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Between 1853 and 1897, German chemists learned to efficiently combine sodium salicylate with acetyl chloride to produce acetylsalicylic acid. That compound, trademarked as aspirin, proved to be a remarkable antiinflammatory and antithrombotic agent and one of the most widely used drugs in pharmaceutical history. As the medical community’s understanding of platelet biology and atherothrombosis evolved, it became clear that aspirin was highly effective in the secondary prevention of cardiovascular events. Subsequent large-scale primary prevention trials, including the Physicians’ Health Study and the Women’s Health Study, provided evidence of small-to-modest cardiovascular benefits in high-risk patients, albeit with an increased risk of . . .

Lifelong exposure to raised concentrations of LDL cholesterol increases cardiovascular event rates, and the use of statin therapy as an adjunct to diet, exercise, and smoking cessation has proven highly effective in reducing the population burden associated with hyperlipidaemia. Yet, despite consistent biological, genetic, and epidemiological data, and evidence from randomised trials, there is controversy among national guidelines and clinical practice with regard to LDL cholesterol, its measurement, the usefulness of population-based screening, the net benefit-to-risk ratio for different LDL-lowering drugs, the benefit of treatment targets, and whether aggressive lowering of LDL is safe. Several novel therapies have been introduced for the treatment of people with genetic defects that result in loss of function within the LDL receptor, a major determinant of inherited hyperlipidaemias. Moreover, the usefulness of monoclonal antibodies that extend the LDL-receptor lifecycle (and thus result in substantial lowering of LDL cholesterol below the levels achieved with statins alone) is being assessed in phase 3 trials that will enrol more than 60 000 at-risk patients worldwide. These trials represent an exceptionally rapid translation of genetic observations into clinical practice and will address core questions of how low LDL cholesterol can be safely reduced, whether the mechanism of LDL-cholesterol lowering matters, and whether ever more aggressive lipid-lowering provides a safe, long-term mechanism to prevent atherothrombotic complications.

Using a polygenic score of DNA sequence polymorphisms, the authors of this study quantified genetic risk and assessed four healthy lifestyle factors. Among participants at high genetic risk, a healthy lifestyle was associated with a reduced risk of coronary disease. Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide. 1 A familial pattern in the risk of coronary artery disease was first described in 1938 and was subsequently confirmed in large studies involving twins and prospective cohorts. 2 – 6 Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease. 7 – 15 These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility. 16 – 24 Much . . .

In view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use. In the randomised, double-blind JUPITER trial, 17 603 men and women without previous cardiovascular disease or diabetes were randomly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation, or cardiovascular death) and the protocol-prespecified secondary endpoints of venous thromboembolism, all-cause mortality, and incident physician-reported diabetes. In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m2 or higher, or glycated haemoglobin A1c greater than 6%. The trial is registered at ClinicalTrials.gov, NCT00239681. Trial participants with one or more major diabetes risk factor (n=11 508) were at higher risk of developing diabetes than were those without a major risk factor (n=6095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio [HR] 0·61, 95% CI 0·47–0·79, p=0·0001), a 36% reduction in venous thromboembolism (0·64, 0·39–1·06, p=0·08), a 17% reduction in total mortality (0·83, 0·64–1·07, p=0·15), and a 28% increase in diabetes (1·28, 1·07–1·54, p=0·01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0·48, 95% CI 0·33–0·68, p=0·0001), a 53% reduction in venous thromboembolism (0·47, 0·21–1·03, p=0·05), a 22% reduction in total mortality (0·78, 0·59–1·03, p=0·08), and no increase in diabetes (0·99, 0·45–2·21, p=0·99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1·25, 95% CI 1·05–1·49, p=0·01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0·63, 95% CI 0·25–1·60) was consistent with that for the trial as a whole (0·56, 0·46–0·69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5·4 weeks (84·3 [SD 47·8] weeks on rosuvastatin vs 89·7 [50·4] weeks on placebo). In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes. AstraZeneca.

We conducted a genome-wide association analysis of 7 subfractions of low density lipoproteins (LDLs) and 3 subfractions of intermediate density lipoproteins (IDLs) measured by gradient gel electrophoresis, and their response to statin treatment, in 1868 individuals of European ancestry from the Pharmacogenomics and Risk of Cardiovascular Disease study. Our analyses identified four previously-implicated loci (SORT1, APOE, LPA, and CETP) as containing variants that are very strongly associated with lipoprotein subfractions (log(10)Bayes Factor > 15). Subsequent conditional analyses suggest that three of these (APOE, LPA and CETP) likely harbor multiple independently associated SNPs. Further, while different variants typically showed different characteristic patterns of association with combinations of subfractions, the two SNPs in CETP show strikingly similar patterns--both in our original data and in a replication cohort--consistent with a common underlying molecular mechanism. Notably, the CETP variants are very strongly associated with LDL subfractions, despite showing no association with total LDLs in our study, illustrating the potential value of the more detailed phenotypic measurements. In contrast with these strong subfraction associations, genetic association analysis of subfraction response to statins showed much weaker signals (none exceeding log(10)Bayes Factor of 6). However, two SNPs (in APOE and LPA) previously-reported to be associated with LDL statin response do show some modest evidence for association in our data, and the subfraction response proles at the LPA SNP are consistent with the LPA association, with response likely being due primarily to resistance of Lp(a) particles to statin therapy. An additional important feature of our analysis is that, unlike most previous analyses of multiple related phenotypes, we analyzed the subfractions jointly, rather than one at a time. Comparisons of our multivariate analyses with standard univariate analyses demonstrate that multivariate analyses can substantially increase power to detect associations. Software implementing our multivariate analysis methods is available at http://stephenslab.uchicago.edu/software.html.

In six trials comparing the anti–PCSK9 antibody bococizumab with placebo, the reduction in LDL cholesterol at 12 weeks was 55.2 percentage points lower with bococizumab. However, antidrug antibodies that developed in many patients reduced the magnitude of the reduction. Reducing levels of low-density lipoprotein (LDL) cholesterol with statin therapy is a highly effective method for reducing cardiovascular risk. 1 Trial data, observational studies, and genetic analyses indicate that further reductions in LDL cholesterol levels are likely to confer greater cardiovascular benefits. 2 – 4 Yet, recent studies have shown wide variability in the individual response of patients to statin therapy in terms of the percent reduction in LDL cholesterol levels. 5 , 6 Inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) reduce plasma LDL cholesterol levels by slowing PCSK9-mediated degradation of the LDL receptor. 7 Fully human monoclonal antibodies such as alirocumab and evolocumab that . . .

Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48 421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. When individuals were divided into low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22–1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55–1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. National Institutes of Health.

Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.