Greater Reductions In Low-density Lipoprotein Cholesterol Research Articles

Cardiac rehabilitation makes a difference: lipid control targets and prognosis

Abstract Funding Acknowledgements None. Introduction Cardiac rehabilitation (CR) has become a fundamental element in the recovery of patients with acute coronary syndrome, since it achieves greater therapeutic adherence and better control of cardiovascular risk factors (CVRF). Purpose We aim to describe the characteristics of patients with ST-elevation acute coronary syndrome (STEACS) included in a cardiac rehabilitation program, as well as the achievement of prevention objectives and the occurrence of mayor adverse cardiovascular events (MACE). Methods We present a prospective registry of 664 patients admitted to a Coronary Unit with a diagnosis of STEACS during the years 2017-2020. They were classified according to their participation in a CR program. We compared history, lipid-lowering treatment (prior, at discharge and titration), lipid levels at discharge and at 1-year follow-up, and degree of compliance with lipid targets. MACE were observed at 2-year follow-up. Results From 664 patients, 351 were excluded due to lack of follow-up or early mortality. From a total of 313 patients (mean age 59.9±11.2 and 81% male), 55.3% were included in the CR program, with this group presenting a lower mean age (55.46±8.7 vs 65.39±11.5 p<0.001), as well as a higher frequency of a history of early ischemic heart disease and smoking, and a lower frequency of arterial hypertension and diabetes (Table). Lipid-lowering treatment at discharge was similar in both groups. In patients undergoing CR there was a lower level of total cholesterol and low-density lipoprotein cholesterol (LDLc) at one year (126.2±27 vs 137.2±34, p=0.002; 57.8±23 vs 67.5±26, p<0.001) compared to the group without CR. A greater reduction in LDLc (41.4% vs 0.86%, p<0.001) was achieved even from higher initial LDLc values. Titration of lipid-lowering treatment was also greater, with the old target of LDLc < 70 being achieved in a greater number of cases (81.5% vs 59.3%, p<0.001). At 1-year follow-up, the new cholesterol reduction target (LDL <55 or 50% reduction) was achieved in only 26.8% of patients, with a greater reduction being obtained in the CR group (34.1% vs 17.9%; p=0.02). At 2-year follow up, in CR group we found low rates of re-infarction (3.2% vs 4.1%), new revascularization (5.8% vs 7.3%), not statistically significant, but we could observe differences in mortality from all causes (0% vs 4.8%, p<0.01). Conclusions Participation in a CR program is associated with better lipid control in patients admitted for STEACS. These programs represent a basic tool for achieving increasingly demanding LDLc targets. Longer follow-up is needed to detect clinically important adverse events.

An “Inclisiran First” Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease

BackgroundMost patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. ObjectivesThis study evaluated the effectiveness of an “inclisiran first” implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease. MethodsVICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician’s discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. ResultsWe randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The “inclisiran first” strategy led to significantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with “inclisiran first” (6.0%) were noninferior vs usual care (16.7%). More “inclisiran first” patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with “inclisiran first” than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively). ConclusionsAn “inclisiran first” implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an “Inclisiran First” Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [≥70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249)

The CNIC-polypill (acetylsalicylic acid, atorvastatin, and ramipril), an effective and cost-saving secondary prevention strategy compared with other therapeutic options in patients with ischaemic heart disease.

The retrospective NEPTUNO study evaluated the effectiveness of the Centro Nacional de Investigaciones Cardiovasculares (CNIC)-polypill (including acetylsalicylic acid, ramipril, and atorvastatin) vs. other therapeutic approaches in secondary prevention for cardiovascular (CV) disease. In this substudy, the focus was on the subgroup of patients with ischaemic heart disease (IHD). Patients on four strategies: CNIC-polypill, its monocomponents as loose medications, equipotent medications, and other therapies. The primary endpoint was the incidence of recurrent major adverse CV events (MACEs) after 2 years. After matching, 1080 patients were included in each cohort. The CNIC-polypill cohort had a significantly lower incidence of recurrent MACE compared with monocomponents, equipotent drugs, and other therapies cohorts (16.1 vs. 24, 24.4, and 24.3%, respectively; P < 0.001). The hazard ratios (HRs) for recurrent MACE were higher in monocomponents (HR = 1.12; P = 0.042), equipotent drugs (HR = 1.14; P = 0.031), and other therapies cohorts (HR = 1.17; P = 0.016) compared with the CNIC-polypill, with a number needed to treat of 12 patients to prevent a MACE. The CNIC-polypill demonstrated a greater reduction in LDL cholesterol (LDL-c; -56.1 vs. -43.6, -33.3, and -33.2% in the monocomponents, equipotent drugs, and other therapies, respectively; P < 0.001) and systolic blood pressure (-13.7 vs. -11.5, -10.6, and -9.1% in the CNIC-polypill, monocomponents, equipotent drugs, and other therapies, respectively; P < 0.001) compared with other cohorts. The CNIC-polypill intervention was less costly and more effective than any other therapeutic option, with €2317-€2407 cost savings per event prevented. In IHD, the CNIC-polypill exemplifies a guideline-recommended secondary prevention treatment linked to better outcomes and cost saving compared with other therapeutic options.

