The metabolic syndrome is a clinical condition characterized by the presence of multiple interrelated risk factors for type 2 diabetes and cardiovascular disease. Component features include ...dysglycemia, increased blood pressure, increased triglycerides, decreased HDL cholesterol concentrations, and obesity (in particular, abdominal obesity). The underlying biology, optimal diagnostic criteria, and clinical implications, once diagnosed, have been matter for intense debate. Despite these areas of controversy, there is now general consensus that the observed risk factor clustering signifies heightened cardiovascular risk.
The influence of sex on the clinical expression and pathophysiology of the syndrome is underrecognized, and is an issue of increasing importance given the alarming increase in prevalence among young women. This minireview will highlight sex differences in the epidemiology, etiology, biology, and clinical expression of the metabolic syndrome. In particular, key sex differences include distinctions in (a) prevalence of dysglycemia, (b) body fat distribution, (c) adipocyte size and function, (d) hormonal regulation of body weight and adiposity, and (e) the influence of estrogen decline on risk factor clustering.
Accumulated and emerging data convincingly demonstrate that significant heterogeneity exists between men and women developing the metabolic syndrome, in large part related to hormonal regulation of body fat distribution and attendant metabolic abnormalities.
Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and ...hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins.
We did a collaborative analysis of patients with—or at high risk of—atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment.
31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20–1·43; p<0·0001), cardiovascular mortality (2·68, 2·22–3·23; p<0·0001), and all-cause mortality (2·42, 2·12–2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98–1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07–1·50; p=0·0086) and all-cause death (1·16, 1·03–1·32; p=0·025).
Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
Kowa Research Institute, Amarin, AstraZeneca.
Patients with coronary artery disease were randomly assigned to either methotrexate (15 to 20 mg weekly) or placebo. At a median of 2.3 years, there was no difference between the two groups in the ...rate of myocardial infarction, stroke, or cardiovascular death.
Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to ...drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease.
The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD).
In a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.
The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio HRQ4: 3.05 95% confidence interval (CI): 1.46 to 6.39; ptrend = 0.002; PAD HRQ4: 2.58 95% CI: 1.18 to 5.63; ptrend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71 95% CI: 1.59 to 8.63; ptrend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl).
TRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women’s Health Study; NCT00000479)
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Abstract
Background
Triglycerides, cholesterol, and their metabolism are linked due to shared packaging and transport within circulating lipoprotein particles. While a case for a causal role of ...cholesterol-carrying low-density lipoproteins (LDLs) in atherosclerosis is well made, the body of scientific evidence for a causal role of triglyceride-rich lipoproteins (TRLs) is rapidly growing, with multiple lines of evidence (old and new) providing robust support.
Content
This review will discuss current perspectives and accumulated evidence that an overabundance of remnant lipoproteins stemming from intravascular remodeling of nascent TRLs—chylomicrons and very low-density lipoproteins (VLDL)—results in a proatherogenic milieu that augments cardiovascular risk. Basic mechanisms of TRL metabolism and clearance will be summarized, assay methods reviewed, and pivotal clinical studies highlighted.
Summary
Remnant lipoproteins are rendered highly atherogenic by their high cholesterol content, altered apolipoprotein composition, and physicochemical properties. The aggregate findings from multiple lines of evidence suggest that TRL remnants play a central role in residual cardiovascular risk.
Summary Background 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. Methods 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 A 1c greater than 6%. The trial is registered at ClinicalTrials.gov , NCT00239681. Findings 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). Interpretation 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. Funding AstraZeneca.
BACKGROUND:The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces ...cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain.
METHODS:We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death.
RESULTS:At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was −60.5% (95% confidence interval CI, −61.2 to −59.8; P<0.001; median change, −65.4%) as compared to 6.6% (95% CI, −1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81–1.66), and 1.62 (95% CI, 1.14–2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30–50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87).
CONCLUSIONS:In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifiersNCT01975376, NCT01975389.
Background Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. Design ...The Cardiovascular Inflammation Reduction Trial (CIRT) ( ClinicalTrials.gov NCT01594333 ) 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. Summary 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.
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