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  • Mendelian Randomization

    Abstract Full Text
    JAMA. 2017; 318(19):1925-1926. doi: 10.1001/jama.2017.17219

    This JAMA Guide to Statistics and Methods reviews the concepts underlying mendelian randomization and provides examples of its application to clinical trial design.

  • Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk

    Abstract Full Text
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    JAMA. 2017; 318(10):947-956. doi: 10.1001/jama.2017.11467

    This mendelian randomization analysis of individual-participant data estimated the association between changes in levels of low-density lipoprotein cholesterol (and other lipoproteins) and risk of cardiovascular events due to CETP variants, alone and in combination with HMGCR variants.

  • JAMA September 12, 2017

    Figure 4: Association of Genetic Variants With Naturally Occurring Discordance Between Changes in Concentrations of LDL-C and apoB and the Risk of CHD Among CARDIoGRAMplusC4D Consortium Participants

    Analyses are based on summary data from up to 62 240 participants with coronary heart disease (CHD) and 127 299 control participants from the Coronary Artery DIsease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium. Effect sizes are standardized per 10-mg/dL lower level of low-density lipoprotein cholesterol (LDL-C) or 10-mg/dL lower level of apolipoprotein B (apoB). MR-Egger regression estimates are presented for sensitivity analyses. Data markers indicate point estimates of effect; error bars, 95% confidence intervals.
  • JAMA September 12, 2017

    Figure 1: Study Design

    CARDIoGRAMplusC4D indicates Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; CETP, cholesteryl ester transfer protein; HMGCR, 3-hydroxy-3-methyl-glutaryl-CoA reductase; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9.
  • JAMA September 12, 2017

    Figure 2: Association of CETP Score With Risk of Major Cardiovascular Events Among 102 837 Participants From 14 Cohort or Case-Control Studies

    All information derived from the individual-participant data. A total of 102 837 participants who experienced a total of 13 821 first major cardiovascular events were included in the analysis. Among all participants, median cholesteryl ester transfer protein (CETP) genetic score was 34.8 (interquartile range [IQR], 28.3-41.1; range, 0-54.3). For participants in the group with CETP scores below the median, median CETP score was 28.2 (IQR, 23.3-32.0; range, 0-34.7). For participants in the group with CETP scores equal to or above the median, median CETP score was 41.1 (IQR, 37.9-44.8; range, 34.8-54.3). Higher scores indicate a greater number of high-density lipoprotein cholesterol (HDL-C)–raising alleles (weighted by the effect of each allele on HDL-C level) and is analogous to treatment with increasingly potent CETP inhibitors. Lipid and lipoprotein values are presented in mg/dL (to convert HDL-C and low-density lipoprotein cholesterol [LDL-C] values to mmol/L, multiply by 0.0259) as the difference in mean value for each group compared with the reference group, with 95% confidence intervals. Associations with major cardiovascular events were calculated using an inverse variance–weighted fixed-effects meta-analysis of the study-specific estimates of effect. In panels B and C, the association between the CETP score and risk of major cardiovascular events is compared with the association between the risk of major cardiovascular events and genetic scores consisting of variants in the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) gene (encodes the target of statins), proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (encodes target of PCSK9 inhibitors), and Niemann-Pick C1-Like 1 intracellular cholesterol transporter 1 (NPC1L1) gene (encodes target of ezetimibe). All associations between the genetic scores and risk of major cardiovascular events are standardized per 10-mg/dL lower level of LDL-C (panel B) or 10-mg/dL lower level of apolipoprotein B (apoB) (panel C) and measured in the overall sample of studies that contributed individual-participant data. Data markers indicate point estimates of effect and are of equal size because the analysis compared approximately equal-sized groups divided by the median CETP score value or quartiles of the CETP score (panel A). OR indicates odds ratio.
  • JAMA September 12, 2017

    Figure 3: Separate and Combined Effects of the CETP and HMGCR Scores on Risk of Major Cardiovascular Events Among 102 837 Participants From 14 Cohort or Case-Control Studies

    All information derived from the individual-participant data. A total of 102 837 participants who experienced a total of 13 821 first major cardiovascular events were included in the analysis. Among all participants, the median cholesteryl ester transfer protein (CETP) genetic score was 34.8 (interquartile range [IQR], 28.3-41.1; range, 0-54.3). The median CETP and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) score, IQR, and range of values for each group is presented in Table 2. Lipid and lipoprotein values are presented in mg/dL (to convert high-density lipoprotein cholesterol [HDL-C] and low-density lipoprotein cholesterol [LDL-C] values to mmol/L, multiply by 0.0259) as the difference in mean value for each group compared with the reference group, with 95% confidence intervals. Associations with major cardiovascular events were calculated using an inverse variance–weighted fixed-effects meta-analysis of the study-specific estimates of effect. In panel B, the study population was first divided into 2 groups based on whether the HMGCR score was below or equal to or greater than the median value. The association between the CETP score and the risk of major cardiovascular events was then estimated modeling the CETP score as a continuous variable scaled to the lipid effects in the dichotomous score analysis. There was evidence for effect modification of the HMGCR score on the association between the CETP genetic score and the risk of major cardiovascular events (P = .04). Data markers indicate point estimates of effect and are of equal size because the analysis compared approximately equal-sized groups divided into a factorial analysis (panel A) or the median HMGCR score value (panel B). Error bars represent 95% confidence intervals. apoB indicates apolipoprotein B; OR, odds ratio.
  • Genetic Studies Help Clarify the Complexities of Lipid Biology and Treatment

