Intensive Low-density Lipoprotein Cholesterol Lowering Research Articles

Comparative Efficacy of Colchicine and Intensive Low-density Lipoprotein Cholesterol Lowering in Patients with Atherosclerotic Diseases receiving Statins: A Network Meta-analysis of Randomized Controlled Trials.

Adding intensive low-density lipoprotein cholesterol (LDL-C)-lowering agents or colchicine to statin has been shown to result in additional cardiovascular benefits for patients with atherosclerotic cardiovascular diseases (ASCVD). We aimed to compare the efficacy and safety of these supplementary agents in patients with ASCVD receiving statin. We performed a systematic review and frequentist network meta-analysis of randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death, and all-cause mortality, respectively. The safety endpoints were treatment discontinuation and non-cardiovascular death. We obtained estimates for efficacy outcomes and safety endpoints and presented these estimates as risk ratio (RR) with 95% confidence intervals. We ranked the comparative efficacy and safety of all drugs with P-scores. Seventeen trials totaling 85,823 participants treated with colchicine (5926 participants), intensive LDL-C lowering (37,854 participants) via proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor or ATP citrate lyase (ACL) inhibitor, or statin alone (42,043 participants) were included. Colchicine was associated with a greater reduction in the risk of MACE (RR 0.72, 0.69-0.91), stroke (RR 0.55, 0.33-0.92), and coronary revascularization (RR 0.73, 0.60-0.90) compared with NPC1L1 inhibitor, and it provided a larger reduction in the risk of MACE (RR 0.79, 0.69-0.91) compared to PCSK9 inhibitor. However, colchicine was associated with increased risk of non-cardiovascular death compared with NPC1L1 inhibitor (RR 1.48, 1.04-2.10) and PCSK9 inhibitor (RR 1.57, 1.08-2.27). Although no regimen prolonged survival, colchicine had worse performance on non-cardiovascular death and all-cause mortality. In patients with ASCVD receiving statin, colchicine seems to be more effective than intensive LDL-C-lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor for cardiovascular prevention. However, using colchicine as an alternative to intensive LDL-C-lowering therapy may need to be weighed against the cardiovascular benefits and the potential harms of higher non-cardiovascular death. PROSPERO Identifier: CRD42023441385.

Navigating Cardiovascular Risk and Lipid Management in Indian Patients: Key Messages from the Lipid Association of India 2024 Consensus Statement IV.

Effective lipid management is crucial for preventing atherosclerotic cardiovascular disease (ASCVD). The Western lipid guidelines may not apply to Indian subjects because of the vast differences in cardiovascular (CV) disease epidemiology. To overcome this challenge, the Lipid Association of India (LAI) in 2016 proposed an ASCVD risk stratification algorithm. The appropriate low-density lipoprotein cholesterol (LDL-C) goals for various risk groups were proposed, with an LDL-C target of <50 mg/dL recommended for the first time globally for patients in the very high-risk group. Subsequently, in 2020, an extreme risk group was added because of observations that patients with more severe or extensive ASCVD, along with multiple risk factors and comorbidities, had increased rates of adverse CV events and could benefit from more intensive LDL-C lowering. The extreme risk group was subdivided into categories A and B, with LDL-C targets as low as 30 mg/dL or lower. The availability of further evidence regarding the significance of novel risk factors and the availability of new LDL-C lowering therapies necessitated refining the ASCVD risk assessment algorithm, defining LDL-C targets for subjects with these risk factors, and incorporating recommendations for attaining very low LDL-C levels in a defined, select group of patients. Accordingly, the LAI expert group recently published the Consensus Statement IV, which is a comprehensive document addressing several key issues about risk stratification and dyslipidemia management in Indian subjects. LDL-C and nonhigh-density lipoprotein cholesterol (non-HDL-C) are not only primary and co-primary targets for lipid-lowering therapy but also risk factors for ASCVD risk stratification. Apolipoprotein B is a secondary target. The risk assessment algorithm has been updated to incorporate several nonconventional yet relevant CV risk factors. Additionally, the role of subclinical atherosclerosis has been highlighted. The CV risk due to subclinical atherosclerosis has been considered equivalent to that of established ASCVD, and hence, similar LDL-C targets have been recommended. Furthermore, a new risk category-extreme risk group category C has been added for the small subgroup of patients who continue to experience ASCVD sequelae despite achieving LDL-C levels of 30 mg/dL or lower. An ultralow LDL-C target (10-15 mg/dL) has been recommended along with optimal control of risk factors and guideline-directed management of comorbidities. Dyslipidemia management should be effective with sustained LDL-C lowering. In high-risk situations (e.g., acute coronary syndrome), the LDL-C target should be achieved as early as possible, preferably within the first 2 weeks. The present document summarizes the key messages from the LAI Consensus Statement IV.

