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BackgroundThe randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.MethodsThere were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients.ResultsNone of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant.ConclusionsWe found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

BackgroundIn the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI).MethodsISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions.ResultsProcedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.

BackgroundExperimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.MethodsWe performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.ResultsA total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03).ConclusionsAmong patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).

Background Kidney function decreases during the lifetime, and this decline is a powerful predictor of both kidney and cardiovascular outcomes. Statins lower cardiovascular risk, which may relate to beneficial effects on kidney function. We studied whether atorvastatin influences kidney function decline and assessed the association between individual kidney function slopes and cardiovascular outcome. Methods and Results Data were collected from 6 large atorvastatin cardiovascular outcome trials conducted in patients not selected for having kidney disease. Slopes of serum creatinine reciprocals representing measures of kidney function change ([mg/dL]-1/y), were analyzed in 30 621 patients. Based on treatment arms, patients were categorized into 3 groups: placebo (n=10 057), atorvastatin 10 mg daily (n=12 763), and 80 mg daily (n=7801). To assess slopes, mixed-model analyses were performed for each treatment separately, including time in years and adjustment for study. These slopes displayed linear improvement over time in all 3 groups. Slope estimates for patients randomized to placebo or atorvastatin 10 mg and 80 mg were 0.009 (0.0008), 0.011 (0.0006), and 0.014 (0.0006) (mg/dL)-1/y, respectively. A head-to-head comparison of atorvastatin 10 and 80 mg based on data from 1 study ( TNT [Treating to New Targets]; n=10 001) showed a statistically significant difference in slope between the 2 doses ( P=0.0009). From a Cox proportional hazards model using slope as a predictor, a significant ( P

BackgroundHigher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants.MethodsAfter 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization.ResultsHigher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction.ConclusionsHigher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients.

BACKGROUND:Some studies have shown that body weight variability is a risk factor for cardiovascular events, but this has not been studied in subjects with diabetes mellitus. METHODS AND RESULTS:We measured intraindividual variations in body weight from baseline and follow-up visits in 6408 subjects with type 2 diabetes mellitus from 3 clinical trials. The primary end point, any coronary event, was a composite of coronary heart disease death, myocardial infarction, resuscitated cardiac arrest, coronary revascularization, and unstable or new-onset angina. After adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body weight variability, measured as average successive variability and used as a time-dependent covariate, was associated with an increase in the risk of any coronary event (hazard ratio, 1.08; 95% CI, 1.01-1.14; P=0.017), major coronary event (hazard ratio, 1.12; 95% CI, 1.04-1.20; P=0.002), any cardiovascular event (hazard ratio, 1.08; 95% CI, 1.03-1.14; P=0.0015), and death (hazard ratio, 1.16; 95% CI, 1.10-1.22; P

BACKGROUND:Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS:Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C

BackgroundHigher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events.ObjectiveThe purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease.MethodsWe assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9 years.ResultsIn the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11-1.21, P

It is not known whether the concentration of high-density lipoprotein (HDL) cholesterol is related to renal function in statin-treated patients. We therefore investigated whether HDL cholesterol levels predicted renal function in atorvastatin-treated patients in the TNT (Treating to New Targets) trial. A total of 9542 participants were included in this analysis. Renal function was assessed by estimated glomerular filtration rate (eGFR). HDL cholesterol levels at month 3 were used as this is the time point at which on-treatment HDL cholesterol levels became stable. Among 6319 participants with a normal eGFR (≥60 mL/min per 1.73 m2) at baseline, higher HDL cholesterol levels at month 3 were significantly associated with lower risk of decline in eGFR (ie, having eGFR

BackgroundProprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease.ObjectivesThe objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a).MethodsWe measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels

BackgroundBody-weight fluctuation is a risk factor for death and coronary events in patients without cardiovascular disease. It is not known whether variability in body weight affects outcomes in patients with coronary artery disease.MethodsWe determined intraindividual fluctuations in body weight from baseline weight and follow-up visits and performed a post hoc analysis of the Treating to New Targets trial, which involved assessment of the efficacy and safety of lowering low-density lipoprotein cholesterol levels with atorvastatin. The primary outcome was any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina). Secondary outcomes were any cardiovascular event (a composite of any coronary event, a cerebrovascular event, peripheral vascular disease, or heart failure), death, myocardial infarction, or stroke.ResultsAmong 9509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P=0.01), any cardiovascular event (2727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P

The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m2), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m2 1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.

