Achieved Low-density Lipoprotein Cholesterol Levels Research Articles

Independence of Lipoprotein(a) and Low-Density Lipoprotein Cholesterol-Mediated Cardiovascular Risk: A Participant-Level Meta-Analysis.

Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48]). These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.

Physician disagreement with treatment guidelines as a critical barrier to achieving low-density lipoprotein cholesterol targets in very high-risk patients: an implementation science study

Abstract Background/Introduction The challenges that physicians face in implementing evidence-based lipid-lowering therapy in patients at high risk of atherosclerotic cardiovascular disease (ASCVD) are relatively undocumented. Purpose This study aimed to provide insights into the challenges that Korean physicians face in assisting their high-risk ASCVD patients in achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) levels. Methods We enrolled 704 patients from 10 tertiary hospitals in South Korea, between November 2020 and November 2022. These patients were at very high risk of ASCVD, with baseline LDL-C levels ≥70mg/dL (1.8 mmol/L) while receiving maximally tolerated statins and/or ezetimibe. We measured the proportion of participants achieving LDL-C levels <70mg/dL at visit 1(0)/ visit 2(6-16)/ visit 3 (18-30 weeks), and recorded physician feedback on lipid-lowering treatment strategies. Results Out of the 704 enrolled patients (mean [IQR] age, 66.0 [59–72] years; 580 men [82.4%]), the median (IQR) baseline LDL-C level was 82.0 (74.0–94.5) mg/dL. Lipid-lowering therapy at baseline included statins in 99.0% (with 1.0% statin intolerant) or statins and ezetimibe in 56.4%. The proportion of participants achieving LDL-C levels <70mg/dL at each visit were 0%, 56.3%, and 58.7%, respectively. Among 307 patients on maximally tolerated statins at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 171 (55.7%) of those patients. (Figure 1) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (70.8%), followed by the patient’s refusal for reasons other than the cost (8.2%), medical limitations such as comorbidities (7.0%), and drug costs (6.4%). Among 397 patients on maximally tolerated statins and ezetimibe at baseline, physicians did not have an intention to intensify the lipid-lowering treatment regimen in 299 (75.3%) of those patients. (Figure 2) Physician disagreement with the guidelines was the major reason for not using the recommended therapy (46.2%), followed by the patient’s refusal for reasons other than the cost (15.7%), medical limitations such as comorbidities (14.4%), and drug costs (12.7%). Conclusion In this implementation science study, the proportion of patients at very high risk of ASCVD who achieved LDL-C levels <70mg/dL via lipid-lowering therapy was less than 60%. Physician disagreement with the guidelines was the main reason for not adopting the recommended intensified LDL-C lowering therapy.Figure 1Figure 2

Estimating the effect of inclisiran on hypercholesterolemia and primary prevention of cardiovascular disease: the NHANES 1999–2018 study

BackgroundHypercholesterolemia has been identified as an independent predictor of cardiovascular disease (CVD). Inclisiran, an innovative small interfering RNA agent, is anticipated to result in a notable reduction of approximately 50% in low-density lipoprotein cholesterol (LDL-C) levels. Given its transformative impact, this study scrutinized the eligibility of the US population for inclisiran treatment and evaluated its potential effects on hypercholesterolemia and the primary prevention of CVD.MethodsThis study applied the eligibility criteria from the ORION 10 and 11 trials to the 1999–2018 National Health and Nutrition Examination Survey (NHANES) dataset to estimate the size of the eligible population for atherosclerotic cardiovascular disease (ASCVD) and ASCVD-risk equivalents. Utilizing the reduction in LDL-C levels from ORION 10, this study predicted the impact of inclisiran on LDL-C levels among ASCVD patients. Similarly, leveraging the changes in lipid levels from ORION 11, this study predicted inclisiran’s effect on the 10-year change in CVD risk and preventable CVD events in the ASCVD-risk equivalents population, employing the Framingham CVD Risk Score.ResultsThe study identified 579 ASCVD patients (5 million) and 382 ASCVD-risk equivalents (2.66 million) who met the eligibility criteria from ORION 10 and 11. Among the ASCVD population, 3.5 million (70.2%) would achieve a ≥ 50% reduction in LDL-C levels after treatment. Furthermore, 4.6 million (91.3%) would achieve LDL-C levels < 70 mg/dL, and 3.8 million (75%) would achieve LDL-C levels < 55 mg/dL after treatment. For the ASCVD-risk equivalents population, the estimated 10-year CVD risk would decrease from 25.3 to 17.7%, an absolute reduction of 7.6% and a relative reduction of 30% following inclisiran treatment, potentially preventing 202,353 CVD events over a decade, including 138,084 coronary heart disease cases, 37,351 strokes, and 23,894 congestive heart failure cases.ConclusionsInclisiran has the potential to substantially reduce the prevalence of hypercholesterolemia and prevent nearly 200,000 CVD events in eligible US adults.