Cardiac rehabilitation can change the destiny of the patient with ST-elevation acute coronary syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiac rehabilitation (CR) has become a basic element in the recovery of patients with acute coronary syndrome, since it achieves greater therapeutic adherence and better control of cardiovascular risk factors. Purpose We aim to describe the characteristics of patients with ST-elevation acute coronary syndrome (STEACS) included in a Cardiac rehabilitation program, as well as the achievement of prevention objectives and the occurrence of mayor adverse cardiovascular events (MACE). Methods Observational prospective study where a total of 664 STEMI patients admitted to a Coronary Unit during the years 2017-2020 were included. They were classified according to their participation in a CR program. We compared medical history, lipid-lowering treatment (prior, at discharge and titration), lipid levels at discharge and at 1-year follow-up, and degree of achievement of lipid targets. MACE (mortality, reinfarction, coronary revascularisation and restenosis) were observed at 2-year follow-up. Results From 664 patients, 351 were excluded due to lack of follow-up or early mortality. From a total of 313 patients (mean age 59.9±11.2 years; 81% male), 55.3% were included in the CR program. This group had a lower mean age (55.46±8.7 vs 65.39±11.5, P&amp;lt;0.001), as well as a higher frequency of early ischaemic heart disease history and smoking, with a lower frequency of hypertension and diabetes (Table). Lipid-lowering treatment at discharge was similar in both groups. In patients undergoing CR, there was a lower level of total cholesterol and low-density lipoprotein cholesterol (LDLc) at one year follow-up (126.2±27 vs 137.2±34, P=0.002; 57.8±23 vs 67.5±26, P&amp;lt;0.001) and a greater reduction in LDLc (41.4% vs 20.86%, P&amp;lt;0.001) was achieved even from higher initial LDLc values. Titration of lipid-lowering treatment was also greater, with the old target of LDLc&amp;lt;70 being achieved in a greater number of cases (81.5% vs 59.3%, P&amp;lt;0.001). At 1-year follow-up, the new lipid reduction target (LDLc&amp;lt;55 + 50% reduction) was achieved in only 26.8% of patients, with a greater reduction in the CR group (34.1% vs 17.9%; P=0.02). Although differences were observed in the follow-up in terms of mortality and new events, in favor of the CR group, these did not reach statistical significance. Conclusions Participation in a CR program is associated with better lipid control in patients admitted for STEACS. These programmes represent a basic tool for achieving lipid and cardiovascular risk factor targets and improved long-term clinical outcomes.

The N-Acetylgalactosamine-conjugated small interfering RNA inclisiran can be coadministered safely with atorvastatin in cynomolgus monkeys resulting in additive low-density lipoprotein cholesterol reductions.

Inclisiran, a small interfering RNA, selectively inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis in the liver and has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by ≥50% in patients with hypercholesterolemia receiving maximally tolerated statins. The toxicokinetic, pharmacodynamic, and safety profiles of inclisiran when coadministered with a statin were characterized in cynomolgus monkeys. Six cohorts of monkeys were administered either atorvastatin (40 mg/kg, reduced to 25 mg/kg during the study, daily, oral gavage), inclisiran (300 mg/kg every 28 days, subcutaneous administration), atorvastatin (40/25 mg/kg) and inclisiran combinations (30, 100, or 300 mg/kg), or control vehicles over 85 days followed by 90 days' recovery. Inclisiran and atorvastatin toxicokinetic parameters were similar in cohorts administered either agent alone or in combination. Inclisiran exposure increased in a dose-proportional manner. At Day 86, atorvastatin increased plasma PCSK9 levels four-fold from pretreatment levels but did not significantly lower serum LDL-C levels. Inclisiran (alone or in combination) reduced PCSK9 (mean decrease 66-85%) and LDL-C (mean decrease 65-92%) from pretreatment levels at Day 86; levels were significantly lower than the control group (p ≤ .05) and remained decreased during the 90-day recovery. Coadministration of inclisiran with atorvastatin resulted in greater reductions in LDL-C and total cholesterol compared with either drug alone. No toxicities or adverse effects were observed in any cohort receiving inclisiran, either alone or in combination. In summary, inclisiran significantly inhibited PCSK9 synthesis and decreased LDL-C in cynomolgus monkeys without increasing the risk of adverse effects when coadministered with atorvastatin.