Association of statins with nonalcoholic fatty liver disease in patients with diabetes.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in patients with diabetes; limited data suggested that statins may reduce the risk of NAFLD progression. This study aimed to examine the association between statins and the development or progression of NAFLD in veterans with diabetes. In a new-user negative control design, we conducted a retrospective propensity score (PS)-matched cohort study of patients with diabetes between 2003 and 2015. After excluding patients with other causes of liver disease, we formed PS using 85 characteristics. The primary outcome was a composite NAFLD progression outcome. Primary analysis examined odds of outcome in PS-matched cohort. Post-hoc analysis included a PS-matched cohort of statin users with intensive lowering of low-density lipoprotein-cholesterol (LDL-C) vs low-intensity lowering. We matched 34,102 pairs from 300,739 statin users and 38,038 non-users. The composite outcome occurred in 8.8% of statin users and 8.6% of non-users (odds ratio (OR) 1.02, 95% confidence interval (95% CI) 0.97-1.08). In the post-hoc analysis, intensive lowering of LDL-C compared to low-intensity showed increased NAFLD progression (OR 1.21, 95% CI 1.13-1.30). This study showed that statin use in patients with diabetes was not associated with decreased or increased risk of NAFLD progression. Intensive LDL-C lowering, compared to low-intensity LDL-C lowering, was associated with an increased risk of NAFLD progression.

Abstract TP250: Poor Control of Hyperlipidemia Prior to Ischemic Stroke

Introduction: Hyperlipidemia is a key modifiable risk factor for ischemic stroke. Data suggest a strong correlation between low-density lipoprotein cholesterol (LDL) levels and the incidence of cardiovascular events. Few studies have addressed the scope of LDL undertreatment prior to ischemic stroke. Methods: A retrospective analysis was conducted on patients with ischemic stroke to study patterns of hyperlipidemia undertreatment using LDL levels as a marker. A total of 826 patients admitted from 2018-2020 were stratified into three LDL categories: 1) High (130-159), 2) Very High (160-189), and 3) Extremely High (190 or higher). A chi-squared analysis was performed to determine if there was a significant difference in proportion based on sex, race, age, diabetes (DM) status, history of heart disease and statin use among patients across the three LDL categories. An ANOVA analysis was also performed to determine if a significant difference exists between the mean ages of the three LDL categories. Results: Of the 826 patients, there were 178 patients (21.5%) whose LDL-C values were greater than 130. 106 (12.8%) were classified as High, 50 (6.0%) as Very High, and 22 (2.7%) as Extremely High. For the High group, 61 (57.5%) were male, 29 (27.4%) had DM, 32 (30%) were older than 70, and 89 (84%) had a history of heart disease. For the Very High group, 16 (32%) had DM and 40 (80%) had a history of heart disease. For the Extremely High group, 32% had DM and 36% had heart disease. There was no significant correlation between the three LDL categories and the various patient characteristics. Conclusion: A broad group of patients (including those of different sexes, races, and ages) presented with markedly elevated LDL at the time of an ischemic stroke. Despite the recommendation for intensive LDL lowering with DM and heart disease, a large portion of patients with these conditions were poorly controlled. Achieving guideline adherence for lipid control could reduce the stroke rate, especially for those with DM and prior heart disease.

