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Background: Statins increase T2D risk despite favorable effects on lipids, inflammation, and cardiovascular disease (CVD). Statins may modulate associations of T2D-related BCAAs with incident T2D. Methods: JUPITER (NCT00239681) randomized rosuvastatin vs. placebo for primary CVD prevention. Plasma BCAAs (isoleucine, leucine, valine) and alanine were quantified via NMR spectroscopy for n=12,441 at baseline and n=9,826 with repeat 12mo samples. We calculated % change in metabolites with mixed effects linear regression. We used Cox models to evaluate baseline and change (per SD) of metabolites with incident T2D (multivariable-adj HR [95%CI]) during 2y of follow-up (max. 5y). Results: Overall, statin vs. placebo increased T2D (HR 1.25 [95% CI: 1.05-1.49]). BCAA metabolites changed modestly at 12mo; only leucine differed with statin vs. placebo (+3.7% vs. +2.4%; p=0.03). Baseline BCAAs were associated with T2D. Each SD increase in isoleucine, leucine, valine, and alanine was associated with HR=1.3 (1.1-1.5), 1.1 (1.0, 1.3), 1.3 (1.1, 1.5), and 1.3 (1.1, 1.5) greater T2D risk (FIGURE). Associations did not differ with statin vs. placebo. Conclusion: High-intensity statin therapy had at most modest effects on BCAA metabolites. Baseline and change in BCAAs and alanine were associated with T2D, including during randomized statin therapy. Disclosure D. K. Tobias: None. P. Ridker: Consultant; Self; 360 Marketing Strategic Services, AstraZeneca, Corvidia Therapeutics, CSL Behring, DalCor Pharmaceuticals, Novartis AG, Omeicos, Flame, Uppton, Agepha, sIRNAomics, Research Support; Self; Amarin Corporation plc, Kowa Pharmaceuticals America, Inc., Novo Nordisk. R. Glynn: Research Support; Self; AstraZeneca, Kowa Research Institute, Inc., Novartis AG, Pfizer Inc. S. Mora: Consultant; Self; Pfizer Inc., Quest Diagnostics, Other Relationship; Self; LabCorp. Funding American Diabetes Association (1-19-JDF-115 to D.K.T.); Brigham and Women’s Hospital (to D.K.T.); National Institutes of Health (R01HL117861, R01HL134811, K24HL136852, R01DK112940 to S.M.); LabCorp

The anti-inflammatory effects of statins have likely not been used to their fullest extent, particularly in reducing venous thromboembolic events. Current therapy for thrombotic events hinges on anticoagulation via heparin, warfarin or new oral anticoagulants. Interventional procedures with thrombectomy may also play a critical role. Unfortunately, thrombotic events can occur and recur despite meticulous anticoagulation therapy. Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE), two complicated and prevalent diseases that can cause chronic disease states such as post-thrombotic syndrome (PTS). In 2009 the JUPITER trial demonstrated that rosuvastatin may be effective when dealing with vascular inflammation by providing an anti-inflammatory effect. Multiple subsequent studies have looked at this association with some promising findings. The mechanism of action for statins is not entirely understood but there has been a variety of proposals and subsequent testing of inflammatory biomarkers. Additional prospective trials are needed to confirm the possible benefit of VTE reduction through an anti-inflammatory effect, but if this can be shown then statins may become a safe adjunctive therapy for VTE prevention.

TPS3141 Background: The human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. Despite its considerable therapeutic potential, the evidence is not yet mature enough for use as treatment in clinical practice. To address this unmet clinical need, we have designed an organ-agnostic basket trial, which covers a variety of solid cancers harboring HER2 amplification. Methods: JUPITER trial is a Japanese multicenter, single-arm, phase 2 basket study of combination therapy with trastuzumab and pertuzumab. Patients with solid cancers harboring HER2 amplification, who have progressed with standard treatment, or rare cancers for which there is no standard treatment, are eligible. Types of cancer include bile duct, urothelial, uterine, ovarian, and other solid cancers that HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. Target sample size is 38. All enrolled patients receive combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unacceptable toxicity, death, or withdrawal of informed consent. Response assessment using RECIST version 1.1 is performed at weeks 9 and 17, followed by every 12 weeks. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, duration of response, and safety. In total, 40 patients were enrolled by June 2020. Data fix is scheduled in September 2021. Trial registration: jRCT2031180150 Clinical trial information: jRCT2031180150.

Our study explored the application of methods to generalize randomized controlled trial results to a target population without individual-level data. We compared 4 methods using aggregate data for the target population to generalize results from the international trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), to a target population of trial-eligible patients in the UK Clinical Practice Research Datalink (CPRD). The gold-standard method used individual data from both the trial and CPRD to predict probabilities of being sampled in the trial and to reweight trial participants to reflect CPRD patient characteristics. Methods 1 and 2 used weighting methods based on simulated individual data or the method of moments, respectively. Method 3 weighted the trial's subgroup-specific treatment effects to match the distribution of an effect modifier in CPRD. Method 4 calculated the expected absolute benefits in CPRD assuming homogeneous relative treatment effect. Methods based on aggregate data for the target population generally yielded results between the trial and gold-standard estimates. Methods 1 and 2 yielded estimates closest to the gold-standard estimates when continuous effect modifiers were represented as categorical variables. Although individual data or data on joint distributions remains the best approach to generalize trial results, these methods using aggregate data might be useful tools for timely assessment of randomized trial generalizability.