Effect of rosuvastatin versus atorvastatin on new-onset diabetes mellitus in patients treated with high-intensity statin therapy for coronary artery disease: a post-hoc analysis from the LODESTAR randomized clinical trial

BackgroundThe impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial.MethodsIn the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest.ResultsAmong 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was < 70 mg/dL (13.9% versus 8.0%; HR = 1.79, 95% CI 1.18 to 2.73, P = 0.007).ConclusionsAmong CAD patients receiving high-intensity statin therapy, the incidence of NODM was not significantly different between rosuvastatin and atorvastatin. However, a drug effect of the statin type on NODM was observed when the achieved LDL-C level was < 70 mg/dL.Trial registrationClinicalTrials.gov, Identifier: NCT02579499.Graphical abstract

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.

Prescription of lipid-lowering therapy, LDLc control, and risk of MACE in patients after ST-elevation myocardial infarction in Mexico

Abstract Funding Acknowledgements None. Background/Introduction Optimal control of low-density lipoprotein cholesterol (LDLc) has been demonstrated to reduce cardiovascular event rates after ST-elevation myocardial infarction (STEMI). However, real-world data shows that a low proportion of patients achieve LDLc targets. Furthermore, the association of LDLc levels and major cardiovascular adverse events (MACE) in post-STEMI patients is limited in developing countries. Purpose In this study, we aimed to assess the prescription patterns of lipid-lowering therapies, LDLc control, and their impact on the risk of MACE after STEMI in Mexico. Methods We conducted a prospective observational study of patients with STEMI. LDLc levels and prescriptions of lipid-lowering therapy were assessed during the first scheduled visit following STEMI hospital discharge. LDLc control was determined in accordance with the 2023 European Society of Cardiology Acute Coronary Syndrome Guidelines, which recommend achieving LDLc levels below 55 mg/dL for secondary prevention. Patients were categorized as controlled (if LDLc &amp;lt;55 mg/dL) and not controlled (if LDLc &amp;gt;55 mg/dL) and were followed for a median of 4.5 years to evaluate the rate of MACE, including cardiovascular death, cardiogenic shock, recurrent MI, and heart failure. Results We included 447 patients with a mean age of 57.87 (± 10.5 years), predominantly male (84.5%). Hypertension (43.8%), smoking (41.1%), type 2 diabetes mellitus (33.5%), obesity (26.6%), and dyslipidemia (21.4%) were highly prevalent. The median LDLc level in the total population was 65.4 mg/dL (IQR 49.2- 87.7). Among these, 34% (152) were considered controlled, while 66% (295) were not. Baseline clinical characteristics did not significantly differ among the groups. Prescription of high-intensity statins reached 94.7%, and ezetimibe and PCSK-9i were used in 1.8% and 0.4% of cases, respectively. We observed no statistically significant difference (Hazard ratio: 1.03, 95% confidence interval 0.74-1.73) in the rate of MACE based on LDLc control (Fig.1). The risk of MACE was also not different based on the use of high-intensity statins. Conclusions In this real-world study of patients post-STEMI, LDLc control was achieved in just one-third of the population. While the prescription of high-intensity statins was high, combination therapy was low. We did not observe a statistically significant association with an increased long-term risk of MACE; however, we noted a higher rate of events compared with other series.

