Cholesteryl Ester Transfer Protein Inhibitors Research Articles

Old target, but new drug: 2nd generation cetp inhibitor, CKD-508

Old target, but new drug: 2nd generation cetp inhibitor, CKD-508

Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87). Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Abstract 16185: Biomarker-based Heart Failure Risk Stratification in Patients With Atherosclerotic Cardiovascular Disease: Observations From HPS-3/TIMI-55-REVEAL

Background: Circulating biomarkers reflecting pathways implicated in heart failure (HF) may improve HF risk assessment in patients with stable atherosclerotic cardiovascular disease (ASCVD). Hypothesis: We aimed to evaluate the performance of circulating biomarkers of hemodynamic stress, myocardial injury, and inflammation for the prediction of hospitalization for HF (HHF) in a large well-characterized cohort with stable ASCVD followed for a median of 4.1 years. Methods: HPS3/TIMI 55-REVEAL was a randomized, double-blind, placebo-controlled trial of the CETP inhibitor anacetrapib in patients with stable ASCVD. We performed a nested prospective biomarker study, measuring high-sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) (all Roche Diagnostics) at randomization (n=29,673). Hazard ratios were adjusted for covariates of a priori clinical relevance to HHF risk: age, prior HF, hypertension, diabetes mellitus, eGFR &lt;60, body-mass index, and polyvascular disease. Discrimination was assessed using Harrell’s c-index. Results: A significant graded risk of HHF was observed with increasing deciles of hsTnT, NT-proBNP, and GDF-15 (p-trend &lt;0.001 for each) ( Figure ). These associations remained significant after multivariable adjustment for clinical risk factors (p&lt;0.001 for each). When added to a multivariable Cox regression model of clinical risk indicators (c-index 0.74), these 3 biomarkers significantly improved the prognostic performance of the model (c-index 0.85; p&lt;0.001). There was no treatment interaction with anacetrapib. Conclusions: In patients with stable ASCVD, biomarkers of myocardial injury, hemodynamic stress, and inflammation provide incremental information for prediction of HHF. Future studies should address whether these patients are more likely to benefit from emerging HF preventive therapies.

Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.

Emerging Pharmacotherapy to Reduce Elevated Lipoprotein(a) Plasma Levels.

Lipoprotein(a) is a unique form of low-density lipoprotein. It is associated with a high incidence of premature atherosclerotic disease such as coronary artery disease, myocardial infarction, and stroke. Plasma levels of this lipoprotein and its activities are highly variable. This is because of a wide variability in the size of the apolipoprotein A moiety, which is determined by the number of repeats of cysteine-rich domains known as "kringles." Although the exact mechanism of lipoprotein(a)-induced atherogenicity is unknown, the lipoprotein has been found in the arterial walls of atherosclerotic plaques. It has been implicated in the formation of foam cells and lipid deposition in these plaques. Pharmacologic management of elevated levels of lipoprotein(a) with statins, fibrates, or bile acid sequestrants is ineffective. The newer and emerging lipid-lowering agents, such as the second-generation antisense oligonucleotides, cholesteryl ester transfer protein inhibitors, and proprotein convertase subtilisin/kexin type 9 inhibitors offer the most effective pharmacologic therapy.

The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats

We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds. Following multiple once daily oral administration of 14C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24 h after the last dose, there was a relatively high concentration of radioactivity in the mesenteric lymph nodes, liver, adrenal glands and fat. After the last dose to rats, the radioactivity was almost completely recovered in the urine and faeces, indicating that dalcetrapib is not retained in the body, probably due to the reversibility of the disulfide bonds despite being covalent bonds.

Bempedoic Acid: A Novel LDL Cholesterol-Lowering Agent.