Background— Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo. Methods and Results— In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility–measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88–1.21). In contrast, associations with CVD events were observed for baseline non–high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01–1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11–1.48), and ion mobility–measured non-HDL particles (HR, 1.19; 95% CI, 1.05–1.35) and LDL particles (HR, 1.21; 95% CI, 1.07–1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility–measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk. Conclusions— In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility–measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

We read with interest the correspondence of Lai .1 Whether statin therapy impacts the risk of osteoporosis is still a matter of debate. We have recently shown that there is a dose-dependent relationship between statins and diagnosis of osteoporosis; while low-dose statin treatment was related to an underrepresentation of diagnosed osteoporosis when compared with non-statin-treated patients, we found in patients on higher dosages of statins an overrepresentation of diagnosed osteoporosis in the general Austrian population.2 Although osteoporosis is often underdiagnosed until incident fractures, our data are based on diagnoses derived from in-patient treatment. Even though there are data available suggesting that some statins could have protective effects on osteoporosis,3 in the JUPITER trial, an international, randomised, double-blind and placebo-controlled study in which 17 802 patients were investigated, it has been shown that high-potency statin treatment did not reduce the risk of fractures.4 The fact that statin treatment might not only have positive …

Background Although lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial. Objectives This study examined the association and clinical utility of Lp(a) with incident CVD in women. Methods A turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women’s Health Study] [N = 24,558], a case-cohort sample from the WHI [Women’s Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification. Results In the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER. Conclusions In 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents.

Background Levels of LDL (low‐density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid‐related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. Methods and Results We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low‐density lipoprotein) particle subclasses in 11 984 JUPITER trial participants ( NCT 00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95% CI ] per SD increment) among placebo‐allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non–high‐density lipoprotein cholesterol, and triglycerides, but not LDL‐c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On‐statin levels of the smallest VLDL particle subclass were associated with a 68% per‐ SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk—this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C‐index 0.780 versus 0.712; P CATHGEN ), similar patterns of lipoprotein‐related risk were observed. Conclusions Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00239681.

Previously, we showed that sex-specific complete blood count (CBC) risk scores strongly predicted risk of all-cause mortality in multiple sets of general medical patients. This study evaluated the CBC risk score in an independent, well-studied international primary risk population of lower-risk individuals initially free from cardiovascular (CV) disease.Observational secondary analysis of a randomized trial population.The previously derived and validated CBC score was evaluated for association with all-cause mortality among CV disease-free females (n = 6568) and males (n = 10,629) enrolled for up to 5 years in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Associations of the CBC score with CV mortality and with major CV disease were also tested.The CBC score predicted all-cause mortality, with univariable hazard ratio (HR) 4.83 (95% CI 3.70-6.31) for the third CBC score tertile vs. the first tertile, and HR 2.31 (CI 1.75-3.05) for the second tertile (p trend 0.001). The CBC score retained significance after adjustment: HR 1.97 (CI 1.46-2.67) and 1.51 (CI 1.13-2.00) for tertiles 3 and 2 vs. 1, respectively (p trend 0.001). The CBC score also predicted CV mortality (p trend = 0.025) and the primary JUPITER endpoint (p trend = 0.015). c-statistics for mortality were 0.729 among all, and 0.722 and 0.750 for females and males, respectively.The CBC risk score was strongly associated with all-cause mortality among JUPITER trial participants and had good discrimination. It also predicted CV-specific outcomes. This CBC score may be useful in identifying cardiac disease-free individuals at increased risk of mortality.

Statins are indicated in patients with elevated levels of high-sensitivity C-reactive protein and normal low-density lipoprotein cholesterol based on results of the multicountry trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (2003-2008), but the benefit in real-world populations remains unknown. We sought to generalize JUPITER results to trial-eligible population using data from the UK Clinical Practice Research Datalink (CPRD), 2001-2014. We multiply imputed missing baseline characteristics for the CPRD population and selected the trial-eligible participants as the target population based on observed and imputed values. Trial participants were weighted to be representative of the CPRD population (n = 383,418) based on individual predicted probability of selection into the trial. Trial participants were also standardized to the CPRD population without missing values (n = 2,677). In JUPITER, rosuvastatin reduced cardiovascular risk with a 3-year risk difference of -2.0% (95% confidence interval (CI): -2.9, -1.1). The rosuvastatin effect was muted in the first 2 years but remained strong at 3 years after standardizing to the imputed CPRD population (3-year risk difference = -2.7%; 95% CI: -5.8, 0.4) and the CPRD population without missing data (3-year risk difference = -1.7%; 95% CI: -3.5, 0.1). The study serves as an illustration of possible approaches to understanding generalizability of trials using real-world databases given limitations due to missing data on inclusion/exclusion criteria.