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality

Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Genetically predicted apoB, LDL-C, and TG. The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

Impact of Intensive Low-Density Lipoprotein Cholesterol-Lowering Therapy on Coronary Artery Plaques in Acute Coronary Syndrome

Acute coronary syndrome (ACS) is associated with a high incidence of unstable plaques beyond the culprit lesion, leading to early recurrence of cardiovascular events. Coronary computed tomography angiography (CCTA) can be used to noninvasively observe plaques throughout the coronary arteries. To evaluate the impact of intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy on quantitative changes in coronary plaque, assessed using CCTA in a study population with ACS. In total, 81 consecutive patients with ACS who underwent CCTA at discharge and at 1-year follow-up from April 2018 to March 2020 were analyzed. The patients were divided into 2 groups: those who achieved LDL-C <70 mg/100 ml and those who did not. Changes in plaque morphology within and between the 2 groups were compared using CCTA. A total of 198 vessels were analyzed. The calcified plaque volume was significantly increased in the LDL-C <70 group (65.8 ± 80.1 mm3 to 73.6 ± 83.7 mm3, p=0.007), whereas no significant change was observed in the LDL-C ≥70 group (106.9 ± 161.7 mm3 to 105.7 ± 137.5 mm3, p=0.552). Percent change in low-attenuation plaque volume in the LDL <70 group was significantly lower than in the LDL-C ≥70 group (17.2 ± 90.9% vs 84.4 ± 162.6%, p=0.020). Receiver operating characteristic curve analysis demonstrated that the target LDL-C level for low-attenuation plaque volume regression was 64 mg/100 ml. In conclusion, noninvasive CCTA demonstrated that intensive LDL-C lowering in high-risk patients with ACS could potentially lead to plaque stabilization.

Effect of proprotein convertase subtilisin/kexin type 9 inhibition on cancer events: A pooled, post hoc, competing risk analysis of alirocumab clinical trials.

Assess the risk of new and worsening cancer events among participants who received the lipid-lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Pooled post hoc analysis. Six phase 3 or phase 4 placebo-controlled randomised trials with alirocumab. A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low-density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high-intensity or maximum-tolerated statin therapy. The first new or worsening incident cancer events were assessed during the treatment-emergent adverse event period. Four outcomes were evaluated: any-neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancers, and stricter definition of hormone-sensitive cancers. Sub-distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancer and strict definition of hormone-sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub-distribution hazards ratio [95% CI], 0.93 [0.82-1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub-distribution hazards ratio 0.83; 95% CI, 0.70-0.99). Intensive low-density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events.

Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum.

Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.

Interrelation between baseline plaque characteristics and changes in coronary atherosclerosis with the PCSK9-inhibitor alirocumab: insights from the PACMAN-AMI randomized trial

Abstract Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p&amp;lt;0.001). Compared with placebo (statin alone), alirocumab added to statin resulted in greater PAV reduction (−2.13% vs. −0.92%; p&amp;lt;0.001), greater maxLCBI4mm reduction (−79.42 vs. −37.60; p=0.006), and greater increase in FCTmin (62.67 vs. 33.19 μm; p=0.001). Changes in PAV and maxLCBI4mm were inversely related to on-treatment LDL-C levels, and change in FCTmin was positively related to on-treatment LDL-C levels (Figure 1). Across all patients, we found significant, inverse relationships between change in PAV and baseline PAV [slope: −0.072 (95% CI −0.101 to −0.042); p&amp;lt;0.001], between change in maxLCBI4mm and baseline maxLCBI4mm [slope: −0.437 (95% CI −0.505 to −0.369); p&amp;lt;0.001], and between change in FCTmin and baseline FCTmin [slope: −0.436 (95% CI −0.541 to −0.332); p&amp;lt;0.001]; these findings indicate greater PAV and maxLCBI4mm regression in lesions with greater PAV and LCBI4mm at baseline, and greater fibrous cap thickening in lesions with thinner fibrous caps at baseline. Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

†Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled Post hoc Analysis of the phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

