Higher intake of marine n-3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation ...with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear.
We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D
(at a dose of 2000 IU per day) and marine n-3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n-3 fatty acids with placebo.
A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval CI, 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.
Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).
Current statin guidelines in Europe and Canada advocate achieving a fixed LDL target or the attainment of a ≥50% reduction in low-density lipoprotein cholesterol (LDLC), while current US guidelines ...advocate the use of statin therapies that reduce LDLC by <50% (moderate intensity) or ≥50% (high intensity). Data are limited, however, linking the achievement of these % reduction thresholds to subsequent cardiovascular outcomes particularly for contemporary high-intensity regimens.
In a randomized trial of 17 082 initially healthy men and women with median baseline LDLC of 108 mg/dL (interquartile range 94-119), we (i) used waterfall plots to assess the variability in LDLC response to rosuvastatin 20 mg daily and (ii) evaluated the impact of reaching ≥50% reductions in LDLC on risk of developing the first cardiovascular events. Among rosuvastatin allocated participants, 3640 individuals (46.3%) experienced an LDLC reduction ≥50%; 3365 individuals (42.8%) experienced an LDLC reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDLC compared with baseline. These % LDLC reductions directly related to the risks of first cardiovascular events; at trial completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1000 person-years for those in the placebo, no LDLC reduction, LDLC reduction <50%, and LDLC reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment per cent reductions in LDLC were 0.91 (95%CI 0.54-1.53), 0.61 (95%CI 0.44-0.83), and 0.43 (95%CI 0.30-0.60) (P < 0.00001). Similar relationships between % reduction and clinical outcomes were observed in analyses focusing on non-HDLC or apolipoprotein B.
As documented for low- and moderate-intensity regimens, variability in % LDLC reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors should these agents prove broadly effective for cardiovascular event reduction.
It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.
We conducted a nationwide, randomized, ...placebo-controlled trial, with a two-by-two factorial design, of vitamin D
(cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo.
A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval CI, 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified.
Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259 .).
Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) are strong predictors of type 2 diabetes mellitus (T2D), but their association with cardiovascular disease (CVD) is ...uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk and evaluated whether this was dependent on an intermediate diagnosis of T2D.
Participants in the Women's Health Study prospective cohort were eligible if free of CVD at baseline blood collection (n=27 041). Plasma metabolites were measured via nuclear magnetic resonance spectroscopy. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for BCAAs with incident CVD (myocardial infarction, stroke, and coronary revascularization).
We confirmed 2207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, body mass index, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD: HR, 1.13; 95% CI, 1.08-1.18), comparable to LDL-C (low-density lipoprotein cholesterol) with CVD (per SD: HR, 1.12; 95% CI, 1.07-1.17). BCAAs were associated with coronary events (myocardial infarction: HR, 1.16; 95% CI, 1.06-1.26; revascularization: HR, 1.17; 95% CI, 1.11-1.25), and borderline significant association with stroke (HR, 1.07; 95% CI, 0.99-1.15). The BCAA-CVD association was greater (
interaction=0.036) among women who developed T2D before CVD (HR, 1.20; 95% CI, 1.08-1.32) versus women without T2D (HR, 1.08; 95% CI, 1.03-1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance eliminated the associations of BCAAs with CVD.
Circulating plasma BCAAs were positively associated with incident CVD in women. Impaired BCAA metabolism may capture the long-term risk of the common cause underlying T2D and CVD.
Although lipoprotein(a) Lp(a) is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial.
This study examined the association and clinical utility ...of Lp(a) with incident CVD in women.
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.
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.
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.
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Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) Lp(a) consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve ...stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
Chemically measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL measures such as HDL size or particle number ...(HDL-P) as determinants of residual risk after potent statin therapy.
In Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10 886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/d or placebo. Levels were examined with first CVD (n=234). HDL-P correlated better with apoA-I (Spearman r=0.69, P<0.0001) than with HDL-C (r=0.55, P<0.0001). Rosuvastatin lowered low-density lipoprotein cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%), and HDL size (1.2%); all P<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% confidence interval per 1 standard deviation: 0.79 0.63-0.98, 0.75 0.62-0.92, and 0.81 0.67-0.97, respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57-0.93, P=0.01) than HDL-C (0.82, 0.63-1.08, P=0.16) or apoA-I (0.86, 0.67-1.10, P=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53-0.97, P=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD.
In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL.
http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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.
Although models have been developed for predicting severity of COVID-19 from the medical history of patients, simplified models with good accuracy could be more practical. In this study, we examined ...utility of simpler models for estimating risk of hospitalization of patients with COVID-19 and mortality of these patients based on demographic characteristics (sex, age, race, median household income based on zip code) and smoking status of 12,347 patients who tested positive at Mass General Brigham centers. The corresponding electronic records were queried (02/26-07/14/2020) to construct derivation and validation cohorts. The derivation cohort was used to fit generalized linear models for estimating risk of hospitalization within 30 days of COVID-19 diagnosis and mortality within approximately 3 months for the hospitalized patients. In the validation cohort, the model resulted in c-statistics of 0.77 95% CI 0.73-0.80 for hospitalization, and 0.84 95% CI 0.74-0.94 for mortality among hospitalized patients. Higher risk was associated with older age, male sex, Black ethnicity, lower socioeconomic status, and current/past smoking status. The models can be applied to predict the absolute risks of hospitalization and mortality, and could aid in individualizing the decision making when detailed medical history of patients is not readily available.
The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein ...quantification for cardiovascular risk management.
We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (
) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (
) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (
) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol.
Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.
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