Since the publication of the JUPITER trial, attention has been focused on the adverse glycemic effects of statin therapy. Although the modest increase in the risk of new diabetes mellitus is outweighed by the reduction in cardiovascular events for statins, emerging biochemical and genetic links between lipid metabolism and glycemic control raise the prospect of a broader diabetogenic effect of lipid-lowering therapies. For the novel and powerful PCSK9-inhibitor class available evidence does not support a major glycaemic effect with the results of large scale trials awaited although preliminary genetic data does suggest a link. In contrast, there is clear evidence of a diabetogenic effect for the now outdated but well-studied niacin. For ezetimibe and fibrates, evidence is scarce but currently broadly unconcerning. For now, the glycemic effects of lipid-lowering therapies should have a limited influence on clinical decision-making. Further study in this topical area is needed.

Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy.In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1, which encodes organic anion-transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia.Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism.There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.

Background: Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. Methods: HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. Results: Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r = 0.39, 0.48, and 0.39 respectively; P P P =0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66–1.02; P =0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67–1.03; P =0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change −1.5%, 95% CI, −13.3 to +10.2; P =0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42–0.92; P =0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33–0.77; P Conclusions: In JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

Background GlycA, a novel protein glycan biomarker of N ‐acetyl side chains of acute‐phase proteins, was recently associated with incident cardiovascular disease ( CVD ) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown. Methods and Results In the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin ( JUPITER ) trial ( NCT 00239681), participants with low‐density lipoprotein cholesterol CRP ) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow‐up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD : multivariable‐adjusted hazard ratio ( HR ) per SD increment, 1.20 (95% CI , 1.08–1.34; P =0.0006). After additionally adjusting for hs CRP , this was slightly attenuated (HR, 1.18; 95% CI , 1.04–1.35; P =0.01). On‐treatment GlycA levels were also associated with CVD ; corresponding multivariable‐adjusted HR s per SD before and after additionally adjusting for hs CRP : 1.27 (95% CI , 1.13–1.42; P CI , 1.07–1.44; P =0.004), respectively. Tests for heterogeneity by treatment arm were not significant ( P for interaction, >0.20). Conclusion In the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hs CRP . Clinical Trials Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00239681.

Importance Statins decrease levels of low-density lipoprotein (LDL) and triglycerides as well as cardiovascular events but increase the risk for a diagnosis of type 2 diabetes mellitus (T2DM). The risk factors associated with incident T2DM are incompletely characterized. Objective To investigate the association of lipoprotein subclasses and size and a novel lipoprotein insulin resistance (LPIR) score (a composite of 6 lipoprotein measures) with incident T2DM among individuals randomized to a high-intensity statin or placebo. Design, Setting, and Participants This secondary analysis of the JUPITER trial (a placebo-controlled randomized clinical trial) was conducted at 1315 sites in 26 countries and enrolled 17 802 men 50 years or older and women 60 years or older with LDL cholesterol levels less than 130 mg/dL, high-sensitivity C-reactive protein levels of at least 2 mg/L, and triglyceride levels less than 500 mg/dL. Those with T2DM were excluded. A prespecified secondary aim was to assess the effect of rosuvastatin calcium on T2DM. Incident T2DM was monitored for a median of 2.0 years. Data were collected from February 4, 2003, to August 20, 2008, and analyzed (intention-to-treat) from December 1, 2013, to January 21, 2016. Interventions Rosuvastatin calcium, 20 mg/d, or placebo. Main Outcomes and Measures Size and concentration of lipids, apolipoproteins, and lipoproteins at baseline (11 918 patients with evaluable plasma samples) and 12 months after randomization (9180 patients). The LPIR score, a correlate of insulin resistance, was calculated as a weighted combination of size and concentrations of LDL, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) particles. Results Among the 11 918 patients (4334 women [36.4%]; median [interquartile range] age, 66 [60-71] years), rosuvastatin lowered the levels of LDL particles (−39.6%; 95% CI, –49.4% to –24.6%), VLDL particles (−19.6%; 95% CI, −40.6% to 10.3%), and VLDL triglycerides (−15.2%; 95% CI, −35.9% to 11.3%) and shifted the lipoprotein subclass distribution toward smaller LDL size (−1.5%; 95% CI, −3.7% to 0.5%), larger VLDL size (2.8%; 95% CI, −5.8% to 12.7%), and lower LPIR score (−3.2%; 95% CI, −20.6% to 16.9%). In analyses adjusted for age, sex, race or ethnic origin, exercise, educational level, family history, and smoking, the hazard ratio (HR) for T2DM per SD of LPIR score in the placebo arm was 1.99 (95% CI, 1.64-2.42); in the rosuvastatin arm, 2.06 (95% CI, 1.74-2.43). After additional adjustment for systolic blood pressure, body mass index, high-sensitivity C-reactive protein, hemoglobin A1c, HDL cholesterol, LDL cholesterol, and triglycerides, the LPIR score remained associated with T2DM in the placebo arm (HR, 1.35; 95% CI, 1.03-1.76) and rosuvastatin arm (HR, 1.60; 95% CI, 1.27-2.03). Similar trends were seen at 12 months. The LPIR score improved the model likelihood ratio (χ2 = 18.23;P Conclusions and Relevance In apparently healthy people, LPIR score was positively associated with incident T2DM, including during rosuvastatin therapy. Trial Registration clinicaltrials.gov Identifier:NCT00239681