<h3>Lead Author's Financial Disclosures</h3> Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. <h3>Study Funding</h3> Novartis Pharma AG, Basel, Switzerland. <h3>Background/Synopsis</h3> Approximately 25% of patients with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD) involving 2 or more coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular events (MACE) and death. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDL-C) concentrations and MACE incidence in patients with PVD. Inclisiran is a small interfering RNA agent targeting PCSK9 messenger RNA that is well tolerated and provides effective and sustained LDL-C reductions. <h3>Objective/Purpose</h3> To describe the effect of inclisiran vs placebo in patients with and without PVD. <h3>Methods</h3> This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or ASCVD or its risk equivalents randomized 1:1 to 300mg inclisiran sodium (equivalent to 284mg inclisiran) or placebo at baseline, Day 90, and 6 monthly thereafter in ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800). Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 to Day 540, with both evaluated by PVD presence or absence, and safety over 540 days. <h3>Results</h3> Baseline characteristics for 470 patients (13.6%) with PVD and 2984 (86.4%) without PVD were generally balanced between treatment arms in both groups, with higher cardiovascular risk factors and lower LDL-C concentrations in patients with PVD (Table 1). Mean (95% CI) placebo-corrected LDL-C percentage changes from baseline to Day 510 with inclisiran were −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in those without (Table 2). Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were similar between treatment arms irrespective of PVD status, although reported TESAEs trended higher with PVD in both treatment arms (Table 2). Clinically relevant injection site TEAEs were more frequent with inclisiran vs placebo in both groups; all were mild or moderate. Few patients had clinically relevant laboratory measurements (Table 2). <h3>Conclusions</h3> Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in patients with ASCVD irrespective of their PVD status, with a safety profile similar to that of placebo except for a modest increase in mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in patients with PVD, which was likely due to their more advanced disease. Since patients with PVD are at high risk of cardiovascular events, intensive LDL-C lowering may be beneficial to reduce this risk.

Low levels of low-density lipoprotein cholesterol, intracerebral haemorrhage, and other safety issues: is there still a matter of debate?

Although some observational studies suggest a potential association of low levels of low-density lipoprotein cholesterol (LDL-C) with intracerebral haemorrhage (ICH), these analyses have issues of confounding where other factors (e.g. older age, frailty) that likely explain the findings, and the number of events was very low. More recent results from randomized clinical trials have not found an increased risk in ICH, most notably trials using PCSK9 inhibitors that achieve very low levels of LDL-C, but also in the long-term follow-up of the IMPROVE-IT trial. Also, other statin-associated safety issues, including new onset diabetes and the cancer risk should not be the reason of statin discontinuation, especially for the former, the benefits highly outweigh the risk (even 5×), and for the latter, there is no confirmed link suggesting any increased risk, in opposite, data exist suggesting benefits of statin therapy in cancer prevention. Furthermore, use of intensive lipid-lowering strategies with statins and non-statin drugs leads to decrease of ischaemic major adverse cardiac events, without safety concern, in a large population of patients with atherosclerotic cardiovascular disease (ASCVD). These data should promote the concept ‘the earlier, the lower, the longer, the better’ for the lipid management of patients with ASCVD. While few uncertainties remain in several populations that have been underrepresented in clinical trials (African American and Asian patients, low weight individuals), the most recent data with intensive LDL-C lowering with PCSK9 inhibitors are reassuring that the benefit outweighs any possible risk.

Serum Lipid Profiles and All-Cause Mortality: A Retrospective Single Center Study on Chinese Inpatient Centenarians.

ObjectivesTo analyze the serum lipid profiles and investigate the relationship between the lipoprotein cholesterol levels and all-cause mortality in Chinese inpatient centenarians.DesignRetrospective study.MethodsCentenarians aged 100 years and older were admitted from January 2010 to January 2021 in our hospital. All centenarians completed a follow up visit till April 2021 of all-cause mortality and serum lipid profiles, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels. Cox proportional hazard models were used to assess the association between lipid profiles and all-cause mortality.Results(1) These 121 centenarians on average were 100.85 ± 1.37 years old (100~107 years), including 114 males and 7 females. (2) The rate of treatment with lipid-lowering drugs was 69.4%, and the lipid-lowering drugs were mainly statins (63.6%). (3) The results of serum lipid profiles were as follows: TC 3.90 ± 0.69 mmol/L, TG 1.36 ± 0.55 mmol/L, HDL-C 1.14 ± 0.24 mmol/L, and LDL-C 2.05 ± 0.46 mmol/L. (4) The median follow-up time was 589 days (95% CI: 475, 703), and the all-cause mortality rate was 66.1%. (5) Multivariable analysis showed that higher TC level (HR = 1.968, 95% CI = 1.191–3.253, P = 0.008), lower LDL-C level (HR = 0.379, 95% CI = 0.212–0.677, P = 0.001) was independent factors contributed to all-cause mortality. Sensitivity analysis showed that the above results were stable. The therapy and complication morbidity did not present significant publication bias.ConclusionsThe serum lipid profiles of Chinese inpatient centenarians were lower than those of the previous studies. Low LDL-C level was associated with an increased risk of all-cause mortality, which may indicate that more intensive lowering of LDL-C had a potential adverse effect on all-cause mortality for centenarians.