Efficacy and safety of proprotein covertase subtilisin/kexin type 9 inhibitors among patients with acute coronary syndrome: a meta-analysis of randomized controlled trials

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have formed part of the armamentarium of lipid-lowering therapy, most especially low-density lipoprotein-cholesterol (LDL-C) reduction, which in turn decreases the risk of atherosclerotic cardiovascular diseases and adverse cardiovascular events. However, studies are sparse on the benefit of initiating PCSK9 inhibitors during the early phase of an acute coronary sydrome (ACS). Purpose The objective of this meta-analysis is to investigate the efficacy and safety of the PCSK9 inhibitors evolocumab and alirocumab in the acute setting of an ACS. Methods A systematic search for randomized controlled trials (RCTs) that involve the use of PCSK9 inhibitors in ACS was done using MEDLINE/PubMed and Cochrane Library. Results Three RCTs (n=385 participants) were included in this meta-analysis comparing PCSK9 inhibitors versus placebo in patients hospitalized for ACS. Among patients being managed for ACS, PCSK9 inhibitors demonstrated a greater reduction in LDL-C compared to placebo as early as day 3 (WMD −41.65%, 95% CI [−60.09, −23.21], p&amp;lt;0.00001), and was maintained until week 4 (WMD −45.67%, 95% CI [−64.82, −26.53], p&amp;lt;0.00001). The occurrence of adverse events did not significantly differ between the two groups in terms of hospitalization for recurrent ACS (OR 0.99, 95% CI 0.10–9.98, p=1.0), hospitalization for heart failure (OR 6.18, 95% CI 0.26–146.78, p=0.26), or cerebrovascular events (OR 3.12, 95% CI 0.31–31.30, p=0.33). Conclusion In patients admitted for ACS, the early administration of PCSK9 inhibitors such as evolocumab and alirocumab during the first 24 hours of hospitalization resulted in a rapid and significant reduction of LDL-C without any significant adverse event as compared to placebo. Further validation of the role of PCSK9 inhibitors in the setting of ACS is needed to robustly investigate its contribution in improving hard cardiovascular outcomes. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): St. Luke's Medical Center Global City

Achieving Lower LDL-C Levels After a Recent Myocardial Infarction Might Be Associated with Lower Healthcare Resource Use and Costs in Spain.

IntroductionThere is little evidence on the relationship between achieved low-density lipoprotein cholesterol (LDL-C) levels and costs in patients on lipid-lowering therapy (LLT). We described healthcare resource use and costs (direct and indirect) by achieved LDL-C in patients receiving LLT after a recent myocardial infarction (MI) in Spain.MethodsThis was a retrospective observational study of anonymized electronic medical records from seven regions in Spain (BIG-PAC® database; n = 1.9 million). Eligible patients were adults (≥ 18 years) hospitalized for an MI between January 2015 and December 2017, treated with a statin and/or ezetimibe, and having recorded LDL-C values at baseline and during follow-up. Healthcare resource use and direct and indirect costs (in 2018, €) were described by achieved LDL-C levels during a follow-up of 18 months.ResultsOf 6025 patients (mean age, 69.7 years; 77% male), only 11% achieved LDL-C goals as defined in the 2016 ESC/EAS guidelines (< 70 mg/dL), and just 1% reached the lower target (< 55 mg/dL) in the current 2019 guidelines. Achieving lower LDL-C levels translated to lower healthcare resource use and costs. Mean total (direct and indirect) costs ranged from €5044 for patients with LDL-C < 55 mg/dL to €7567 for patients with LDL-C ≥ 130 mg/dL.ConclusionVery few patients achieved recommended LDL-C goals despite using LLT. Achieving lower LDL-C levels after an MI might be associated with lower healthcare resource use and costs. Use of more intensive LLT, leading to greater reductions in LDL-C, could therefore be beneficial both from a clinical and an economic perspective.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02187-1.

Comparison of Efficacy and Safety of Statin-Ezetimibe Combination Therapy with Statin Monotherapy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Studies.

Dyslipidemia in diabetes mellitus is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). Additionally, the potentially increased risk of morbidity and mortality following atherosclerotic cardiovascular diseases should be considered in the treatment of dyslipidemia in patients with diabetes. We performed a meta-analysis of the published data to compare the effects of HMG-CoA reductase inhibitor (statin)-ezetimibe combination therapy and statin monotherapy on lipid and glucose parameters in patients with diabetes. We also compared safety based on the adverse events reported for the two groups. In total, 17 articles were included in this meta-analysis. In the efficacy assessment, the combination treatment afforded a significantly greater reduction in LDL-C than did statin monotherapy (standard difference in means 0.691; 95% confidence interval 0.534-0.847). A significantly greater improvement effect was observed in the levels of HDL-C, total cholesterol, triglyceride, and apolipoprotein B, but not apolipoprotein A1, with combination therapy than with statin monotherapy. Additionally, combination therapy reduced fasting blood glucose levels more significantly than did statin monotherapy. In terms of safety, there were no significant differences in treatment-related adverse events between the two treatments. Statin-ezetimibe combination therapy enhances levels of LDL-C and other lipids without increasing the risk of adverse events compared with statin monotherapy. The present meta-analysis presents valid evidence for appropriate drug regimens to treat dyslipidemia in patients with diabetes. PROSPERO Identifier Number CRD42021244578.