Purpose To examine HMG-CoA reductase inhibitor (statin) drug dispensing patterns to Nova Scotia Seniors' Pharmacare program (NSSPP) beneficiaries over a 14-year period in response to: 1) rosuvastatin market entry in 2003, 2) JUPITER trial publication in 2008, and 3) generic atorvastatin availability in 2010. Methods All NSSPP beneficiaries who redeemed at least one prescription for a statin from April 1, 1999 to March 31, 2013 were included. Aggregated, anonymous monthly prescription counts were extracted by the Nova Scotia Department of Health and Wellness (Nova Scotia, Canada) and changes in dispensing patterns of statins were measured. Data were analyzed using descriptive analyses and interrupted time series methods. Results The percentage of NSSPP beneficiaries dispensed any statin increased from 5.3% in April 1999 to 20.7% in March 2013. In 1999, most NSSPP beneficiaries were dispensed either simvastatin (29.5%) or atorvastatin (28.7%). When rosuvastatin was added to the NSSPP Formulary in August 2003, prescriptions dispensed for simvastatin, lovastatin, pravastatin, and fluvastatin declined significantly (slope change, -0.0027; 95% confidence interval (CI), (-0.0046, -0.0009)). This significant decline continued following the publication of JUPITER (level change, -0.1974; 95% CI, (-0.2991, -0.0957)) and the availability of generic atorvastatin (level change, -0.2436; 95% CI, (-0.3314, -0.1558)). Atorvastatin was not significantly affected by any of the three interventions, although it maintained an overall decreasing trend. Only upon the availability of generic atorvastatin did the upward trend in rosuvastatin use decrease significantly (slope change, -0.0010, 95% CI, (-0.0015, -0.0005)). Conclusions The type and rate of statins dispensed to NSSPP beneficiaries changed from 1999 to 2013 in response to the availability of new agents and publication of the JUPITER trial. The overall proportion of NSSPP beneficiaries dispensed a statin increased approximately 4-fold during the study period. In 2013, rosuvastatin was the most commonly dispensed statin (44.1%) followed by atorvastatin (39.1%).

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk., Circulating metabolites reflect human health and disease. Here, Kettunen et al. perform a genome-wide association study on 123 circulating metabolic traits and identify novel genetic loci influencing systemic metabolism. They also link new molecular pathways with a known cardiovascular risk factor Lp(a).

BACKGROUND Although lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with cardiovascular events, Lp-PLA2 is physically linked to LDL cholesterol (LDL-C). Whether measures of Lp-PLA2 mass or activity continue to predict risk after LDL-C reduction by statin therapy is uncertain. METHODS Lp-PLA2 mass concentration and activity were evaluated at baseline and after treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial comparing rosuvastatin 20 mg to placebo among 17 802 men and women without cardiovascular disease or diabetes at study entry. The relationships of Lp-PLA2 mass and activity with risk of future vascular events were evaluated in the placebo and rosuvastatin groups. RESULTS Before randomization, levels of Lp-PLA2 mass and activity correlated moderately with each other and with LDL-C. The magnitude of these correlations increased after statin therapy. Rosuvastatin reduced Lp-PLA2 mass by 33.8%, Lp-PLA2 activity by 33.2%, and LDL-C by 48.7% (all P < 0.0001). Among those study participants allocated to placebo, increasing quartiles of Lp-PLA2 activity (Ptrend = 0.04) but not Lp-PLA2 mass (Ptrend = 0.92) were associated with incident cardiovascular events after adjustment for LDL-C and conventional risk factors. Comparable analyses conducted among those allocated to rosuvastatin revealed no significant relationship between Lp-PLA2 levels and subsequent vascular events. The ability of rosuvastatin to reduce vascular events was not significantly modified by baseline Lp-PLA2 level. CONCLUSIONS Among JUPITER trial participants allocated to placebo, levels of Lp-PLA2 activity, but not mass, were associated with cardiovascular risk. However, Lp-PLA2 no longer predicted risk or modified clinical outcomes when participants were treated with rosuvastatin.

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the anti-inflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.

Background— In statin trials, each 20 mg/dL reduction in cholesterol results in a 10–15% reduction of annual incidence rates for vascular events. However, interindividual variation in low-density lipoprotein cholesterol (LDL-C) response to statins is wide and may partially be determined on a genetic basis. Methods and Results— A genome-wide association study of LDL-C response was performed among a total of 6989 men and women of European ancestry who were randomly allocated to either rosuvastatin 20 mg daily or placebo. Single nucleotide polymorphisms (SNPs) for genome-wide association ( P −8 ) with LDL-C reduction on rosuvastatin were identified at ABCG2 , LPA , and APOE , and a further association at PCSK9 was genome-wide significant for baseline LDL-C and locus-wide significant for LDL-C reduction. Median LDL-C reductions on rosuvastatin were 40, 48, 51, 55, 60, and 64 mg/dL, respectively, among those inheriting increasing numbers of LDL-lowering alleles for SNPs at these 4 loci ( P trend=6.2×10 −20 ), such that each allele approximately doubled the odds of percent LDL-C reduction greater than the trial median (odds ratio, 1.9; 95% confidence interval, 1.8–2.1; P =5.0×10 −41 ). An intriguing additional association with sub–genome-wide significance ( P -6 ) was identified for statin related LDL-C reduction at IDOL , which mediates posttranscriptional regulation of the LDL receptor in response to intracellular cholesterol levels. In candidate analysis, SNPs in SLCO1B1 and LDLR were confirmed as associated with LDL-C lowering, and a significant interaction was observed between SNPs in PCSK9 and LDLR . Conclusions— Inherited polymorphisms that predominantly relate to statin pharmacokinetics and endocytosis of LDL particles by the LDL receptor are common in the general population and influence individual patient response to statin therapy.