Whether biomarkers associated with cardiovascular disease risk also predict incident diabetes mellitus (DM) is unknown. Our objective was to determine if a panel of 18 biomarkers previously associated with risk of cardiovascular disease also predicts incident DM in statin-treated patients with coronary artery disease (CAD). The Treating to New Targets (TNT) study is a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of coronary heart disease events. Fasting plasma levels of standard lipids and of 18 emerging CAD risk biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in a random sample of 1,424 TNT patients. After exclusion of patients with DM at baseline (n = 253), 101 patients developed DM during the median follow-up of 4.9 years. Patients with incident DM had lower levels of total and high-molecular weight adiponectin, lipoprotein-associated phospholipase A2 (Lp-PLA2), soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. In contrast, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with those without. Plasma levels of C-reactive protein, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro-B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with and without incident DM. After multivariate adjustment, total and high-molecular weight adiponectin as well as Lp-PLA2 were negatively associated with incident DM. Results of this study suggest that plasma lipids and some emerging CAD risk biomarkers, such as adiponectin and Lp-PLA2, may be useful for predicting incident DM in statin-treated patients with stable CAD.

AimsThe effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.Methods and resultsWe searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

BackgroundStatins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.MethodsWe used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.FindingsData were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).InterpretationThe increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.FundingThe funding sources are cited at the end of the paper.

AimHigh-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.ObjectiveTo investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).Design and settingA prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion.PatientsFive hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.InterventionPatients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.Main outcome measuresThe primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.ResultsThe nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.ConclusionCER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2;Trial registration numberNCT01201837.

Features of the metabolic syndrome are independent risk factors for new-onset diabetes mellitus (NODM) related to statin therapy. Obesity is the predominant underlying risk factor for the metabolic syndrome and diabetes mellitus. This study investigated whether change in body weight may predict NODM in statin-treated patients. A total of 7,595 patients without prevalent diabetes mellitus at baseline from the Treating to New Targets (TNT) study were included in this analysis. They were randomized to atorvastatin 10 or 80 mg/day and monitored for a median of 4.9 years. NODM developed in 659 patients (8.1% in the 10-mg group and 9.2% in the 80-mg group). There was a significant increase in body weight (0.9 kg, p

UnlabelledSeveral plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive of recurrent MCVEs (P ≤ 0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.Trial registrationClinicalTrials.gov NCT00327691.

ObjectivesThe purpose of this study was to compare the incidence of new-onset diabetes (NOD) with cardiovascular (CV) event reduction at different levels of NOD risk.BackgroundStatins reduce the number of CV events but increase the incidence of NOD. We previously reported that 4 factors independently predicted NOD: fasting blood glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body mass index >30 kg/m(2), and history of hypertension.MethodsWe compared NOD incidence with CV event reduction among 15,056 patients with coronary disease but without diabetes at baseline in the TNT (Treating to New Targets) (n = 7,595) and IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) (n = 7,461) trials. CV events included coronary heart disease death, myocardial infarction, stroke, and resuscitated cardiac arrest.ResultsAmong 8,825 patients with 0 to 1 of the aforementioned NOD risk factors at baseline, NOD developed in 142 of 4,407 patients in the atorvastatin 80 mg group and in 148 of 4,418 in the atorvastatin 10 mg and simvastatin 20 to 40 mg groups (3.22% vs. 3.35%; hazard ratio [HR]: 0.97; 95% confidence intervals [CI]: 0.77 to 1.22). Among the remaining 6,231 patients with 2 to 4 NOD risk factors, NOD developed in 448 of 3,128 in the atorvastatin 80 mg group and in 368 of 3,103 in the lower-dose groups (14.3% vs. 11.9%; HR: 1.24; 95% CI: 1.08 to 1.42; p = 0.0027). The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.ConclusionsCompared with lower-dose statin therapy, atorvastatin 80 mg/day did not increase the incidence of NOD in patients with 0 to 1 NOD risk factors but did, by 24%, among patients with 2 to 4 NOD risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both NOD risk groups.

ObjectiveThis study evaluated the success in attaining non-HDL-cholesterol (non-HDL-C) goals in the multinational L-TAP 2 study.Methods9955 patients ≥20 years of age with dyslipidemia on stable lipid-lowering therapy were enrolled from nine countries.ResultsSuccess rates for non-HDL-C goals were 86% in low, 70% in moderate, and 52% in high-risk patients (63% overall). In patients with triglycerides of >200 mg/dL success rates for non-HDL-C goals were 35% vs. 69% in those with ≤200 mg/dL (p < 0.0001). Among patients attaining their LDL-C goal, 18% did not attain their non-HDL-C goal. In those with coronary disease and at least two risk factors, only 34% and 30% attained respectively their non-HDL-C and LDL-C goals. Rates of failure in attaining both LDL-C and non-HDL-C goals were highest in Latin America.ConclusionsNon-HDL-C goal attainment lagged behind LDL-C goal attainment; this gap was greatest in higher-risk patients.

There is a well-established link between dyslipidemia and cardiovascular events, although this risk is modified by age. Little is known about how treatment of dyslipidemia and low-density lipoprotein (LDL) cholesterol goal attainment differ between older and younger patients. We obtained clinical data from 9,926 dyslipidemic patients across 9 countries in North and Latin America, Europe, and Asia from 2006 through 2007. Multivariate regressions were performed to determine predictors of lipid level goal attainment. The study sample consisted of 5,733 adults

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p