Abstract 13666: Effectiveness and Durability of Remote Algorithmic Cholesterol Management

Introduction: In collaboration with an insurer, a remote cholesterol management pilot in patients with elevated LDL cholesterol (LDL-C) with, or at increased risk of, ASCVD achieved an average 45% LDL-C reduction in program completers. A key question for this novel strategy is the durability of this benefit, reported here at 1 year vs LDL control in a matched cohort. Methods: 469 Blue Cross Blue Shield (BCBS) patients completed the Brigham-Lipid Optimization (B-LO) program between 2/2016-12/2017. Retrospectively, we identified a control cohort of non-BCBS commercial patients (n=3955) matched for demographic and clinical characteristics. A difference-in-differences analytic approach compared LDL-C changes as adjusted for sex, age, race, prior statin intolerance, diabetes, ASCVD, and prior LDL&gt;190. Results: B-LO patients who completed the program achieved 45.3% greater reduction in LDL-C from baseline to program exit than observed among matched-control patients receiving standard of care. This greater LDL-C reduction occurred despite higher baseline LDL-C among B-LO participants vs controls, even after extensive matching. 99% of program participants reached LDL goal, vs 16% of control patients (p&lt;0.01.). (Figure) At 1-year post intervention, adjusted estimates of being at LDL goal were 83% of intervention patients vs. 52% of control patients. Conclusions: A remote cholesterol algorithmic management program that reduced LDL-C effectively also achieved more durable LDL control 12 months post-intervention, and to a greater extent than in matched controls. The efficacy of remote LDL management may also offer longer term effectiveness than usual care, arguing for further study into scalability and economic feasibility of remote population-level health interventions.

Hydrophilic or Lipophilic Statins?

Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media. The predominantly lipophilic statins (simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin) can easily enter cells, whereas hydrophilic statins (rosuvastatin and pravastatin) present greater hepatoselectivity. Although the beneficial role of statins in primary and secondary cardiovascular prevention has been unequivocally confirmed, the possible superiority of one statin or other regarding their solubility profile is still not well-established. In this respect, although some previously published observational studies and clinical trials observed a superiority of lipophilic statins in cardiovascular outcomes, these results could also be explained by a greater low-density lipoprotein cholesterol reduction with this statin type. On the other hand, previous studies reported conflicting results as to the possible superiority of one statin type over the other regarding heart failure outcomes. Furthermore, adverse events with statin therapy may also be related to their solubility profile. Thus, the aim of the present review was to collect clinical evidence on possible differences in cardiovascular outcomes among statins when their solubility profile is considered, and how this may also be related to the occurrence of statin-related adverse effects.

Lipid Management and 2-Year Clinical Outcomes in Japanese Patients with Acute Coronary Syndrome: EXPLORE-J

Aim: The prevalence of atherosclerotic cardiovascular (CV) disease has risen in Japan due to increasing metabolic risk factors, including dyslipidemia. A positive linear correlation between low-density lipoprotein cholesterol (LDL-C) levels, incidence of CV events, and preventive effects of lipid-lowering therapy (LLT) is well established; however, data in Japan are limited. This analysis evaluated current lipid management practices and risk of recurrent CV events in Japanese post-acute coronary syndrome (ACS) patients. Methods: EXPLORE-J is a multicenter, 2-year observational study of hospitalized ACS patients in Japan. Results: At 2-year follow-up ( n =1944, mean age 66 years, 80.3% male), the cumulative incidence of major adverse cardiovascular events (MACE; death associated with myocardial infarction/cerebrovascular accident [CVA] and other CV death, non-fatal ACS, and non-fatal CVA requiring hospitalization during the observation period) was 6.2%; respective incidences of CV death, non-fatal ACS, and CVA were 0.7%, 4.5%, and 1.7%. Statin, intensive statin, and ezetimibe were prescribed for 93.6%, 8.2%, and 3.9% at visit (V)1 (Day[D]1＋14), and 92.3%, 10.5%, and 11.6% of patients at V5 (D730±30 days), respectively. Mean LDL-C was reduced from first post-ACS measurement (121.3 mg/dL) to V5 (79.8 mg/dL). A limited number of patients achieved LDL-C ＜70 mg/dL from V1–V5 (14.4%–34.6%); those with a greater LDL-C reduction by V1 had a lower probability of MACE, indicating the benefits of early LDL-C reduction post ACS. Conclusions: Guideline-recommended LDL-C target achievement post ACS in Japan is suboptimal, suggesting the need for LLT intensification. Additional analyses by risk stratification of the study population and the benefits of lipid management are planned.