Background: Evidence from observational studies have raised the possibility that statin treatment reduces the incidence of certain bacterial infections, particularly pneumonia. We analyzed data from a randomized controlled trial of rosuvastatin to examine this hypothesis. Methods: We analyzed data from the randomized, double-blind, placebo-controlled JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). In this trial, 17 802 healthy participants (men 50 years and older and women 60 and older) with a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater were randomly assigned to receive either rosuvastatin or placebo. We evaluated the incidence of pneumonia on an intention-to-treat basis by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments. Results: Among 17 802 trial participants followed for a median of 1.9 years, incident pneumonia was reported as an adverse event in 214 participants in the rosuvastatin group and 257 in the placebo group (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.69–1.00). In analyses restricted to events occurring before a cardiovascular event, pneumonia occurred in 203 participants given rosuvastatin and 250 given placebo (HR 0.81, 95% CI 0.67–0.97). Inclusion of recurrent pneumonia events did not modify this effect (HR 0.81, 95% CI 0.67–0.98), nor did adjustment for age, sex, smoking, metabolic syndrome, lipid levels and C-reactive protein level. Interpretation: Data from this randomized controlled trial support the hypothesis that statin treatment may modestly reduce the incidence of pneumonia. (ClinicalTrials.gov trial register no. NCT0023968.)

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin. The effects of statins on thrombosis are unclear, prompting this literature review. A literature search was performed (1950 to February 2011) with MEDLINE, EMBASE, and PUBMED databases including the following keywords: "statins", "hydroxymethylglutaryl-CoA reductase inhibitors", "VTE", "PE", "DVT", and either "anti-coagulation" or "inflammation". Editorials, reviews, case reports, meta-analysis and duplicates were excluded. Inflammatory biomarkers of DVT, include interleukin (IL)-6, CRP, IL-8, and monocyte chemotactic protein 1 (MCP-1). Statin therapy reduces IL-6 expression of CRP and MCP-1, usually elevated in VTE. Reduction of IL-6 induced MCP-1 has been linked to vein wall fibrosis, promoting post thrombotic syndrome (PTS) and recurrent DVT in patients. Also, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. This work supports that statin therapy has the ability to decrease the incidence and recurrence of VTE and the potential to decrease PTS. This is mainly due to the anti-inflammatory effects of statins and may explain why normolipidemic patients, with elevated CRP, appear to have the greatest reduction in VTE. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential.

BACKGROUND Although statin therapy is known to increase concentrations of PCSK9, whether this effect is related to the magnitude of LDL reduction is uncertain. This study was undertaken to understand the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol (LDL-C) reduction. METHODS We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 year in 500 men and 500 women participating in the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial that randomly allocated participants to rosuvastatin 20 mg daily or placebo. We also evaluated rs11591147, a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations. RESULTS At baseline, median (interquartile range) PCSK9 concentrations were higher in women [73 (62–90)] ng/mL than in men [69 (57–81) ng/mL] (P < 0.005). During 1 year, there was no change in PCSK9 concentrations in the placebo arm, suggesting stability in time. In contrast, the rosuvastatin increased PCSK9 by 35% in women [101 (82–117) ng/mL] and 28% in men [89 (71–109) ng/mL] (P < 0.0001). Among those allocated to rosuvastatin, greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales (r = −0.15, P < 0.0005). Furthermore PCSK9 (rs11591147) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use. CONCLUSIONS In this randomized trial, rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction; the LDL-C response to statin could not be inferred by PCSK9 concentrations.

Aims Increasing evidence supports a role for inflammation in promoting atrial fibrillation (AF) and statins have anti-inflammatory effects that may be relevant for the prevention of AF. However, studies of statin therapy and incident AF have yielded mixed results and not focused on individuals with an underlying pro-inflammatory response. We studied whether high-sensitivity C-reactive protein is associated with incident AF and whether treatment with rosuvastatin is associated with a lower incidence of AF compared with placebo. Methods and results We randomized men and women with LDL cholesterol