Abstract 16434: 104-Week Safety and Effectiveness of Low-Density Lipoprotein Cholesterol-Lowering Therapy With Evolocumab in Patients With Familial Hypercholesterolemia/Hypercholesterolemia in Japan: Results of Post-Marketing Surveillance

Introduction: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia (HC). Aims: This study assessed the 104-week safety and effectiveness of low-density lipoprotein cholesterol (LDL-C)-lowering therapy with evolocumab in patients with FH (homo/heterozygous) and HC in a real-world setting in Japan. Methods: Overall, 3721 and 2792 patients (108 and 91 homozygous FH, 2007 and 1613 heterozygous FH, 1606 and 1088 HC) from 668 clinical sites comprised the safety and effectiveness analysis sets, respectively. Primary safety endpoints: incidence (%) and number of patients with adverse drug reactions and serious adverse events. Effectiveness endpoints: % change in LDL-C from baseline at Week 12 (n=2386, primary endpoint) and Weeks 4-104 (secondary endpoint). Results: Mean age: 63.2 years; female: 33.8%. The mean±SD follow-up duration was 545.5±218.8 days. Adverse drug reaction subject incidence was 5.2%. Serious adverse event subject incidence was 8.9% (330/3721). The adverse event incidences of myocardial infarction and stroke were 0.6% (n=23/3721) and 0.6% (n=21/3721; 0.3% ischemic stroke [n=12]/0.2% hemorrhagic stroke [n=9]), respectively. Table 1 shows adverse events by lowest achieved LDL-C levels. The mean±SD % change in LDL-C from baseline to Weeks 12 and 104 were –45.7%±28.2% (n=84) and –50.9±21.1% (n=48) in homozygous FH patients ( P &lt;0.001 vs baseline; two-sided paired t -test), –56.0%±28.9% (n=1440) and –54.5±28.3% (n=905) in heterozygous FH patients ( P &lt;0.001), and –63.3%±23.7% (n=862) and –60.8±28.1% (n=352) in HC patients ( P &lt;0.001), respectively. Conclusions: There were no trends between the lowest achieved LDL-C levels and adverse events in Japanese patients. Evolocumab was well tolerated and sustained LDL-C reduction in patients with FH and HC in a real-world clinical setting in Japan.

Abstract 14664: Integrated Atherosclerotic Cardiovascular Disease Lipid Management Initiative

Introduction: In the US, 48.6% of adults ≥40 years of age are eligible for statin therapy. Since the release of updated ACC/AHA guidelines in 2018, statin use and mean low-density lipoprotein cholesterol (LDL-C) levels remained unchanged, suggesting that enhanced efforts to understand and implement guideline-directed therapies are needed. Objective: The ASCVD Lipid Management Initiative’s primary goals are to increase the proportion of very-high risk ASCVD patients achieving LDL-C levels &lt; 70 mg/dl and to increase appropriate referrals to lipid management clinics. Methods: The AHA has engaged a cohort of six diverse health systems (caring for 40,000 patients) to characterize current clinical lipid management care pathways, identify barriers to treatment and to partner to refine lipid management strategies. The methods of the 3-year intervention focus on implementation science, peer-to-peer learning, and patient engagement. Results: In the first 12 months of the intervention, health systems collectively identified several common barriers and developed corrective actions to promote standardization of lipid management ( Table ). Organizations are participating in regular quality improvement discussions with an AHA consultant and attending quarterly ASCVD Learning Collaborative calls to share insights and strategies. This initiative has implemented a Referral to Lipid Management measure in the Get With The Guidelines(R) - Stroke and Coronary Artery Disease registries and piloted an outpatient registry with a focus on ASCVD and risk factor related measures. A unique identifier system is being developed to follow patients from inpatient to outpatient settings, as well as an app to facilitate patient activation. Conclusion: Together, AHA and health systems are identifying barriers to lipid management and implementing strategies to optimize ASCVD care pathways. We will evaluate the impact of the intervention on LDL-C and referrals for lipid management.