Hypercholesterolemia is commonly associated with diabetes. In combination with diabetes, it puts patients at an increased risk for premature coronary heart disease and atherosclerosis (1). Lipoproteins are developed in one of two ways, via the exogenous or endogenous pathways. LDL cholesterol is a product of VLDL metabolism via the endogenous pathway. Levels of LDL in the plasma are determined by the rate of LDL production and clearance. The LDL production rate from VLDL depends on LDL receptor activity. High receptor activity leads to a decrease in LDL production. Alternatively, low LDL receptor activity leads to an increase in LDL production. These levels of receptors in the liver are regulated by the cholesterol content of the hepatocytes. If the content is low, LDL receptor activity increases to allow for the increased uptake of cholesterol. If the content is higher, LDL receptor activity is decreased, and the LDL uptake is diminished (2). Many medications are available today to manage hypercholesterolemia. The most commonly used are statins, fibrates, bile acid sequestrants, niacin, and dietary cholesterol uptake inhibitors. Less commonly used therapies for cholesterol management include PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, and apolipoprotein B-100 antisense oligonucleotides. None of these therapies have the same mechanism of action as the novel therapy bempedoic acid (Esperion Therapeutics). Bempedoic acid has been shown to significantly lower LDL cholesterol levels when added to maximally tolerated statin therapies compared with ???

Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease

Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown. To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease. A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020. Participants received evacetrapib, 130 mg/d, or matching placebo. The ACCELERATE trial found no significant benefit or harm of evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a). High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2 mg/L or more but not less than 2 mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2 mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rank P < .001) when hsCRP levels were 2 mg/L or more but not less than 2 mg/L. Sensitivity analyses in the ACCELERATE placebo-treated group yielded similar significant associations exclusively in the group with hsCRP of 2 mg/L or more. Elevated Lp(a) levels during treatment are related to CV death, MI, and stroke when hsCRP levels are 2 mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of lowering Lp(a) in patients with residual systemic inflammation despite receipt of optimal medical therapy. ClinicalTrials.gov Identifier: NCT01687998.

A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519.

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang’s distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia.

Apolipoprotein F: a natural inhibitor of cholesteryl ester transfer protein and a key regulator of lipoprotein metabolism.

The aim of this study is to highlight recent studies that have advanced our understanding of apolipoprotein F (ApoF) and its role in lipid metabolism. Previous studies showed that ApoF hepatic mRNA levels are suppressed by fat-enriched diets. Recent studies show this downregulation is mediated by agonist-induced binding of liver X receptor (LXR) and PPARalpha to a regulatory element in the ApoF promoter. First-of-kind in-vivo studies show ApoF lowers low-density lipoprotein levels and enhances reverse cholesterol transport in fat-fed hamsters. Diverse studies collectively provide compelling evidence that cholesteryl ester transfer protein (CETP) plays an important role in regulating lipid metabolism. Inhibiting CETP raises HDL cholesterol. However, considering the recent failures of pharmacological inhibitors of CETP in clinical trials, it does not seem likely that global inhibition of CETP will be beneficial. ApoF is a minor apolipoprotein that functions as a natural inhibitor of CETP. However, ApoF is not a general inhibitor of CETP, but rather it preferentially inhibits CETP activity with LDL. Therefore, ApoF tailors CETP activity so that less tissue-derived cholesterol traffics from HDL into the LDL compartment. Lower LDL cholesterol levels have recognized clinical benefit for reduced cardiovascular disease.

2D QSAR studies on a series of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one as CETP inhibitors

ABSTRACT Cardiovascular disease (CVD) is one of the major causes of human death. Preliminary evidence indicates that the inhibition treatment of Cholesteryl Ester Transfer Protein (CETP) causes the most pronounced increase in HDL cholesterol reported so far. Merck has disclosed certain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]−4-methyl-1,3-oxazolidin-2-one derivatives, which show potent CETP inhibitory activity. Therefore, it would be desirable to develop computational models to facilitate the screening of these inhibitors. In the present work, quantitative structure–activity relationship (QSAR) models have been developed to predict the therapeutic potency of 108 derivatives of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]−4-methyl-1,3-oxazolidin-2-one: Multiple Linear Regression (MLR), Support Vector Regression (SVR) and Feedforward Neural Network using Particle Swarm Optimization (FNN-PSO). Six descriptors were selected using genetic algorithms, whereas, internal and external validation of the models was performed according to all available validation strategies. It was shown that CETP inhibitory activity is mainly governed by electronegativity, the structure of the molecule, and the electronic properties. The best results were obtained with the SVR model. The results obtained may assist in the design of new CETP inhibitors.