This study estimated the long-term health outcomes, healthcare costs, and cost-effectiveness of rosuvastatin 20 mg therapy in primary prevention of major cardiovascular disease (CVD) in a Swedish population.Based on data from the JUPITER trial, long-term CVD outcomes with rosuvastatin vs no active treatment were estimated for patients with an elevated baseline CVD risk (Framingham CVD score20%, sub-population of JUPITER population) and for a population similar to the total JUPITER population. Using a decision-analytic model, trial CVD event rates were combined with epidemiological and cost data specific for Sweden. First and subsequent CVD events and death were estimated over a lifetime perspective. The observed relative risk reduction was extrapolated beyond the trial duration. Incremental effectiveness was measured as life-years gained (LYG) and quality-adjusted life-years (QALYs) gained.Treating 100,000 patients with rosuvastatin 20 mg was estimated to avoid 14,692 CVD events over the lifetime (8021 non-fatal MIs, 3228 non-fatal strokes, and 4924 CVD deaths) compared to placebo. This translated into an estimated gain of 42,122 QALYs and 36,865 total life years (LYG). Rosuvastatin was both more effective and less costly over a lifetime perspective, and rosuvastatin is subsequently a dominant alternative compared to no treatment in the assessed population. Using the overall JUPITER population, rosuvastatin was dominant for the lifetime horizon. In the sensitivity analysis, rosuvastatin was the dominant treatment strategy over a 20-year time horizon, and cost-effective with an incremental cost-effectiveness ratio (cost per QALY) of SEK 1783 over a 10-year time horizon.Some model inputs were derived from literature or other data sources, but uncertainty was controlled by sensitivity analyses.Results indicate that rosuvastatin 20 mg treatment is a cost-effective option vs no-treatment in patients with Framingham CVD risk20% in Sweden and might even be cost saving if taking a long-term perspective.

Perhaps no recent trial in primary prevention of cardiovascular disease has resulted in more controversy than the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, which was first published in 2008. The study evaluated a patient cohort previously considered to be "healthy," ie, men 50 years of age or older and women 60 years of age or older, who did not have a history of cardiovascular disease and, at the initial screening visit, had a low-density lipoprotein cholesterol level of130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level ≥2.0 mg/L. The trial showed that rosuvastatin is a powerful statin that, at lower doses, can reduce low-density lipoprotein cholesterol to levels previously not seen with other agents. Concurrently, it can also reduce high-sensitivity C-reactive protein to levels below what are considered normal, but that might be more physiologic. In the trial participants who achieved such lowering, major cardiovascular events, including venous thromboembolic events, were reduced even in the short term. Despite these results, many still question whether the trial results should influence high-sensitivity C-reactive protein testing or the prescription of statins for individuals at low risk for cardiovascular disease.

The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values.950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1-100, or100). We calculated 5-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata.Median follow-up was 5·8 years (IQR 5·7-5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1-100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99-9·25) for coronary heart disease, and of 2·57 (1·48-4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment.CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources.National Institutes of Health-National Heart, Lung, and Blood Institute.

Statins, belonging to a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleiotropic properties, such as anti-inflam- matory action. The purpose of this study was to evaluate the antinociceptive and anti-inflammatory effects of simvastatin in five models of nociceptive behaviour. Oral gavage administration of simvastatin induced a dose-dependent inhibition of noci- ception for 1 day in the acetic acid writhing (ED50 = 5.59 € 0.07), tail-flick (ED50 = 112.96 € 8.00), hot-plate (ED50 = 134.87 € 2.20), formalin hind paw (ED50 = 19.86 € 1.12 in phase I and 23.30 € 2.05 in phase II) and orofacial formalin (ED50 = 5.54 € 2.74 in phase I and 11.48 € 1.88 in phase II) tests. However, after 3 days, the values were in the acetic acid writhing (ED50 = 6.14 € 0.51), tail-flick (ED50 = 154 € 8.88), hot-plate (ED50 = 136.14 € 2.94), formalin hind paw (ED50 = 15.93 € 0.42 in phase I and 17.10 € 1.80 in phase II) and orofacial formalin (ED50 = 6.79 € 0.66 in phase I and 5.80 € 1.49 in phase II) tests. This study demonstrated the antinociceptive and anti-inflammatory activities of simvastatin in five models of tonic or phasic pain. These actions seem to be related to the inhibition of cytokine and prostanoid release and stimulation of nitric oxide synthesis. A possible clinical role of simvastatin could be related to the potentially beneficial effects in the neuropathic pain, and by their pleiotropic properties, they could play a clinical role in anti-inflammatory disease. Statins, a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleio- tropic properties, including a slight anti-inflammatory action. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacoki- netic profiles and lipid-modifying efficacy. The overall con- clusion of the recent JUPITER trial study was that statins had anti-inflammatory properties independent of their ability to lower cholesterol (1).

