Newer and Emerging LDL-C Lowering Agents and Implications for ASCVD Residual Risk.
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SUBMITTER: Rikhi R
PROVIDER: S-EPMC9369522 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Newer and Emerging LDL-C Lowering Agents and Implications for ASCVD Residual Risk.
Rikhi Rishi R Shapiro Michael D MD
Journal of clinical medicine 20220808 15
Multiple lines of evidence demonstrate that low-density lipoprotein-cholesterol causes atherosclerotic cardiovascular disease. Thus, targeting and lowering low-density lipoprotein-cholesterol is the principal strategy to reduce cardiovascular disease risk in primary and secondary prevention. Statin therapy is the foundation of lipid-lowering treatment, but adherence rates are low, and many individuals do not attain target low-density lipoprotein-cholesterol values. Additionally, most statin-trea ...[more]
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Project description:AimsCurrent 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.Methods and resultsIn 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.ConclusionsAs 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.
| S-EPMC4852064 | biostudies-literature
Project description:BackgroundThe log linear association between on-treatment LDL-C levels and ASCVD events is amplified in higher risk patient subgroups of statin versus placebo trials.ObjectivesUpdate previous systematic review to evaluate how the log linear association influences the magnitude of cardiovascular risk reduction from intensifying LDL-C lowering therapy.MethodsMEDLINE/PubMED, Clinical trials.gov, and author files were searched from 1/1/2005 through 10/30/2019 for subgroup analyses of cardiovascular outcomes trials of moderate versus high intensity statin, ezetimibe, and PCSK9 mAbs with an ASCVD endpoint (nonfatal myocardial infarction or stroke, cardiovascular death). Annualized ASCVD event rates were used to extrapolate 5-year ASCVD risk for each treatment group reported in subgroup analyses, which were grouped into a priori risk groups according to annualized placebo/control rates of ≥4%, 3-3.9%, or <3% ASCVD risk. Data were pooled using a random-effects model. Weighted least-squares regression was used to fit linear and log-linear models.ResultsSystematic review identified 96 treatment subgroups from 2 trials of moderate versus high intensity statin, 2 trials of a PCSK9 mAb versus placebo, and 1 trial of ezetimibe versus placebo. A log linear association between on-treatment LDL-C and ASCVD risk represents the association between on-treatment LDL-C levels and ASCVD event rates, especially in higher risk subgroups. Greater relative and absolute cardiovascular risk reductions from LDL-C lowering were observed when baseline LDL-C was >100 mg/dl and in extremely high risk ASCVD patient groups.ConclusionsGreater cardiovascular and mortality risk reduction benefits from intensifying LDL-C lowering therapy may be expected in those with LDL-C ≥100 mg/dl, or in extremely high risk patient groups. When baseline LDL-C <100 mg/dl, the log linear association between LDL-C and event rates suggests that treatment options other than further LDL-C lowering should also be considered for optimal risk reduction.
| S-EPMC7595281 | biostudies-literature
Project description:BackgroundRecently, there has been an increasing interest in targeting inflammation to reduce major adverse cardiovascular events (MACE) in patients with cardiovascular risk. Statins, PCSK9 inhibitors, and ezetimibe have been shown to reduce MACE owing to reduction in low-density lipoproteins cholesterol (LDL-c). Herein, we investigate whether the intensity of these agents is associated with (i) discernible reduction in inflammation measured by the levels of high-sensitivity C-reactive protein (hsCRP); (ii) reduction in MACE; (iii) if there is an association between the baseline hsCRP and MACE.Methods and resultsElectronic databases were searched for randomized controlled trials (RCTs) that compared statins, ezetimibe, PCSK9 inhibitors with placebos/active controls and reported MACEs and hsCRP (mg/L). Studies were stratified based on baseline hsCRP (<2, 2-3, >3) with subgroup analysis conducted across each stratum. Fourteen RCTs including 133 109 patients randomized into more intensive therapy (MIT) and less intensive therapy were selected. Meta-analysis did not demonstrate any significant differences between use of MIT and hsCRP levels (mean difference, -0.02; CI, -0.06, 0.02; P = 0.31). The MIT significantly reduced the risk of MACE (RR, 0.82; CI, 0.75, 0.91; P < 0.001). The relative risk and absolute risk remained consistent across the strata. However, there was a 0.5% statistically significant absolute risk reduction in all-cause mortality in patients with higher hsCRP (RD, -0.005; CI, -0.009, -0.001; P = 0.01).ConclusionOverall, LDL-c lowering therapies reduce relative risk of MACEs particularly in patients with higher baseline hsCRP. However, there appears to be a residual inflammatory risk despite the use of contemporary lipid lowering agents.