Statin therapy in individuals with intermediate cardiovascular risk

BackgroundAs intermediate cardiovascular risk group accounts for a large part of the total population, determining appropriate cholesterol target in this population is critical. Herein, we investigated the optimal low-density lipoprotein cholesterol (LDL-C) level in individuals with intermediate cardiovascular risk after statin therapy. MethodsThis was a nationwide observational and validation cohort study (median duration of follow-up: 7.5 and 8.7 years, respectively), using data from the Korean National Health Insurance Service and a tertiary hospital database. Among individuals who underwent regular health examinations, those with ≥2 cardiovascular risk factors except diabetes mellitus, LDL-C 100–189 mg/dL, and newly used statins were enrolled. Of the 358,694 screened people, 57,594 met the inclusion criteria, of whom 27,793 were finally analyzed. The study population was stratified according to post-treatment LDL-C levels as follows: <100, 100–119, 120–139, and ≥ 140 mg/dL. The primary outcome variable was composite cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). From the patients screened of Severance Hospital cohort, 1859 meeting inclusion criteria were used for validation. ResultsThe rates of composite events ranged from 7.74 to 9.10 (mean 8.38)/1000 person-years in the three lower LDL-C groups. Adjusted hazard ratios (aHRs) ranged from 0.78 to 0.95 in the three groups with lower LDL-C, and a lower event risk was more evident in the groups that achieved LDL-C levels <120 mg/dL (p = 0.001–0.009). The total mortality risk did not differ between groups. In the validation cohort, the mean rate of composite events was 10.83/1000 person-years. aHRs ranged from 0.52 to 0.78 in the groups with lower LDL-C, and a lower risk was more obvious in patients who achieved LDL-C levels <100 mg/dL (p = 0.006–0.03). ConclusionsIndividuals with intermediate cardiovascular risk who achieved LDL-C levels <120 mg/dL after statin therapy had lower event risk. This result provides clinically useful evidence on target LDL-C levels in this population.

Association of Strict Versus Lenient Cholesterol Lowering with Cardiac Outcomes, Diabetes Progression and Complications, and Mortality in Patients with Diabetes Treated with Statins: Is Less More?

Whereas some guidelines recommend statin use to achieve low-density lipoprotein cholesterol (LDL-C) goal < 70 mg/dL for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients at higher risk, others recommend against a target LDL-C level. Achieving a target level < 70 mg/dL commonly requires the use of high intensity statins, which has been associated with higher risk of diabetes progression. The objective of this study is to assess the association of strict (≤ 70 mg/dL) versus lenient (> 70 to100 mg/dL) LDL-C lowering on major adverse cardiovascular events (MACE), diabetes progression, diabetes microvascular complications, and total mortality in patients with diabetes. This was a retrospective propensity score (PS)-matched study from a national cohort of, predominantly male, veterans diagnosed with diabetes without prior cardiovascular disease (from fiscal years 2003-2015), who were initiated on a statin. We created PS to match strict (mean LDL-C during follow-up ≤ 70 mg/dL) versus lenient (mean LDL-C during follow up > 70-100 mg/dL) using 65 baseline characteristics including comorbidities, risk scores, medication classes usage, vital signs, and laboratory data. Outcomes included MACE, diabetes progression, microvascular diabetes complications, and total mortality. From 80,110 eligible patients, we PS-matched 21,294 pairs of statin initiators with strict or lenient LDL-C lowering. The mean (SD) age was 64 (9.5) years and mean (SD) duration of follow-up was 6 (3) years. MACE was similar in the PS-matched groups [6.1% in strict versus 5.8% in lenient; odds ratio (OR): 1.06; 95% confidence interval (95% CI) 0.98-1.15, P = 0.17]. Diabetes progression was higher among the strict vs lenient group (66.7% in strict versus 64.1% in lenient; OR 1.12; 95% CI 1.08-1.17, P < 0.001). There was no difference in microvascular diabetes complications (22.3% in strict versus 21.9% in lenient; OR 1.02; 95% CI 0.98-1.07, P = 0.31) and no difference in total mortality (14.6% in strict versus 15% in lenient; OR 0.97; 95% CI 0.92-1.02, P = 0.20). Strict compared with lenient lowering of LDL-C with statins in men with diabetes without preexisting ASCVD did not decrease the risk of MACE but was associated with an increased diabetes progression. Clinicians should monitor their patients for diabetes progression upon escalating statins to achieve LDL-C levels ≤ 70 mg/dL.

Comparison of on-Statin Lipid and Lipoprotein Levels for the Prediction of First Cardiovascular Event in Type 2 Diabetes Mellitus.