Background— Hypothesis-generating data raise the possibility that carriers of the kinesin-like protein 6 ( KIF6 ) 719 arginine (Arg) allele preferentially benefit from statin therapy, and, on this basis, a commercial assay for KIF6 has been developed. Methods and Results— In the recently completed JUPITER trial, men and women without prior cardiovascular disease or diabetes who had baseline low-density lipoprotein cholesterol KIF6 719Arg allele on outcomes in this primary prevention trial, both among Caucasian participants and in the trial as a whole. Among 8781 Caucasian trial participants, we observed no increase in vascular event rates among carriers of the KIF6 719Arg allele as compared with noncarriers (hazard ratio, 0.91; 95% confidence interval, 0.66 to 1.26) nor any difference in percent low-density lipoprotein cholesterol reduction with rosuvastatin according to genotype (−52 versus −52 mg/dL, P =0.11). Rosuvastatin allocation was associated with an almost identical reduction in the trial primary end point among carriers (hazard ratio, 0.61; 95% confidence interval, 0.43 to 0.87) as among noncarriers (hazard ratio, 0.59; 95% confidence interval, 0.39 to 0.88) ( P -interaction=0.90). Genotype had no impact on rosuvastatin efficacy in further analyses that included all-cause mortality, in analyses conducted in the total trial cohort that adjusted for race, or in analyses using generalized models of inheritance rather than recessive models. Conclusions— In the large primary prevention JUPITER trial, rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the KIF6 719Arg allele. Thus, at least for rosuvastatin, there appears to be no clinical utility to screening for KIF6 genotype as a method to determine vascular risk or to predict statin efficacy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

Objectives The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels Background The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain. Methods A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C Results During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C Conclusions Among adults with LDL-C

Much controversy surrounds the use of high-sensitivity C-reactive protein (hs-CRP) as a marker of cardiovascular (CV) risk. Although data regarding the association of hs-CRP with CV disease is extensive and consistent, its role in clinical practice remains unclear. The American Heart Association (AHA) recently published a scientific statement regarding criteria for evaluation of novel markers of CV risk. This article provides a comprehensive review of data regarding hs-CRP as a risk marker for CV disease in the context of these AHA criteria. The impact of the JUPITER trial on the utility of hs-CRP as a risk marker is emphasized. The review concludes with an evidence-based statement regarding the current role of hs-CRP in CV risk prediction.

There is still some disagreement about how dyslipidemia should be treated in particular population groups. This article provides a review of indications for lipid-lowering treatment, preferably for primary prevention, in specific groups of patients: women, the elderly, and those with an HIV infection, chronic kidney disease or metabolic syndrome. Special emphasis is placed on data obtained in the JUPITER trial and in other studies of rosuvastatin.

Rosuvastatin (Crestor®) is an HMG-CoA reductase inhibitor (statin) that has both lipid-lowering and anti-inflammatory effects. The drug has various indications in the US, including the primary prevention of cardiovascular disease (CVD) in patients with no clinical evidence of coronary heart disease who are at increased risk of CVD based on their age, a high-sensitivity C-reactive protein (hsCRP) level of ≥2 mg/L, and at least one other CVD risk factor. The efficacy of rosuvastatin in apparently healthy women (aged ≥60 years) or men (aged ≥50 years) with normal low-density lipoprotein cholesterol (LDL-C) levels and elevated hsCRP levels was demonstrated in the large, randomized, double-blind, multinational, JUPITER trial. Relative to placebo, rosuvastatin 20 mg once daily for a median follow-up of 1.9 years significantly reduced the occurrence of first major cardiovascular events in this trial (primary endpoint). A between-group difference in favor of rosuvastatin was also demonstrated for various other endpoints, including overall deaths and the nonatherothrombotic endpoint of venous thromboembolism. Rosuvastatin remained more effective than placebo when primary endpoint results were stratified according to various baseline factors, including in patient subgroups thought to be at low risk of CVD. In addition, rosuvastatin was associated with reductions in LDL-C and hsCRP levels, and these reductions appeared to occur independently of each other. The greatest clinical benefit was observed in rosuvastatin recipients achieving an LDL-C level of

Aims On the basis of the JUPITER trial, European health authorities recently approved the use of rosuvastatin to reduce first major cardiovascular events among ‘high' global risk primary prevention patients defined either by Framingham risk score >20% or European systematic coronary risk evaluation (SCORE) ≥5%. However, as these are post hoc analyses, data describing these subgroups have not previously been available to the clinical community. Methods and results We randomized 17 802 apparently healthy men aged ≥50 and women ≥60 with low-density lipoprotein cholesterol (LDL-C) 20% or SCORE risk ≥5%. During 1.8-year median follow-up (maximum 5 years) of patients with Framingham risk >20%, the rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.27–0.93, P = 0.028]. Among patients with SCORE risk ≥5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age ≥65 years (HR: 0.57, 95% CI: 0.43–0.78, P = 0.0003) and rates were 5.9 and 12.7 when risk for age was capped at 65 years (HR: 0.47, 95% CI: 0.32–0.68, P < 0.0001). Conclusion In primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk ≥5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events. ClinicalTrial.gov Identifier: NCT00239681