Evidence for intensive LDL-C lowering for acute coronary syndrome: Recommendations from the Lipid Association of India

Patients with acute coronary syndrome (ACS) have a high risk of subsequent adverse cardiovascular outcomes, particularly within the first 30 days. Although it is well documented that initiation of statin therapy in the setting of ACS improves short- and long-term cardiovascular outcomes, and achievement of lower levels of low density lipoprotein cholesterol (LDL-C) incrementally improves outcomes, many patients with ACS have persistent hypercholesterolemia after discharge from the hospital. This is a missed opportunity that prompted the Lipid Association of India to develop recommendations for earlier initiation of more aggressive LDL-C lowering treatment, particularly for patients of South Asian descent who are well-documented to have earlier onset of more aggressive atherosclerotic cardiovascular disease. The Lipid Association of India recommends individualized aggressive LDL-C goals after ACS, which can be rapidly achieved with high intensity statin therapy and subsequent goal-directed adjunctive treatment with ezetimibe and PCSK9 inhibitors. Improved treatment of hypercholesterolemia achieved within weeks after ACS has the potential to reduce the high rate of morbidity and mortality in these high risk patients.

Intensive low-density lipoprotein cholesterol lowering improves fibrin clot properties: Association with lipoproteins and C-reactive protein

ObjectiveDense fibrin networks resistant to lysis characterize coronary artery disease (CAD) patients. We investigated whether a statin-induced decrease of low-density lipoprotein cholesterol (LDL-C) could improve fibrin clot phenotype in CAD patients. MethodsWe recruited 130 consecutive patients with advanced CAD (baseline LDL-C of 4.4 [IQR, 3.8–4.8] mmol/L), who on statins did not achieve the LDL-C goal based on the 2016 ESC/EAS guidelines. On standard statin treatment and after 6–12 months of high-dose statin treatment (atorvastatin 80 mg/day or rosuvastatin 40 mg/day), plasma fibrin clot permeability (Ks), clot lysis time (CLT), thrombin generation, coagulation and fibrinolytic factors were determined. ResultsAfter a median high-dose statin therapy of 7 months there was 25% reduction in LDL-C associated with increased Ks and shorter CLT, together with lower thrombin activatable fibrinolysis inhibitor, factor VIII, D-dimer, and C-reactive protein (CRP); thrombin generation was unaltered. The patients who achieved the therapeutic goal (n = 49, 37.7%) had 29.2% increase in Ks and 16.3% shorter CLT compared with the standard therapy, while there were no similar changes in the remaining patients. After adjustment for potential confounders, including CRP, an increase in Ks (by 1 × 10−9 cm2) and decrease in CLT (by 10 min) were independently predicted by on-treatment LDL-C goal (odds ratio [OR] 6.23, 95% confidence interval [CI] 1.97–20.33 and OR 3.11, 95% CI 1.05–8.99, respectively). ConclusionsFor the first time we showed that a decrease of LDL-C ≤ 1.8 mmol/L, or a reduction of at least 50% if the baseline LDL-C is between 1.8 and 3.5 mmol/L, is associated with favorable alterations to fibrin clot phenotype, with a stronger impact of lipoprotein reduction than CRP lowering, which might suggest that other potent cholesterol-lowering drugs can exert similar antithrombotic actions.

Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention

The benefits and risks associated with intensive low-density lipoprotein cholesterol (LDL-C)-lowering statin-based therapies to lessen the risk of recurrent stroke have not been established. To conduct a meta-analysis of randomized clinical trials to evaluate the association of more intensive vs less intensive LDL-C-lowering statin-based therapies with outcomes for patients with ischemic stroke. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1970, to July 31, 2021. This meta-analysis included randomized clinical trials that compared more intensive vs less intensive LDL-C-lowering statin-based therapies and recorded the outcome of recurrent stroke among patients with stroke. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Relative risk (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive LDL-C lowering with primary and secondary outcomes. The primary outcome was recurrent stroke, and the secondary outcomes were major cardiovascular events and hemorrhagic stroke. The final analysis included 11 randomized clinical trials with 20 163 patients (13 518 men [67.0%]; mean [SD] age, 64.9 [3.7] years) with stroke. The mean follow-up was 4 years (range, 1-6.1 years). Pooled results showed that more intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of recurrent stroke compared with less intensive LDL-C-lowering statin-based therapies (absolute risk, 8.1% vs 9.3%; RR, 0.88; 95% CI, 0.80-0.96) and that the benefit associated with these LDL-C-lowering therapies was not different among LDL-C-lowering strategies (statins vs no statins: RR, 0.90; 95% CI, 0.81-1.01; more statins or ezetimibe vs less statins or ezetimibe: RR, 0.77; 95% CI, 0.62-0.96; and proprotein convertase subtilisin/kexin type 9 inhibitors plus statins vs placebo plus statins: RR, 0.90; 95% CI, 0.71-1.15; P = .42 for interaction). More intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of major cardiovascular events, but with an increased risk of hemorrhagic stroke, compared with less intensive LDL-C-lowering statin-based therapies. More intensive LDL-C-lowering statin-based therapies were associated with a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR, 0.79; 95% CI, 0.69-0.91), but not in trials with most patients not having evidence of atherosclerosis (RR, 0.95; 95% CI, 0.85-1.07; P = .04 for interaction), compared with less intensive LDL-C-lowering statin-based therapies. This study suggests that the benefits and risks of more intensive LDL-C-lowering statin-based therapies for recurrent stroke risk reduction might be more favorable than the benefits and risks of less intensive LDL-C-lowering statin-based therapies, especially for patients with evidence of atherosclerosis.

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

Efficacy and safety of inclisiran in patients with polyvascular disease: pooled, post hoc analysis of the ORION-9, ORION-10 and ORION-11, phase 3 randomised controlled trials

Abstract Background Approximately 25% of patients (pts) with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD), which involves ≥2 coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular (CV) events (MACE) and death.[1,2] Agents that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) resulted in reduced low-density lipoprotein cholesterol (LDL-C) concentration and MACE incidence in pts with PVD.[3,4] Inclisiran is a small interfering RNA (siRNA) agent targeting PCSK9 messenger RNA that provided effective and sustained reduction in LDL-C concentration and was well tolerated.[5] Purpose To describe the effect inclisiran versus placebo (pbo) in pts with and without PVD. Methods This was a post hoc analysis from the ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800) trials. Pts with heterozygous familial hypercholesterolaemia, ASCVD or risk equivalents were randomised 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or pbo at baseline, Day 90, and 6-monthly thereafter. LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 and to Day 540 were evaluated by presence or absence of PVD (intention-to-treat population). Safety was assessed over 540 days (safety population). Results Of 3454 pts, 470 (13.6%) had PVD and 2984 (86.4%) did not. Baseline characteristics were generally balanced between treatment arms in both groups (Table 1). A greater proportion of pts with vs without PVD had CV risk factors at baseline. Mean LDL-C concentration at baseline was lower in pts with vs without PVD (Table 1). Mean (95% CI) pbo-corrected LDL-C percentage change from baseline to Day 510 with inclisiran was −48.9 (−55.6 to −42.2) in pts with PVD and −51.5 (−53.9 to −49.1) in pts without PVD (Table 2). Proportions of pts with treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events (TESAE) were similar between treatment arms irrespective of PVD status although reported TESAEs were numerically greater in both treatment arms for pts with PVD (Table 2). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo in both groups but all were mild or moderate (Table 2). Proportions of pts with clinically relevant laboratory measurements were low and similar between treatment arms for both groups (Table 2). Conclusions Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in pts, irrespective of their PVD status, with a safety profile similar to pbo, except for a modest excess of mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in pts with PVD, which was likely due to their more advanced disease. Since pts with PVD are at high risk of CV events, intensive LDL-C lowering may be beneficial to reduce this risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland

Past, Present, and Future of Familial Hypercholesterolemia Management.

Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.

The Potential Benefits and Costs of an Intensified Approach to Low Density Lipoprotein Cholesterol Lowering in People with Abdominal Aortic Aneurysm

The aims of this study were to assess the incidence of major vascular events (MVE) and peripheral vascular events (PVE) in people with a small asymptomatic abdominal aortic aneurysm (AAA) and model the theoretical benefits and costs of an intensified low density lipoprotein cholesterol (LDL-C) lowering programme. A total of 583 participants with AAAs measuring 30 - 54mm were included in this study. The control of LDL-C and prescription of lipid lowering drugs were assessed by dividing participants into approximately equal tertiles depending on their year of recruitment into the study. The occurrence of MVE (myocardial infarction, stroke, cardiovascular death, and coronary or non-coronary revascularisation) and PVE (non-coronary revascularisation, AAA repair, and major amputation) were recorded prospectively, and the incidence of these events was calculated using Kaplan-Meier analysis. The relative risk reduction reported for these events in a previous randomised control trial (RCT) was then applied to these figures to model the absolute risk reduction and numbers needed to treat (NTT) that could theoretically be achieved with a mean LDL-C lowering of 1mmol/L. The maximum allowable expense for a cost effective intensive LDL-C lowering programme was estimated using a cost utility analysis. At entry, only 28.5% of participants had an LDL-C of < 1.8mmol/L and only 18.5% were prescribed a high potency statin (atorvastatin 80mg or rosuvastatin 40mg). The five year incidences of MVE and PVE were 38.1% and 44.7%, respectively. It was estimated that if the mean LDL-C of the cohort had been reduced by 1mmol/L, this could have reduced the absolute risk of MVE and PVE by 6.5% (95% CI 4.4 - 8.7; NNT 15) and 5.3% (95% CI 1.4 - 7.5; NNT 19), respectively. It was estimated that the maximum allowable expense for a cost effective LDL-C lowering programme would be between $1 239 AUD (€768) and $1 582 AUD (€981) per person per annum over a five year period. People with a small asymptomatic AAA are at high risk of MVE and PVE. This study provides evidence of the possible benefits and allowable expense for a cost effective intensive LDL-C lowering programme in this population.

Halving cardiovascular risk with combined blood pressure and cholesterol lowering – Why are we not there yet?

BackgroundWe aimed to assess whether the modest major adverse cardiovascular events (MACE) reductions in previous trials testing combined blood pressure (BP) and low density lipoprotein cholesterol (LDL-C) reduction were due to modest risk factor reduction and/or a negative interaction, whereby the joint effects of therapy are less than expected. MethodsWe performed a systematic review of randomized controlled trials comparing patients who received combination BP and cholesterol lowering treatment versus placebo. We calculated the expected relative risk reduction (RRR) in MACE based on the observed reductions in systolic BP and LDL-C in each trial and previous meta-analysis of the individual modalities. ResultsAll five included trials achieved small SBP reductions (range 1 to 6 mmHg) and small-to-moderate LDL-C reductions (range 0.5 to 1.1 mmol/L), which were all less than expected. Each of the three largest trials achieved significant reductions in MACE and the observed vs expected RRRs were closely aligned: - ASCOT observed RRR 32% (95% CI 18–43%) vs expected RRR 24% (95% CI 20–28%); HOPE-3 observed RRR 28%, (95% CI 10–42%) vs expected RRR 28% (95% CI 23%–31%); TIPS-3 observed RRR 20% (95% CI 0%–36%) vs expected RRR 21% (95% CI 18–24%). ConclusionsMACE reductions seen in past trials of combined BP and LDL-C reflect the degree of risk factor reduction. Sustained and substantial reductions in BP and LDL-C (eg. ≥15 mmHg and ≥ 1.5 mmol/L) are required to halve cardiovascular risk, which in turn requires long-term adherence to intensive LDL-C lowering and combination BP therapy.