Effect of a novel functional tomato sauce (OsteoCol) from vine-ripened tomatoes on serum lipids in individuals with common hypercholesterolemia: tomato sauce and hypercholesterolemia

BackgroundMost studies focused on the benefits of lycopene on serum lipids but no studies have been specifically designed to assess the role of a tomato sauce from vine-ripened tomatoes on patients affected by polygenic hypercholesterolemia. The aim of this study was to compare the lipid-lowering effect of a novel functional tomato sauce with a well-known functional food with a lipid-lowering effect, i.e. a sterol-enriched yogurt.MethodsIn this cross-over study, we evaluated a population of 108 ambulatory patients affected by polygenic hypercholesterolemia of both gender, who were allocated to a tomato sauce (namely OsteoCol) 150 ml/day or a sterol-enriched yogurt (containing sterols 1.6 g/die) treatment, for 6 weeks. Carotenoids content was 3.5 mg per gram of product. We measured serum lipids and creatinine and transaminases at basal and follow-up visit.ResultsA total of 91 subjects completed the protocol. A significant difference in LDL-cholesterol change was found between participants taking yogurt, tomato sauce (high adherence) and tomato sauce (low adherence) (− 16; − 12; + 8 mg/dl respectively; p < 0.001). We found a greater LDL-cholesterol reduction in the participants with a basal LDL-cholesterol more than 152 mg/dl (15% for sterol-enriched yogurt and 12% for tomato sauce at high adherence).ConclusionA novel functional tomato sauce from vine-ripened tomatoes compares favourably with a commercialised sterol-enriched yogurt in term of absolute LDL-cholesterol change. Intake of a tomato sauce with a high carotenoid content may support treatment of patients affected by common hypercholesterolemia. The present study has various limitations. The presence of other dietary components, which may have influenced the results, cannot be ruled out. Of course, these results cannot be extrapolated to other populations. Furthermore, there was a low adherence rate in the tomato sauce group. Moreover, we did not report serum carotenoids data.Trial registration: ID: 13244115 on the ISRCTN registry, retrospectively registered in 2019-5-14. URL: http://www.isrctn.com/ISRCTN13244115

Resource utilization and costs associated with achieved LDL-C levels in patients following a myocardial infarction treated with lipid-lowering therapies in Spain

Abstract Background/Introduction Reduction in low-density lipoprotein cholesterol (LDL-C) significantly reduces cardiovascular (CV) risk, especially in patients with atherosclerotic CV disease. There is, however, a lack of evidence on the association between achieved LDL-C and resource utilization and costs. Purpose Assess the association of achieved LDL-C levels and resource use and costs in patients treated with lipid-lowering therapies (LLT) following a myocardial infarction (MI). Methods Retrospective observational study using the BIG-PAC® database, with anonymized electronic medical records from 1.9 million inhabitants from 7 regions in Spain. Eligible patients were adults (≥18 years), hospitalized for an MI (index date) between January 2015 and December 2017, treated with LLTs (statins and/or ezetimibe) during follow-up (up to 18 months), and with recorded LDL-C values at baseline and follow-up. Direct (related to health care interventions) and indirect (related to loss of productivity) costs were estimated in 2018€. Costs incurred during follow-up were computed by achieved LDL-C. Achieved LDL-C was obtained in the year following the MI and at least 2 months after the index date. LDL-C categories were defined as per the 2016 and 2019 ESC/EAS guidelines for dyslipidaemias management: &amp;lt;55 mg/dL, 55–69 mg/dL, 70–99 mg/dL, 100–129 mg/dL and ≥130 mg/dL. Results were adjusted for age, gender, CV disease history and comorbidities. Results 6025 patients were included. Mean age (SD) was 69.7 (12.2) and 77% were male. Resource use (not reported in this abstract) and costs monotonically increased with achieved LDL-C. Mean total costs ranged from 5044€ for patients with LDL-C &amp;lt;55 mg/dL to 7567€ for patients with LDL-C ≥130 mg/dL (Table 1). Only 11% (641/6025) of patients reached recommended LDL-C levels for very-high-risk patients as per 2016 ESC/EAS guidelines (&amp;lt;70 mg/dL), and 1% (68/6025) the LDL-C levels (&amp;lt;55 mg/dL) proposed in the 2019 guidelines. Conclusions Achieving lower LDL-C levels following an MI may be associated to lower resource use and costs. Many patients do not achieve recommended LDL-C levels despite treatment with LLT. These data suggest that use of more intense LLT, with a greater reduction in LDL-C, would be beneficial from a clinical and economic perspective. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen (Europe) GmbH