This study assessed the long-term cost effectiveness of rosuvastatin therapy compared with placebo in reducing the incidence of major cardiovascular (CVD) events and mortality.A probabilistic Monte Carlo simulation model estimated long-term cost effectiveness of rosuvastatin therapy (20 mg daily) for the prevention of CVD mortality and morbidity. The model included three stages: (1) CVD prevention simulating the 4 years of the JUPITER trial, (2) initial CVD prevention beyond the trial, and (3) subsequent CVD event prevention. A US payer perspective was assessed reflecting direct medical costs, and up to a lifetime horizon. Sensitivity analyses tested the robustness of the model estimates.For a hypothetical cohort of 100,000 patients at moderate and high risk of CVD events based on Framingham risk of ≥10%, estimated quality-adjusted life-years (QALYs) gained with rosuvastatin therapy compared with placebo was 33,480 over a lifetime horizon, and 25,380 and 9916 over 20-year and 10-year horizons, respectively. Approximately 12,073 events were avoided over the lifetime; 6,146 non-fatal MIs, 2905 non-fatal strokes, and 4030 CVD deaths avoided. Estimated incremental cost-effectiveness ratio (ICER) for cost per QALY was $7062 (lifetime), $10,743 (20-year horizon), and $44,466 (10-year horizon). For a hypothetical cohort similar to the overall JUPITER population, the cost per QALY ICER was $11,025 for the lifetime and $60,112 for a 10-year horizon.The cost-effectiveness comparison of rosuvastatin 20 mg was against no active treatment (as opposed to an alternative statin) due to lack of comparative cardiovascular morbidity and mortality risk reduction data for other statins in a population similar to the JUPITER trial population. The analysis was conducted from the payer perspective and lack of inclusion of indirect costs limit interpretability of results from a societal perspective.Treatment with rosuvastatin 20 mg daily, is a cost-effective treatment alternative to no treatment in patients at a higher risk (Framingham risk≥10%) of CVD.

Background HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Methods Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. Findings For 17802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p

Evidence for the role of inflammation in the pathogenesis of atherosclerosis is compelling and has generated interest in high‐sensitivity C‐reactive protein (hs‐CRP) as a marker of cardiovascular risk. Data regarding hs‐CRP and cardiovascular risk, though largely consistent, is of unclear clinical relevance. Most recently, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial has led to further debate regarding the utility of hs‐CRP. This article provides a comprehensive review of the data regarding cardiovascular risk and hs‐CRP with an emphasis on the JUPITER trial and concludes with an evidence‐based analysis of the current role of hs‐CRP in cardiovascular risk assessment. Copyright © 2010 Wiley Periodicals, Inc.

Analysis of a secondary end point of the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) found that a statin reduced the risk of venous thromboembolism (VTE) in apparently healthy people with high levels of C-reactive protein and normal levels of low-density lipoprotein cholesterol (N Engl J Med 2009; 360:1851- 1861). Still, pending more study, statins should not be substituted for proven prophylaxis and anticoagulation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.

Justification for the Use of Statins in Primary Prevention: An Intervention Trial Using Rosuvastatin (JUPITER) reported reduced cardiovascular and all-cause mortality with statin treatment in patients with elevated C-reactive protein (CRP) and average cholesterol levels who were not eligible for lipid-lowering treatment on the basis of existing guidelines. The aim of this study was to determine the prevalence of eligibility and mortality in a general population sample on the basis of eligibility for statin treatment using the JUPITER criteria. The study group consisted of 30,229 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of US African American and white participants agedor =45 years, enrolled in their homes from 2003 to 2007 and followed biannually by telephone. Among 11,339 participants age eligible for JUPITER and without vascular diagnoses or using lipid-lowering treatment, 21% (n = 2,342) met JUPITER entry criteria. Compared with JUPITER participants, they had similar low-density lipoprotein cholesterol and CRP levels, were more often women, were more often black, had metabolic syndrome, and used aspirin for cardioprotection. Over 3.5 years of follow-up, the mortality rate in REGARDS participants eligible for JUPITER was 1.17 per 100 patient-years (95% confidence interval 0.94 to 1.42). Compared with those otherwise JUPITER eligible who had CRP levels2 mg/L (n = 2,620), those with CRP levelsor =2 mg/L had a multivariate-adjusted relative risk of 1.5 (95% confidence interval 1.1 to 2.2) for total mortality. In conclusion, 21% not otherwise eligible would be newly eligible for lipid lowering treatment on the basis of JUPITER trial eligibility.

Using the results of the JUPITER trial, a recent report estimated that up to 11 million older United States (US) adults with C-reactive protein (CRP) levelsor =2 mg/L not currently recommended statins may benefit from treatment. However, the need to measure CRP in making this treatment decision has not been evaluated. Using data from 887 older US men and women (menor =50 years old, womenor =60 years old) not currently on or recommended statin therapy participating in the National Health and Nutrition Examination Survey 2003 to 2006, we determined the sensitivity, specificity, and positive and negative predictive values of patient characteristics in identifying the presence of CRPor =2 mg/L. If CRPor =2 mg/L were included as an indication for statin therapy, then 90% of older US adults would be recommended treatment. Patients with CRPor =2 mg/L were more likely (p0.05) to be current smokers, obese, and have chronic kidney disease. However, characteristics (including demographics, cigarette smoking, obesity, chronic kidney disease, and metabolic syndrome) had low positive predictive values (70%) for identifying patients with CRPor =2 mg/L and negative predictive values (60%) for those with CRP2 mg/L. In conclusion, these findings suggest patient characteristics cannot be easily used to identify patients with CRPor =2 mg/L. Given the demonstrated benefits of statin therapy, cost of measuring CRP, and large percentage of older US adults with high CRP, universal statin therapy for older US adults warrants investigation.