| S-EPMC7850089 | biostudies-literature
Project description:Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.
| S-EPMC5978933 | biostudies-literature
Project description:BACKGROUND AND AIMS:Non-high-density (HDL)-cholesterol, low-density lipoprotein (LDL)-particle number, apolipoprotein B, lipoprotein(a) (Lp(a)), and small-dense (sdLDL) and large-buoyant (lbLDL) LDL-subfractions are emerging apo B-containing atherosclerotic cardiovascular disease (ASCVD) risk factors. Current guidelines emphasize lifestyle, including weight loss, for ASCVD risk management. Whether weight change affects these emerging risk factors beyond that predicted by traditional triglyceride and LDL-cholesterol measurements remains to be determined. METHOD:Regression analyses of fasting ?apo B-containing lipoproteins vs. ?BMI were examined in a large anonymized clinical laboratory database of 33,165 subjects who did not report use of lipid-lowering medications. Regression slopes (±SE) were estimated as: *?mmol/L per ?kg/m2, †?g/L per ?kg/m2, ‡?% per ?kg/m2, and §??mol/L per ?kg/m2. RESULTS:When adjusted for age, ?BMI was significantly related to ?nonHDL-cholesterol (males: 0.0238?±?0.0041, P?=?7.9?×?10-?9; females: 0.0330?±?0.0037, P?<?10-?16)*, ?LDL-particles (males: 0.0128?±?0.0024, P?=?2.1?×?10-?7; females: 0.0114?±?0.0022, P?=?3.2?×?10-?7)*, ?apo B (males: 0.0053?±?0.0010, P?=?7.9?×?10-?8; females: 0.0073?±?0.0009, P?=?2.2?×?10-?16)†, ?sdLDL (males: 0.0125?±?0.0015, P?=?2.2?×?10-?16; females: 0.0128?±?0.0012, P?<?10-?16)*, ?percent LDL carried on small dense particles (%sdLDL, males: 0.296?±?0.035, P?<?10-?16; females: 0.221?±?0.023, P?<?10-?16)‡, ?triglycerides (males: 0.0358?±?0.0049, P?=?2.0?×?10-?13; females: 0.0304?±?0.0029, P?<?10-?16)*, and ?LDL-cholesterol (males: 0.0128?±?0.0034, P?=?0.0002; females: 0.0232?±?0.0031, P?=?1.2?×?10-?13)* in both males and females. Age-adjusted ?BMI was significantly related to ?lbLDL in females (0.0098?±?0.0024, P?=?3.9?×?10-?5)* but not males (0.0007?±?0.0026, P?=?0.78)*. Female showed significantly greater increases in ?LDL-cholesterol (P?=?0.02) and ?lbLDL (P?=?0.008) per ?BMI than males. ?BMI had a greater effect on ?LDL-cholesterol measured directly than indirect estimate of ?LDL-cholesterol from the Friedewald equation. When sexes were combined and adjusted for age, sex, ?triglycerides and ?LDL-cholesterol, ?BMI retained residual associations with ?nonHDL-cholesterol (0.0019?±?0.0009, P?=?0.03)*, ?LDL-particles (0.0032?±?0.0010, P?=?0.001)*, ?apo B (0.0010?±?0.0003, P?=?0.0008)†, ?Lp(a) (-?0.0091?±?0.0021, P?=?1.2?×?10-?5)§, ?sdLDL (0.0001?±?0.0000, P?=?1.6?×?10-?11)* and ?%sdLDL (0.151?±?0.018, P?<?10-?16) ‡. CONCLUSIONS:Emerging apo B-containing risk factors show associations with weight change beyond those explained by the more traditional triglyceride and LDL-cholesterol measurements.