A substantial cardiovascular disease risk remains even after optimal statin therapy. Comparative predictiveness of major lipid and lipoprotein parameters for cardiovascular events in patients with type 2 diabetes mellitus (T2DM) who are treated with statins is not well documented. From the Korean Nationwide Cohort, 11,900 patients with T2DM (≥40 years of age) without a history of cardiovascular disease and receiving moderate- or high-intensity statins were included. The primary outcome was the first occurrence of major adverse cardiovascular events (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death. The risk of MACE was estimated according to on-statin levels of low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), highdensity lipoprotein cholesterol (HDL-C), and non-HDL-C. MACE occurred in 712 patients during a median follow-up period of 37.9 months (interquartile range, 21.7 to 54.9). Among patients achieving LDL-C levels less than 100 mg/dL, the hazard ratios for MACE per 1-standard deviation change in ontreatment values were 1.25 (95% confidence interval [CI], 1.07 to 1.47) for LDL-C, 1.31 (95% CI, 1.09 to 1.57) for non-HDL-C, 1.05 (95% CI, 0.91 to 1.21) for TG, and 1.16 (95% CI, 0.98 to 1.37) for HDL-C, after adjusting for potential confounders and lipid parameters mutually. The predictive ability of on-statin LDL-C and non-HDL-C for MACE was prominent in patients at high cardiovascular risk or those with LDL-C ≥70 mg/dL. On-statin LDL-C and non-HDL-C levels are better predictors of the first cardiovascular event than TG or HDL-C in patients with T2DM.

Appropriateness of Dyslipidemia Management Strategies in Post-Acute Coronary Syndrome: A 2023 Update.

It has been consistently demonstrated that circulating lipids and particularly low-density lipoprotein cholesterol (LDL-C) play a significant role in the development of coronary artery disease (CAD). Several trials have been focused on the reduction of LDL-C values in order to interfere with atherothrombotic progression. Importantly, for patients who experience acute coronary syndrome (ACS), there is a 20% likelihood of cardiovascular (CV) event recurrence within the two years following the index event. Moreover, the mortality within five years remains considerable, ranging between 19 and 22%. According to the latest guidelines, one of the main goals to achieve in ACS is an early improvement of the lipid profile. The evidence-based lipid pharmacological strategy after ACS has recently been enhanced. Although novel lipid-lowering drugs have different targets, the result is always the overexpression of LDL receptors (LDL-R), increased uptake of LDL-C, and lower LDL-C plasmatic levels. Statins, ezetimibe, and PCSK9 inhibitors have been shown to be safe and effective in the post-ACS setting, providing a consistent decrease in ischemic event recurrence. However, these drugs remain largely underprescribed, and the consistent discrepancy between real-world data and guideline recommendations in terms of achieved LDL-C levels represents a leading issue in secondary prevention. Although the cost-effectiveness of these new therapeutic advancements has been clearly demonstrated, many concerns about the cost of some newer agents continue to limit their use, affecting the outcome of patients who experienced ACS. In spite of the fact that according to the current recommendations, a stepwise lipid-lowering approach should be adopted, several more recent data suggest a "strike early and strike strong" strategy, based on the immediate use of statins and, eventually, a dual lipid-lowering therapy, reducing as much as possible the changes in lipid-lowering drugs after ACS. This review aims to discuss the possible lipid-lowering strategies in post-ACS and to identify those patients who might benefit most from more powerful treatments and up-to-date management.

Effect of alirocumab on cataracts in patients with acute coronary syndromes

BackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels.MethodsThe ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab.ResultsOver median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94).ConclusionTreatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts.Trial registrationClinicalTrials.gov Identifier: NCT01663402.

Evolocumab attenuate pericoronary adipose tissue density via reduction of lipoprotein(a) in type 2 diabetes mellitus: a serial follow-up CCTA study