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

OBJECTIVEIncident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome.RESEARCH DESIGN AND METHODSIn the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random).RESULTSAt baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.CONCLUSIONSIn patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial

BackgroundHigh-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL)...

Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery.

Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). Mounting evidence supports that HDLs are atheroprotective, therefore, many therapeutic approaches have been developed to increase HDL cholesterol (HDL-C) levels. Nevertheless, HDL-raising therapies, such as cholesteryl ester transfer protein (CETP) inhibitors, failed to ameliorate cardiovascular outcomes in clinical trials, thereby casting doubt on the treatment of cardiovascular disease (CVD) by increasing HDL-C levels. Therefore, HDL-targeted interventional studies were shifted to increasing the number of HDL particles capable of promoting ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. One such approach was the development of reconstituted HDL (rHDL) particles that promote ABCA1-mediated cholesterol efflux from lipid-enriched macrophages. Here, we explore the manipulation of rHDL nanoparticles as a strategy for the treatment of CVD. In addition, we discuss technological capabilities and the challenge of relating preclinical in vivo mice research to clinical studies. Finally, by drawing lessons from developing rHDL nanoparticles, we also incorporate the viabilities and advantages of the development of a molecular imaging probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear.

Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Potential of Lipoprotein(a)-Lowering Strategies in Treating Coronary Artery Disease.

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person's lifetime to identify those with inherited Lp(a) levels > 180mg/dL (> 430nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20-50%. AKCEA-APO(a)-LRX is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50-80%. A Phase III study with AKCEA-APO(a)-LRX will start in order to evaluate the effect on cardiovascular outcomes.

CETP inhibition in the REVEAL trial: could we aim higher?

CETP inhibition in the REVEAL trial: could we aim higher?

Impact of Baseline Glycemic Control on Residual Cardiovascular Riskin Patients With Diabetes Mellitus and High-Risk Vascular Disease Treated With Statin Therapy.

BackgroundThe contemporary impact of glycemic control on patients with diabetes mellitus at high cardiovascular risk remains unclear. We evaluated the utility of hemoglobin A1c (HbA1c) as a marker of risk on the composite end point of cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization in an optimally treated population with diabetes mellitus and established coronary artery 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.Methods and ResultsWe included all patients with established diabetes mellitus and measured HbA1c (N=8145) and estimated Kaplan‐Meier (KM) events rates, stratified by increasing baseline HbA1c levels censored at 30 months. We then performed a multivariable regression for the primary end point. Increasing baseline HbA1c was strongly associated with the occurrence of the primary end point (KM estimate, 12.6–18.2; P<0.001). Increasing baseline HbA1c was also associated with the triple end point of death, nonfatal myocardial infarction, and stroke (KM estimate, 7.8–11.3; P=0.003) as well as the individual end points of nonfatal myocardial infarction (KM estimate, 3.1–7.0; P<0.001), hospitalization for unstable angina (KM estimate, 1.8–5.0; P=0.003), and revascularization (KM estimate, 7.3–11.1; P=0.001), although not stroke (KM estimate, 1.4–2.4; P=0.45). The rates of cardiovascular mortality (KM estimate, 2.6–4.3; P=0.21) and all‐cause mortality (KM estimate, 4.8–5.9; P=0.21) were similar regardless of baseline HbA1c levels. When adjusting for relevant baseline characteristics, baseline HbA1c was an independent predictor for the primary end point (hazard ratio, 1.06; 95% CI, 1.02–1.11; P=0.003).ConclusionsGlycemic control, as measured by HbA1c, remains strongly and independently associated with cardiovascular outcomes in high‐risk patients with diabetes mellitus on statin therapy.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01687998.

Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial

High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Plasma Aldosterone Levels Are Not Associated With Cardiovascular Events Among Patients With High-Risk Vascular Disease: Insights From the ACCELERATE Trial.

BackgroundThe failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off‐target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable 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.Methods and ResultsWe included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow‐up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow‐up percentage change (13.6% [−29, 88] versus 17.9% [−24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow‐up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow‐up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics.ConclusionsExposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high‐risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.