| S-EPMC6636168 | biostudies-literature
Project description:BackgroundHypertensive individuals on blood pressure (BP)-lowering treatment with BP in the normal or high-normal range have higher cardiovascular risk than untreated persons with usual BP in the same range. This residual risk (relative and absolute) is not well quantified and may be attributable in part to the higher burden of subclinical disease in treated individuals.Methods and resultsWe assigned 3024 Framingham Offspring Cohort participants to 5 categories based on systolic BP (SBP) and diastolic BP (DBP) and use of BP-lowering treatment: (1) untreated SBP/DBP <120/80 mm Hg; (2) untreated SBP/DB ?120/80 to <140/90 mm Hg; (3) treated SBP/DBP <140/90 mm Hg; (4) untreated SBP/DBP ?140/90 mm Hg; and (5) treated SBP/DBP ?140/90 mm Hg. A composite subclinical disease score was constructed, including information on left ventricular hypertrophy, systolic dysfunction, carotid ultrasound abnormality, peripheral artery disease, and microalbuminuria. The prevalence of subclinical disease rose across BP groups, as did the event rates for incident cardiovascular disease (449 events, median follow-up of 11 years; group 1, 0.65 event per 100 person-years; group 5, 3.20 events per 100 person-years; P<0.0001 for trend). On multivariable adjustment, treated hypertensives in groups 3 and 5 had 50% (95% CI 13% to 99%) and 28% (95% CI -6% to 73%) higher hazards, respectively, of developing cardiovascular disease compared with their untreated counterparts with similar levels of BP (groups 1 and 2 and group 4, respectively). The increased risk of cardiovascular disease in treated hypertensives was attributable in part to greater subclinical disease burden.ConclusionsTreated hypertensives have higher subclinical cardiovascular disease burden, which partly explains their higher cardiovascular disease risk compared with untreated persons with similar BP levels.
| S-EPMC4845218 | biostudies-literature
Project description:BackgroundCurrent guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering.ContentNon-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events.SummaryWe review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.
| S-EPMC7793228 | biostudies-literature
Project description:ImportanceTriglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.ObjectiveTo compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.Design, setting, and participantsMendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.ExposuresDifferences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.Main outcomes and measuresOdds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.ResultsA total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20).Conclusions and relevanceTriglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
| S-EPMC6439767 | biostudies-literature
Project description: Not available
| S-EPMC6865332 | biostudies-literature
Project description:BackgroundThe risk for nephrogenic systemic fibrosis (NSF) after exposure to newer versus older gadolinium-based contrast agents (GBCAs) remains unclear.PurposeTo synthesize evidence about NSF risk with newer versus older GBCAs across the spectrum of kidney function.Data sourcesMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science for English-language references from inception to 5 March 2020.Study selectionRandomized controlled trials, cohort studies, and case-control studies that assessed NSF occurrence after GBCA exposure.Data extractionData were abstracted by 1 investigator and verified by a second. Investigator pairs assessed risk of bias by using validated tools.Data synthesisOf 32 included studies, 20 allowed for assessment of NSF risk after exposure to newer GBCAs and 12 (11 cohort studies and 1 case-control study) allowed for comparison of NSF risk between newer and older GBCAs. Among 83 291 patients exposed to newer GBCAs, no NSF cases developed (exact 95% CI, 0.0001 to 0.0258 case). Among the 12 studies (n = 118 844) that allowed risk comparison between newer and older GBCAs, 37 NSF cases developed after exposure to older GBCAs (exact CI, 0.0001 to 0.0523 case) and 4 occurred (3 confounded) after exposure to newer GBCAs (exact CI, 0.0018 to 0.0204 case). Data were scant for patients with acute kidney injury or those at risk for chronic kidney disease.LimitationsStudy heterogeneity prevented meta-analysis. Risk of bias was high in most studies because of inadequate exposure and outcome ascertainment.ConclusionAlthough NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations.Primary funding sourceU.S. Department of Veterans Affairs. (PROSPERO: CRD42019135783).
| S-EPMC7847719 | biostudies-literature