Prevalence, treatment, and control of severe hyperlipidemia

ObjectiveTo identify the prevalence, treatment, and low-density lipoprotein cholesterol (LDL-C) control of individuals with LDL-C ≥190 ​mg/dL in contemporary clinical practice. MethodsWe included adults (age ≥18 years) with LDL-C ≥190 ​mg/dL, at least one LDL-C level drawn from 255 health systems participating in Cerner HealthFacts database (2000–2017, n ​= ​4,623,851), and a detailed examination within Duke University Health System (DUHS, 2015–2017, n ​= ​267,710). Factors associated with LDL-C control were evaluated using multivariable logistic regression modeling. ResultsThe cross-sectional prevalence of LDL-C ≥190 ​mg/dL was 3.0% in Cerner (n ​= ​139,539/4,623,851) and 2.9% at DUHS (n ​= ​7728/267,710); among these, rates of repeat LDL-C measurement within 13 months were low: 27.9% (n ​= ​38,960) in Cerner, 54.5% (n ​= ​4211) at DUHS. Of patients with follow-up LDL-C levels, 23.6% in Cerner had a 50% of greater reduction in LDL-C, 18.3% achieved an LDL-C <100 ​mg/dL and 2.7% ​< ​70 ​mg/dL. At DUHS, 28.4% had a 50% or greater reduction in LDL-C, 28.4% achieved an LDL-C ≤100 ​mg/dL and 4.4% achieved <70 ​mg/dL. Within DUHS, 71.6% with LDL-C ≥190 ​mg/dL were on any statin during follow-up, but only 28.5% were on a high-intensity statin. In multivariable modeling, seeing a cardiologist (Cerner odds ratio [OR] 1.56, confidence interval [CI] 1.33–1.83; DUHS OR 1.89, 95% CI 1.18–3.01) and having diabetes (Cerner OR 1.34 CI 1.23–1.46; DUHS OR 2.07, CI 1.62–2.65) increased odds of LDL-C control, defined as a ≥50% reduction in LDL-C (at Cerner) or initiation of high intensity statin (at DUHS). Prior atherosclerotic cardiovascular disease (OR 1.19, CI 1.07–1.33), hypertension (OR 1.10, CI 1.03–1.18), African American race (OR 0.79, CI 0.71–0.89), and government (vs. private) insurance (OR 0.90, CI 0.83–0.98) were associated with LDL-C control at Cerner. Female sex was associated with lower odds of appropriate therapy (OR 0.69, CI 0.59–0.81) at DUHS. ConclusionsApproximately 3% of United States adults have LDL-C ≥190 ​mg/dL. Among those with very high LDL-C, rates of repeat measurement within one year were low; of those retested, only about one-fourth met guideline-recommended LDL-C treatment goals.

P0183THE USE OF PCSK9 INHIBITORS COULD REDUCE PROTEINURIA IN CHRONIC KIDNEY DISEASE PATIENTS

Abstract Background and Aims Chronic kidney disease (CKD) is a cardiovascular risk factor per sé and enhances the risk of cardiovascular events. Dyslipidemia is one of the most studied risk factors and current guidelines recommend the universal treatment in CKD patients (not in dialysis) irrespective of low density lipoprotein (LDL) cholesterol level. However, the latest European Cardiology guidelines recommend monitoring LDL cholesterol to achieve levels lower than 70 mg/dl in CKD stage 3 and lower than 55 mg/dl in stages 4 and 5. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) have opened a new era leading greater reduction of LDL cholesterol and subsequently cardiovascular events but real-life data is not available in CKD patients. The aim of the present study is analysing the evolution of renal function and proteinuria in a cohort of patients with PCSK9i. Method This is a retrospective study that included all the patients treated with PCSK9i in our centre. Inclusion criteria were the presence of CKD and dyslipidemia with indication of the use of PCSK9i (not reaching LDL target with maximum tolerated statin dose or intolerance for the use of statins). At baseline, epidemiological data and comorbidities were collected, as well as renal function using glomerular filtration rate (GFR) estimation with CKD-EPI equation, proteinuria (mg/g of creatinine) and lipid profile. During a one-year follow up, renal function, proteinuria, lipid profile and adverse events were collected and analysed. Results: . Forty-one patients were included with a mean age of 70±10 years and 26 men (62%). Thirty-four patients (83%) had hypertension, 11 (27%) were diabetic, 19 (44%) had coronary disease, 8 (20%) history of heart failure, 3 (7%) peripheral vascular disease and 6 (15%) history of stroke. Regarding renal function, at baseline mean of creatinine was 1.3±0.5 mg/dl, GFR 54±19 ml/min/1.73m2 and proteinuria 456±215 mg/g. Lipid profile at baseline demonstrated an LDL cholesterol value of 163±58 mg/dl, triglycerides of 255±389 mg/dl and high density lipoprotein (HDL) of 53±14mg/dl. During follow up, total cholesterol, LDL-cholesterol and triglycerides improved significantly (p&amp;lt;0.001 for all in comparison to baseline values). GFR remained stable during the first year of follow up (CKD-EPI at 1 year 52±20 ml/min/1.73m2). Proteinuria improved at first month (235±71 mg/g), achieving stability at 3 months (124±44 mg/g), 6 months (176±94 mg/g) and 1 year (163±83 mg/g) (p for trend 0.02) (figure 1). No adverse events were registered during follow up, and two patients required hospitalization due to cardiovascular events. Conclusion The treatment of dyslipidemia with PCSK9i could decrease proteinuria in CKD patients via controlling lipoid nephrotoxicity. Clinical trials are needed to further investigate this effect.