BackgroundPericoronary adipose tissue (PCAT) density is a biomarker of vessel inflammation, which is supposed to be increased in patients with type 2 diabetes mellitus (T2DM). However, whether the coronary inflammation revealed by this novel index could be alleviated after evolocumab treatment in T2DM remains unknown.MethodsFrom January 2020 to December 2022, consecutive T2DM patients with low-density lipoprotein cholesterol ≥ 70 mg/dL on maximally tolerated statin and taking evolocumab were prospectively included. In addition, patients with T2DM who were taking statin alone were recruited as control group. The eligible patients underwent baseline and follow-up coronary CT angiography with an interval of 48-week. To render patients with evolocumab as comparable to those controls, a propensity-score matching design was used to select the matched pairs with a 1:1 ratio. Obstructive lesion was defined as the extent of coronary artery stenosis ≥ 50%; the numbers inside the brackets were interquartile ranges.ResultsA total of 170 T2DM patients with stable chest pain were included [(mean age 64 ± 10.6 [range 40–85] years; 131 men). Among those patients, 85 were in evolocumab group and 85 were in control group. During follow-up, low-density lipoprotein cholesterol (LDL-C) level (2.02 [1.26, 2.78] vs. 3.34 [2.53, 4.14], p < 0.001), and lipoprotein(a) (12.1 [5.6, 21.8] vs. 18.9 [13.2, 27.2], p = 0.002) were reduced after evolocumab treatment. The prevalence of obstructive lesions and high-risk plaque features were significantly decreased (p < 0.05 for all). Furthermore, the calcified plaque volume were significantly increased (188.3 [115.7, 361.0] vs. 129.3 [59.5, 238.3], p = 0.015), while the noncalcified plaque volume and necrotic volume were diminished (107.5 [40.6, 180.6] vs. 125.0 [65.3, 269.7], p = 0.038; 0 [0, 4.7] vs. 0 [0, 13.4], p < 0.001, respectively). In addition, PCAT density of right coronary artery was significantly attenuated in evolocumab group (− 85.0 [− 89.0, − 82.0] vs. − 79.0 [− 83.5, − 74.0], p < 0.001). The change in the calcified plaque volume inversely correlated with achieved LDL-C level (r = − 0.31, p < 0.001) and lipoprotein(a) level (r = − 0.33, p < 0.001). Both the changes of noncalcified plaque volume and necrotic volume were positively correlated with achieved LDL-C level and Lp(a) (p < 0.001 for all). However, the change of PCATRCA density only positively correlated with achieved lipoprotein(a) level (r = 0.51, p < 0.001). Causal mediation analysis revealed Lp(a) level mediated 69.8% (p < 0.001) for the relationship between evolocumab and changes of PCATRCA.ConclusionsIn patients with T2DM, evolocumab is an effective therapy to decrease noncalcified plaque volume necrotic volume, and increase calcified plaque volume. Furthermore, evolocumab could attenuate PCAT density, at least in part, via the reduction of lipoprotein(a).

Current Insights on Dyslipidaemia Management for Prevention of Atherosclerotic Cardiovascular Disease: A Malaysian Perspective.

Dyslipidaemia is highly prevalent in the Malaysian population and is one of the main risk factors for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is recognised as the primary target of lipid-lowering therapy to reduce the disease burden of ASCVD. Framingham General CV Risk Score has been validated in the Malaysian population for CV risk assessment. The Clinical Practice Guidelines (CPG) on the management of dyslipidaemia were last updated in 2017. Since its publication, several newer randomised clinical trials have been conducted with their results published in research articles and compared in meta-analysis. This underscores a need to update the previous guidelines to ensure good quality care and treatment for the patients. This review summarises the benefits of achieving LDL-C levels lower than the currently recommended target of < 1.8mmol/L without any safety concerns. In most high and very high-risk individuals, statins are the first line of therapy for dyslipidaemia management. However, certain high-risk individuals are not able to achieve the LDL-C goal as recommended in the guideline even with high-intensity statin therapy. In such individuals, lower LDL-C levels can be achieved by combining the statins with non-statin agents such as ezetimibe and PCSK9 inhibitors. Emerging non-statin lipid-lowering therapies and challenges in dyslipidaemia management are discussed in this article. The review also summarises the recent updates on local and international guidelines for dyslipidaemia management.

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. URL: https://www. gov; Unique identifier: NCT01764633.

Magnitude of low-density lipoprotein reduction and impact on major cardiovascular outcomes.

Magnitude of low-density lipoprotein reduction and impact on major cardiovascular outcomes.

New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a)

Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). There are abundant and unequivocal data to indicate that low-density lipoproteins (LDL) are a cause of ASCVD. Reduction of plasma low-density lipoprotein cholesterol (LDL-C) by medical therapy such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have proven to significantly reduce the risk of cardiovascular events. However, for many reasons, many patients are not able to achieve LDL-C levels recommended by guidelines on currently available therapies. This has led to the development of new drugs lowering LDL-C, such as inclisiran, bempedoic acid, and evinacumab, in the hope of reducing cardiovascular (CV) risk. Drugs targeting lipoprotein (a) (Lp[a]) also have a role in the prevention of atherosclerosis, with genetic studies having established that 20%-30% of the human population inherits plasma Lp(a) levels in the atherogenic range. In this paper, we will review the recent progress made in the approaches to LDL-C and Lp(a) therapeutic modulation.