    Abstract Full Text
    JAMA. 2017; 318(10):915-917. doi: 10.1001/jama.2017.11750
  • Inconsistent Guideline Recommendations for Cardiovascular Prevention and the Debate About Zeroing in on and Zeroing LDL-C Levels With PCSK9 Inhibitors

    Abstract Full Text
    JAMA. 2017; 318(5):419-420. doi: 10.1001/jama.2017.6765

    This Viewpoint discusses variances in cardiovascular prevention guidelines from the United States, Europe, and Canada and the debate surrounding low-density lipoprotein levels as the primary focus.

  • Behavioral Counseling to Promote a Healthful Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Known Cardiovascular Disease Risk Factors: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

    Abstract Full Text
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    JAMA. 2017; 318(2):175-193. doi: 10.1001/jama.2017.3303

    This Evidence Report and systematic review to support a 2017 US Preventive Services Task Force Recommendation Statement summarizes current evidence on benefits and harms of behavioral counseling for primary prevention of cardiovascular disease (CVD) in adults without known CVD risk factors.

  • Therapies That Target PCSK9 Effective at Reducing LDL Cholesterol

    Abstract Full Text
    JAMA. 2017; 317(20):2054-2054. doi: 10.1001/jama.2017.5656
  • JAMA February 14, 2017

    Figure 3: Association of 48-SNP Polygenic Risk Score for WHR Adjusted for BMI With Cardiometabolic Quantitative Traits

    Results are standardized to a 1-SD increase in waist-to-hip ratio (WHR) adjusted for body mass index (BMI) due to polygenic risk score. For systolic blood pressure, a 1-SD genetic increase in WHR adjusted for BMI is associated with a 2.1-mm Hg higher systolic blood pressure (95% CI, 1.2-3.0) or a 0.1-SD increase in systolic blood pressure (95% CI, 0.059-0.15). For anthropometric traits, estimates from Genetic Investigation of Anthropometric Traits (GIANT) derived using inverse variance–weighted fixed-effects meta-analysis) were pooled with data from the UK Biobank (derived instrumental variables regression adjusting for age, sex, 10 principal components of ancestry, and array type) using inverse variance–weighted fixed-effects meta-analysis. For lipids, glycemic, and renal function traits, estimates were derived from genome-wide association studies (Global Lipids Genetics, Meta-analyses of Glucose and Insulin-Related Traits, and Chronic Kidney Genetics Consortia, respectively). For blood pressure, estimates were derived from UK Biobank. Two-hour glucose refers to measured blood glucose levels 2 hours after consumption of dissolved glucose. The threshold of significance was P < .0033 (.05/15 = .0033). Size of data markers is inversely proportional to variance of estimate. To convert total cholesterol, LDL-C, and HDL-C values to mmol/L, multiply by 0.0259; triglyceride values to mmol, multiply by 0.0113; and glucose values to mmol/L, multiply by 0.0555. eGFR indicates estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; OR, odds ratio; WHR, waist-to-hip ratio.aUnits reported in column 1.bCalculated as weight in kilograms divided by height in meters squared.
  • Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial

    Abstract Full Text
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    JAMA. 2016; 316(22):2373-2384. doi: 10.1001/jama.2016.16951

    This randomized clinical trial compares the effects of evolocumab vs placebo on change in percent atheroma volume among adult patients with angiographic coronary disease despite treatment with statins.