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses

Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150mg every 2weeks (Q2W). Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75mg Q2W, with possible dose increase to 150mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150mg Q2W. Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.

P6192Effects of evolocumab on LDL-C by race and ethnicity: an analysis of double-blind and open-label extension studies

Abstract Background/Introduction Cardiovascular risk factors and clinical outcomes of atherosclerotic cardiovascular disease (ASCVD) vary amongst racial and ethnic groups. Purpose To examine the effects of evolocumab on low-density lipoprotein cholesterol (LDL-C) levels and achievement of LDL-C target goals by race or ethnicity. Methods Data from global phase 2 and 3 studies with at least 12 weeks of treatment with approved evolocumab doses vs. placebo or ezetimibe were included in this analysis (n=4375). Results were analysed by patient characteristics (statin intolerance, type 2 diabetes, heterozygous familial hypercholesterolaemia, and hypercholesterolaemia/mixed dyslipidaemia), self-identified race (White, Black/African American, and Asian), and self-identified ethnicity (Hispanic/Latino). Key outcomes included percent change in LDL-C, achievement of LDL-C &lt;1.8 mmol/L (&lt;70 mg/dL), and LDL-C achievement of at least 50% reduction. Results After 12-week evolocumab treatment, mean percent change in LDL-C from baseline ranged from approximately −52% to −59% for white patients to −49% to −67% for non-white patients, across all groups with adequate sample size (n&gt;20) (Table). LDL-C &lt;1.8 mmol/L was achieved in 43–84% of white patients and 62–94% of non-white patients receiving evolocumab (n&gt;20). Similarly, 63–78% of white patients and 58–86% of non-white patients achieved at least a 50% reduction in LDL-C. The magnitude of treatment effect on mean percent change in LDL-C differed significantly only between white and non-white patients with diabetes (interaction p-values of treatment by race for evolocumab every 2 weeks p&lt;0.001; once monthly p=0.007). This was driven by a greater reduction in Asian patients. Mean (standard deviation) percent change in LDL-C levels from baseline, % Achievement of LDL-C &lt;1.8 mmol/L (70 mg/dL)/LDL-C achievement of at least 50% reduction, % Population White Non-White Non-Hispanic Black or African American Asian Hispanic/Latino* White Non-White Non-Hispanic Black or African American Asian Hispanic/Latino* Statin-Intolerant† −55.4 (14.8) −46.3 (20.9) −46.0 (13.4) −49.0 (29.3) −54.6 (12.3) 42.9 / 68.6 26.7 / 60.0 14.3 / 42.9 50.0 / 83.3 0 / 66.7 n=210 n=15 n=7 n=6 n=3 Diabetes‡ −51.5 (25.6) −66.5 (21.2) −50.4 (22.2) −69.6 (20.2) −59.7 (20.5) 82.3 / 63.0 93.9 / 82.0 90.0 / 62.5 95.1 / 86.6 89.2 / 75.3 n=440 n=395 n=40 n=305 n=158 HeFH§ −57.3 (19.7) −64.1 (12.0) −73.8 (4.1) −60.5 (12.8) −35.8§§ 66.1 / 73.7 61.5 / 84.6 100 / 100 53.3 / 80.0 0 / 0 n=236 n=26 n=3 n=15 n=1 Hyper-cholesterolaemia/ −58.8 (19.2) −65.5 (17.0) −51.2 (19.4) −69.4 (13.9) −54.6 (20.3) 83.3 / 77.6 89.7 / 86.0 74.4 / 60.5 94.7 / 93.5 79.1 / 69.2 Mixed Dyslipidaemia¶ n=1399 n=437 n=86 n=339 n=91 Hyper-cholesterolaemia/ −59.4 (17.1) −58.4 (16.9) −52.8 (19.4) −65.8 (10.3) −56.7 (22.1) 80.2 / 78.5 85.7 / 75.7 82.4 / 67.6 96.7 / 93.3 77.3 / 68.2 Mixed Dyslipidaemia†† n=605 n=70 n=34 n=30 n=44 1-Year Study‡‡ −52.1 (27.7) −48.6 (29.2) −50.8 (22.0) −49.5 (29.4) −43.0 (43.1) 84.4 / 67.4 73.6 / 57.5 74.5 / 59.6 76.5 / 58.8 82.1 / 60.7 n=436 n=106 n=47 n=34 n=28 †GAUSS-1, -2 studies; ‡BANTING and BERSON studies; §RUTHERFORD-1, -2 studies; ¶Placebo comparator: MENDEL-1, -2, LAPLACE-TIMI-57, LAPLACE-2 and YUKAWA-1, -2 studies; ††Ezetimibe comparator: MENDEL-2 and LAPLACE-2 atorvastatin cohorts; ‡‡DESCARTES; §§Standard deviation could not be calculated due to insufficient sample size. *A total of 22 patients receiving evolocumab self-identified as Hispanic Black. Conclusion Reduction in LDL-C levels with evolocumab treatment was similar across race and ethnicity, apart from the diabetes population where Asian patients had a greater reduction in LDL-C. Acknowledgement/Funding Amgen Inc.