Post–Acute Coronary Syndrome Disparities in Guideline-Directed Lipid Therapy and Insufficient Achievement of Optimal Low-Density Lipoprotein

Lipid-lowering therapies are an established cornerstone of secondary prevention. For patients with clinical atherosclerotic cardiovascular disease, guidelines provide a class I recommendation for high-intensity statins. Furthermore, patients with low-density lipoprotein cholesterol (LDL-c) levels >70mg/100ml are considered at a higher risk for recurrent cardiovascular events. Previous trends in guideline-directed lipid therapy (GDLT) for secondary prevention have noted insufficiencies. In this study, we aimed to explore GDLT-prescribing patterns and assess subsequent effects on outcomes through LDL-c reduction. We used a cross-sectional study across a large, multisite university hospital system. Electronic medical records were queried for all admitted patients diagnosed with acute coronary syndrome. Data were collected for age, gender, race, and prescribed lipid medication at discharge and 1 year after discharge. Chi-square analysis was performed to assess the statistical differences in prescription rates and achieved optimal LDL-c levels. A total of 3,386 patients were studied with 2/3 of the population identified as non-Hispanic White men. Men were prescribed GDLT at a statistically significant higher rate than women, and subsequently, men were found to achieve optimal LDL-c at a statistically significant higher rate. Interestingly, Black and Hispanic patients were prescribed GDLT at the highest rates; however, these patients achieved optimal LDL-c levels at the lowest rates (significance only met for Black patients). East Indian patients achieved optimal LDL-c levels at the lowest rate among all racial groups, despite having average GDLT prescription rates. White and Asian groups achieved optimal LDL-c levels at the highest rates, with average GDLT prescription rates. Among all patients, those who achieved LDL-c levels <70mg/100ml were prescribed GDLT at a statistically higher rate than those who did not achieve LDL- c levels <70mg/100ml. We found distinct disparities in both GDLT-prescribing rates and achievement of optimal LDL-c levels for patients presenting with clinical atherosclerotic cardiovascular disease. Our findings may help delineate patients who should be considered at a higher risk for recurrent major adverse cardiovascular events. We also found an interesting paradox between GDLT-prescribing patterns and achievement of optimal LDL-c levels among certain racial groups. However, among all patients who achieved LDL-c levels <70mg/100ml, the majority were prescribed GDLT, supporting the efficacy of statins. Prescribing GDLT does not reliably achieve optimal LDL-c levels across genders and racial groups for unclear reasons. Our study adds to the growing body of knowledge assessing the complexity in secondary cardiovascular prevention.

Identification of Secondary Prevention Patients Eligible for PCSK9 Inhibitors Therapy According to the Routine Clinical Practice in Spain.

Many patients at very high risk of cardiovascular (CV) events would benefit from lipid-lowering therapies (LLT) intensification to decrease their risk. This study aimed to identify the real-world secondary prevention patients potentially eligible for proprotein convertase subtilisin-kexin type9 inhibitors (PCSK9i) in Spain. This retrospective cohort study included adult patients registered in the IQVIA Spanish Electronic Medical Records outpatient database (2014-2020), diagnosed with myocardial infarction (MI), unstable angina (UA), ischaemic stroke (IS), transient ischaemic attack (TIA) or peripheral artery disease (PAD) and with ≥ 1 low-density lipoprotein cholesterol (LDL-C) or total cholesterol measurements. Longitudinal data were collected from the initial diagnosis to the end of the study period or follow-up loss. The study included 9516 patients, 63.9% male, mean (SD) age 67.7 (12.5) years and mean LDL-C 117.3 (38.8) mg/dL. MI, IS and PAD were the most severe events reported during the study period (28.5%, 18.7% and 29.3% of patients, respectively). At the time of last available LDL-C assessment (≥ 3months post-event), 64.4% patients were on LLT. Of those, 45.4%, 46.9% and 7.7% were on high-, moderate- and low-intensity LLT. Overall, 9.6% patients achieved LDL-C < 55mg/dL (24.2% LDL-C < 70mg/dL). Furthermore, 17.9% patients receiving optimized oral LLT showed LDL-C > 100mg/dL (LDL-C reimbursement threshold for PCSK9i in Spain). Up to 82% of patients with atherosclerotic CV disease do not achieve LDL-C levels recommended by the 2019 ESC/EAS guidelines despite being on optimized oral LLT therapy. In 17.9% of these patients LDL-C levels exceed 100mg/dL, being eligible for PCSK9i in Spain.