  • JAMA December 13, 2016

    Figure 2: Mean Absolute Change in LDL-C Level

    Error bars indicate 95% CIs. LDL-C indicates low-density lipoprotein cholesterol. To convert LDL-C values to mmol/L, multiply by 0.0259.
  • JAMA December 13, 2016

    Figure 4: Post Hoc Analysis Examining the Relationship Between Achieved LDL-C Level and Change in Percent Atheroma Volume

    Local regression (LOESS) curve illustrating the post hoc analysis of the association (with 95% confidence intervals) between achieved low-density lipoprotein cholesterol (LDL-C) levels and the change in percent atheroma volume in all patients undergoing serial IVUS evaluation. Curve truncated at 20 and 110 mg/dL owing to the small number of values outside that range. To convert LDL-C values to mmol/L, multiply by 0.0259.
  • JAMA December 13, 2016

    Figure 3: Prespecified Subgroup Analysis of Change in Percent Atheroma Volume From Baseline to Week-78 Follow-up

    Results expressed as least squares means with 95% CIs. ACC/AHA indicates American College of Cardiology/American Heart Association; LDL-C indicates low-density lipoprotein cholesterol; non–HDL-C, non–high-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin type 9; PAV, percent atheroma volume; TAV, total atheroma volume.aMedian values: age, 60 years; PAV, 36.88%; TAV, 175.08 mm3; non–HDL-C, 115 mg/dL; PCSK9, 315 ng/mL.bBlack or African American, Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaska native, multiple, or other.cHigh intensity: atorvastatin (≥40 mg), rosuvastatin (≥20 mg), simvastatin (≥80 mg). Moderate intensity: atorvastatin (10-40 mg), rosuvastatin (5-20 mg), simvastatin (20-80 mg), pravastatin (≥40 mg), lovastatin (≥40 mg), fluvastatin (80 mg), pitavastatin (≥2 mg). Low intensity: atorvastatin (<10 mg), rosuvastatin (<5 mg), simvastatin (<20 mg), pravastatin (<40 mg), lovastatin (<40 mg).
  • JAMA December 13, 2016

    Figure 1: Flow of Patients Through the GLAGOV Randomized Clinical Trial

    aPatients could be excluded for more than 1 reason; therefore, the sum of the criteria may be greater than the number of patients. CETP indicates cholesterylester transfer protein; GLAGOV, Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound; IVUS, intravascular ultrasonography; LDL-C, low-density lipoprotein cholesterol.bLDL-C level 80 mg/dL (2.07 mmol/L) or greater, with or without risk factors; less than 60 mg/dL (1.55 mmol/L); or 60 mg/dL or greater to less than 80 mg/dL.cClinically significant heart disease (154), hyperthyroidism or hypothyroidism (38), type 1 diabetes (27), history of malignancy (16), fasting triglyceride level greater than 400 mg/dL (4.52 mmol/L) (15), active liver disease or hepatic dysfunction (11), uncontrolled cardiac arrhythmia (4), creatine kinase level greater than 3 times upper limit of normal (2), history of hereditary muscular disorders (2), known active infection or systemic dysfunctions (2), New York Heart Association III or IV heart failure or left ventricular ejection fraction less than 30% (2), severe renal dysfunction (1), uncontrolled hypertension (1).
  • Cholesterol, Cardiovascular Risk, Statins, PCSK9 Inhibitors, and the Future of LDL-C Lowering

    Abstract Full Text
    JAMA. 2016; 316(19):1967-1968. doi: 10.1001/jama.2016.16575

    This Viewpoint discusses the role of implementation and translational science and digital platforms for improving population cardiovascular risk and advancing precision treatments in an era of intensive statin therapy and PCSK9 inhibitors.

  • Association Between Low-Density Lipoprotein Cholesterol–Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis

    Abstract Full Text
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    JAMA. 2016; 316(13):1383-1391. doi: 10.1001/jama.2016.14568

    This meta-analysis of genetic association studies summarizes associations between molecular targets of lipid-lowering therapy and risk of type 2 diabetes and coronary artery disease.

  • JAMA October 4, 2016

    Figure: Association of Low-Density Lipoprotein Cholesterol (LDL-C)–Lowering Genetic Variants With Coronary Artery Disease and Type 2 Diabetes

    Coronary artery disease data are from 60 801 cases with coronary artery disease and 123 504 controls from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus the Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) Consortium. Type 2 diabetes data are from 50 775 cases of type 2 diabetes and 270 269 controls from European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study, the UK Biobank study, and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM). In addition to the EPIC-InterAct study, the UK Biobank study, and DIAGRAM, type 2 diabetes association analyses of rs12916 at HMGCR included 11 studies (4496 cases and 50 677 controls) previously reported by Swerdlow et al. Therefore, the sample size of HMGCR genetic variants association with type 2 diabetes was 55 271 cases of type 2 diabetes and 320 946 controls. All results are scaled to represent the odds ratio per 1-mmol/L (38.7-mg/dL) genetically predicted reduction in LDL-C.
  • JAMA September 27, 2016

    Figure 4: Association Between Achieved Low-Density Lipoprotein Cholesterol (LDL-C) and Major Coronary Event Rates From 24 Trials of Established Interventions That Lower LDL-C Predominantly Through Upregulation of LDL Receptor Expression

    Levels of LDL-C are expressed as mean or median depending on what was reported in the trial. The solid lines are from meta-regression. To convert LDL-C from mmol/L to mg/dL, divide by 0.0259.