Dose-dependent effects of lifestyle interventions on blood lipid levels: Results from the PREMIER trial

ObjectiveTo assess the effects of comprehensive lifestyle modification on low-density lipoprotein cholesterol (LDL-C) levels and whether greater participation in counseling sessions was associated with greater LDL-C reductions. MethodsMulticenter trial of Pre- or Stage 1 hypertensive adults randomized to: (1)Advice alone, (2)‘Established’ lifestyle intervention implementing physical activity, sodium reduction, and weight loss, if overweight, or (3)‘Established + DASH’ lifestyle intervention with DASH diet counseling. Both intervention groups received behavioral counseling. We used generalized estimating equations to model the intervention’s effects on lipid outcomes. Analyses of number of sessions and lipids were adjusted for demographics and medical history. ResultsAmong 756 participants (mean age 49.7, 63.2% women, 34.7% black), both lifestyle interventions reduced LDL-C, triglycerides, and total cholesterol (TC) at six months. Compared to the ‘Advice’ arm, net mean lipid changes in the Established group were: LDL-C of -5.6 mg/dL (p=0.001) and TC of -7.3 mg/dL (p<0.001). Similarly, changes in the ‘Established + DASH’ group were: LDL-C of -4.0 mg/dL (p=0.03) and TC of -5.7 mg/dL (p=0.006). In dose-response analyses, for every 10-session increase, LDL-C changed by -6.2 mg/dL (p=0.003). ConclusionsComprehensive lifestyle modification lowers LDL-C with greater benefit among persons who attend more counseling sessions. Practice ImplicationsPatient engagement is a critical aspect of effective lifestyle interventions.

Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics.

Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 μg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect.

Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy

While statins are used as first-line treatments for high-risk patients with hypercholesterolemia, statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol (LDL-C) levels. Second-line treatment options include up-titration of statin dose, switching to a more potent statin, or combination therapy, e.g., with ezetimibe. The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease (CVD) and who had been previously treated with a statin. A systematic literature search was performed and evidence bases were established for populations of atorvastatin-, simvastatin-, and rosuvastatin-experienced patients using eligible randomized controlled trials (RCTs). Based on the available data, we constructed networks of evidence and conducted a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome of interest was percent change from baseline in LDL-C. Changes in total cholesterol were explored as a secondary outcome. Across all patient populations, 35 RCTs were identified and included in the evidence base. Among patients on simvastatin therapy, the addition of ezetimibe resulted in a mean difference (MD) in LDL-C of - 13.62% (95% CrI - 19.99, - 6.91; see table below) compared to doubling the starting dose of simvastatin. In the population of patients on atorvastatin therapy, the addition of ezetimibe resulted in an MD in LDL-C of - 14.71% (95% CrI - 16.46, - 12.95) compared to doubling the starting dose of atorvastatin. The addition of ezetimibe to rosuvastatin resulted in an MD in LDL-C of - 14.96% (95% CrI - 17.79, - 12.11), compared to doubling the starting rosuvastatin dose. Similar trends were observed for changes in total cholesterol. Given the available data, the addition of ezetimibe to ongoing simvastatin, atorvastatin, or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose.