzheimer’s disease.

Steering the Lipid Transfer To Unravel the Mechanism of Cholesteryl Ester Transfer Protein Inhibition.

Human plasma cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids from antiatherogenic high-density lipoproteins (HDLs) to proatherogenic low-density lipoproteins (LDLs). Recent cryo-electron microscopy studies have suggested that CETP penetrates its N- and C-terminal domains in HDL and LDL to form a ternary complex, which facilitates the lipid transfer between different lipoproteins. Inhibition of CETP lipid transfer activity has been shown to increase the plasma HDL-C levels and, therefore, became an effective strategy for combating cardiovascular diseases. Thus, understanding the molecular mechanism of inhibition of lipid transfer through CETP is of paramount importance. Recently reported inhibitors, torcetrapib and anacetrapib, exhibited low potency in addition to severe side effects, which essentially demanded a thorough knowledge of the inhibition mechanism. Here, we employ steered molecular dynamics simulations to understand how inhibitors interfere with the neutral lipid transfer mechanism of CETP. Our study revealed that inhibitors physically occlude the tunnel posing a high energy barrier for lipid transfer. In addition, inhibitors bring about the conformational changes in CETP that hamper CE passage and expose protein residues that disrupt the optimal hydrophobicity of the CE transfer path. The atomic level details presented here could accelerate the designing of safe and efficacious CETP inhibitors.

Optimizing Dyslipidemia Management for the Prevention of Cardiovascular Disease: a Focus on Risk Assessment and Therapeutic Options

Primary prevention of incident atherosclerotic cardiovascular disease (ASCVD) as well as decreasing the risk of future events in those with established atherosclerosis is critical from a public health perspective. Management of dyslipidemias constitutes a key target in decreasing the risk of developing ASCVD events. While there have been great strides in the treatment of dyslipidemia over the last three decades, there are important recent developments and ongoing research that will expand the available therapeutic options and enable further cardiovascular risk reduction. PURPOSE OF REVIEW: The purpose of this paper is to review new developments relating to the primary prevention and management of ASCVD with a specific focus on optimizing the treatment of dyslipidemias. RECENT FINDINGS: In the realm of ASCVD risk prediction, mounting evidence over the last decade has demonstrated that coronary artery calcium testing is superior to any serum biomarker in the prediction of future ASCVD events and in discriminating future cardiovascular risk. As such, it has been incorporated into the most recent ACC/AHA primary prevention guideline to help guide management decisions in select patients. In terms of the management of dyslipidemias, PCSK9 inhibitors lower LDL-C by 50-70% and provide an additional 15% reduction in key cardiovascular events in high-risk patients with known ASCVD, as demonstrated in the ODYSSEY and FOURIER trials. Cholesteryl ester transfer protein (CETP) inhibitors, which significantly increase HDL-C levels, demonstrated mixed results in large clinical trials and have helped reframe HDL-C as a risk marker rather than a modifiable risk factor. In regard to the management of triglycerides, the REDUCE-IT trial demonstrated a nearly 5% absolute reduction in key cardiovascular events with a highly purified fish-oil derivative named icosapent ethyl in high-risk patients already on statin therapy. Finally, in regard to lipoprotein(a)-which is a strong risk factor for ASCVD-there are exciting developments in the therapeutic pipeline which reduce circulating lipoprotein(a) levels by nearly 90%. The management of dyslipidemias continues to be an exciting field with several ongoing cardiovascular outcomes trials, improvement in risk prediction models, and new therapeutic agents in the pipeline that will further mitigate residual cardiovascular risk in both primary and secondary prevention patients.

世界最強の作用を有するCETP阻害剤TA-8995（obicetrapib）の創製

世界最強の作用を有するCETP阻害剤TA-8995（obicetrapib）の創製

Impact of ADCY9 Genotype on Response to Anacetrapib.

Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of ADCY9 genotype on response to anacetrapib in the REVEAL trial. Individuals with stable atherosclerotic vascular disease who were treated with intensive atorvastatin therapy received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype. Among 19 210 genotyped individuals of European ancestry, 2504 (13.0%) had a first major vascular event during 4 years median follow-up: 1216 (12.6%) among anacetrapib-allocated participants and 1288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: hazard ratio (HR) = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib. The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib. URL: https://www. gov. Unique identifier: NCT01252953. URL: http://www.isrctn.com. Unique identifier: ISRCTN48678192. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

Design and development of novel therapeutics for coronary heart disease treatment based on cholesteryl ester transfer protein inhibition – in silico approach

Cholesteryl ester transfer protein (CETP) belongs to the group of enzymes which inhibition have the application in the treatment of cardiovascular diseases. This study presents QSAR modeling for a set of compounds acting as CETP inhibitors based on the Monte Carlo optimization with SMILES notation and molecular graph-based descriptors, and field-based 3D modeling. A 3D QSAR model was developed for one random split into the training and test sets, whereas conformation independent QSAR models were developed for three random splits, with the results suggesting there is an excellent correlation between them. Various statistical approaches were used to assess the statistical quality of the developed models, including robustness and predictability, and the obtained results were very good. This study used a novel statistical metric known as the index of ideality of correlation for the final assessment of the model, and the results that were obtained suggested that the model was good. Also, molecular fragments which account for the increases and/or decreases of a studied activity were defined and then used for the computer-aided design of new compounds as potential CETP inhibitors. The final assessment of the developed QSAR model and designed inhibitors was done using molecular docking, which revealed an excellent correlation with the results from QSAR modeling.Communicated by Ramaswamy H. Sarma

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.

DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.

Antisense Oligonucleotides Targeting Lipoprotein(a).

High lipoprotein(a) levels are observationally and causally, from human genetics, associated with increased risk of cardiovascular disease including myocardial infarction and aortic valve stenosis. The European Atherosclerosis Society recommends screening for elevated lipoprotein(a) levels in high-risk patients. Different therapies have been suggested and some are used to treat elevated lipoprotein(a) levels such as niacin, PCSK9 inhibitors, and CETP inhibitors; however, to date, no randomized controlled trial has demonstrated that lowering of lipoprotein(a) leads to lower risk of cardiovascular disease. Synthetic oligonucleotides can be used to inactivate genes involved in disease processes. To lower lipoprotein(a), two antisense oligonucleotides have been developed, one targeting apolipoprotein B and one targeting apolipoprotein(a). Mipomersen is an antisense oligonucleotide targeting apolipoprotein B and thereby reducing levels of all apolipoprotein B containing lipoproteins in the circulation. Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies. AKCEA-APO(a)-LRx is the most recent antisense oligonucleotide targeting apolipoprotein(a) and thereby uniquely targeting lipoprotein(a). It has been tested in a phase 2 study and has shown to lower lipoprotein(a) levels by 50-80%. The treatment of elevated lipoprotein(a) levels with the newest antisense oligonucleotides seems promising; however, no improvement in cardiovascular disease risk has yet been shown. However, a phase 3 study of AKCEA-APO(a)-LRx is being planned with cardiovascular disease as outcome, and results are awaited with great anticipation.

The unbalance in the relative expression of ABCA1 and IRS1 are correlated with pathological metabolic profile and adiposity in individuals with insulin resistance in obesity

Dyslipidemia is a risk factor for atherosclerotic cardiovascular disease (ASCVD). Abundant data indicate that low-density lipoproteins (LDL) are causal for ASCVD; a new class of LDL-lowering medicines, the PCSK9 inhibitors, will address much unmet medical need. Human genetics suggest that triglyceride-rich lipoproteins (TRL) are pro-atherogenic and have pointed to a number of protein regulators of lipoprotein lipase activity that are candidates for therapeutic targeting. Finally, high-density lipoprotein (HDL) cholesterol does not appear to be causally associated with protection from ASCVD, reinforced by the failure of three CETP inhibitors in CV outcome trials, but HDL function remains of interest.

Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.

Trials in "True" Dyslipidemic Patients Are Urged to Reconsider Comprehensive Lipid Management as a Means to Reduce Residual Cardiovascular Risk.

Randomized cardiovascular trials aimed to reduce the excessive residual risk in high‐risk patients through a more aggressive low‐density lipoprotein‐cholesterol control or targeting triglycerides or high‐density lipoprotein‐cholesterol levels have shown a null or, at best, limited incremental benefit. In some cases, the treatment produced meaningful effects only in study subgroups. As a consequence, some compounds were withdrawn (e.g., nicotinic acid derivatives and cholesteryl ester transfer protein inhibitors), whereas others (fibrates) are utilized with reluctance due to the low level of evidence‐based data. By reviewing these trials analytically, we identified a common feature that might explain their meager results: most of them involved patients generically at high cardiovascular risk with normal or near normal lipid levels and not patients with “true” dyslipidemia, who would receive the treatment if it were part of usual care. These observations may warrant re‐examining a central criterion of pragmatism, eligibility, in the outline of forthcoming cardiovascular trials with novel lipid‐modifying drugs.

Evacetrapib reduces preβ-1 HDL in patients with atherosclerotic cardiovascular disease or diabetes

Background and aimsCholesteryl ester transfer protein (CETP) inhibitor-mediated induction of HDL-cholesterol has no effect on the protection from cardiovascular disease (CVD). However, the mechanism is still unknown. Data on the effects of this class of drugs on subclasses of HDL are either limited or insufficient. In this study, we investigated the effect of evacetrapib, a CETP inhibitor, on subclasses of HDL in patients with atherosclerotic cardiovascular disease or diabetes. MethodsBaseline and 3-month post-treatment samples from atorvastatin 40 mg plus evacetrapib 130 mg (n = 70) and atorvastatin 40 mg plus placebo (n = 30) arms were used for this purpose. Four subclasses of HDL (large HDL, medium HDL, small HDL, and preβ-1 HDL) were separated according to their size and quantified by densitometry using a recently developed native polyacrylamide gel electrophoresis (PAGE) system. ResultsRelative to placebo, while evacetrapib treatment dramatically increased large HDL and medium HDL subclasses, it significantly reduced small HDL (27%) as well as preβ-1 HDL (36%) particles. Evacetrapib treatment reduced total LDL, but also resulted in polydisperse LDL with LDL particles larger and smaller than the LDL subclasses of the placebo group. ConclusionEvacetrapib reduced preβ-1 HDL and small HDL in patients with ASCVD or diabetes on statin. Preβ-1 HDL and medium HDL are negatively interrelated. The results could give a clue to understand the effect of CETP inhibitors on cardiovascular outcomes.

Abstract 146: Evolving Clinical Benefits and Social Value of Lipid Lowering Therapies

Background and Objectives: In 2013-14, approximately 30% of adults (20 years of age or older) in the United States (US) had high low-density lipoprotein cholesterol (LDL-C, LDL-C≥ 200 mg/dL). Elevated LDL-C is associated with an increased risk of cardiovascular disease (CVD) related events and death, and a key target for therapy. The lipid lowering treatment (LLT) landscape has evolved significantly over the course of the last 40 years with the introduction of statins, fibrates, ezetimibe, CETP inhibitors, and PCSK9 inhibitors (PCSK9i). Currently, statins are first-line therapy for LDL-C reduction. This study quantified the effect of LLT use since 1987 on CVD-related mortality and morbidity. Methods: Descriptive analyses of the rates of LLT use and LLT spending over time were conducted using both NHANES (1999-2014) and MEPS data (1996-2016), and the association between LDL-C levels and mortality and hospitalizations were identified in the literature. By using hazard ratios from published clinical trials, and NHANES data on the number of LLT users and frequency of non-fatal CVD events among these users, the total number of non-fatal CVD events prevented over time was calculated. Events avoided were calculated as the difference between CVD events observed among LLT users and events that would have occurred in the absence of LLT use. The latter was calculated using the difference in events between treated and untreated patients in LLT trials. The value associated with the prevention of non-fatal CVD events due to LLT use was calculated as the product of the costs associated with treating CVD events and the total number of CVD events prevented. The value of mortality reduction was calculated as the product of the value of a statistical life year ($150,000) and the life expectancy gain from the WOSCOPS and ODYSSEY clinical trials. This value was compared with LLT spending. Results: The uptake of statins and ezetimibe between 1999 and 2014 prevented an estimated total of 2.8M myocardial infarctions (MIs) and 1.7M strokes in the US. The cumulative value derived from MI and stroke events prevented through statin and ezetimibe use, though largely driven by statin use, from 1999–2012 amounted to approximately $258B (2018 USD) and $37B, respectively. The use of statins from 1999–2012 resulted in an additional 12.6 million life-years at a value of $1.9T, and we estimate that statin use could generate an additional $953.1B in value to society from 2018–2025 through reductions in CVD mortality, with patients retaining 94% of the value. Conclusions: Innovation in the LLT landscape, particularly through the introduction and uptake of statins, ezetimibe and PCSK9is, yields significant value to society through the reduction of costs associated with both fatal and non-fatal CVD events. Of the value that accrues to society from the utilization of statins, patients retain approximately 95%.

Baseline fasting plasma insulin levels predict risk for major adverse cardiovascular events among patients with diabetes and high-risk vascular disease: Insights from the ACCELERATE trial.

Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.

Reliable structural information for rational design of benzoxazole type potential cholesteryl ester transfer protein (CETP) inhibitors through multiple validated modeling techniques

The drug design and discovery of lipid modulators is very demanding as no new molecule has entered into the market in the last 35 years. Cholesteryl ester transfer protein (CETP) is a promising target as lipid modulators. Inhibition of the CETP enzyme reduces the risk of cardiovascular events. The first CETP inhibitor torcetrapib and related drug candidates failed in the clinical trial due to the off-target effects leading to high toxicity. Thus, newer CETP inhibitors have now paramount importance to accelerate the drug discovery efforts in the field of cardiovascular disease (CVD). In the present study, 140 benzoxazole compounds were studied by using different chemometric techniques, for example, pharmacophore mapping, molecular docking, three-dimensional quantitative structure–activity relationship comparative molecular field analysis (3D-QSAR CoMFA), topomer CoMFA and Bayesian classification, in order to generate complete and reliable information regarding the structural requirements for the CETP inhibition. The best pharmacophore hypothesis was statistically significant (regression coefficient of 0.957 and a lower root mean square of 0.890). Molecular docking study revealed that cyano-substituted compounds form hydrogen bond with targeted macromolecule. The 3D-QSAR CoMFA model also produced a leave-one-out (LOO) cross-validated Q2 of 0.527, an R2 of 0.853 and an R2Pred of 0.603. Similarly, two topomer CoMFA models were also statistically significant and reliable in terms of their Q2, R2 and R2Pred values. The Bayesian classification study also provided the excellent ROC values of 0.919 and 0.939 for training and test sets, respectively. Overall, this study may help in the rational design of newer benzoxazole type compounds with higher CETP inhibition.Communicated by Ramaswamy H. Sarma

Do Cholesteryl Ester Transfer Protein Inhibitors Have a Role in the Treatment of Cardiovascular Disease?

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism and has presented an attractive target for drug development, primarily resting on the hope that CETP inhibition would reduce cardiovascular events through its ability to increase levels of high-density lipoprotein cholesterol (HDL-C). However, clinical development of CETP inhibitors has proven disappointing, with a spectrum of results spanning from evidence of harm, to futility, to only modest benefit in large-scale cardiovascular outcomes trials. A number of additional insights from genomic studies have suggested potential benefits from these agents in specific clinical settings. We review the current state of CETP inhibitors as an approach to targeting cardiovascular risk.

Is high-density lipoprotein a modifiable treatment target or just a biomarker for cardiovascular disease?

Epidemiological data strongly support the inverse association between high-density lipoprotein cholesterol concentration and cardiovascular risk. Over the last three decades, pharmaceutical strategies have been partially successful in raising high-density lipoprotein cholesterol concentration, but clinical outcomes have been disappointing. A recent therapeutic class is the cholesteryl ester transfer protein inhibitor. These drugs can increase circulating high-density lipoprotein cholesterol levels by inhibiting the exchange of cholesteryl ester from high-density lipoprotein for triacylglycerol in larger lipoproteins, such as very low-density lipoprotein and low-density lipoprotein. Recent trials of these agents have not shown clinical benefit. This article will review the evidence for cardiovascular risk associated with high-density lipoprotein cholesterol and discuss the implications of the trial data for cholesteryl ester transfer protein inhibitors.