Mean Low-density Lipoprotein Cholesterol Reduction Research Articles

Evinacumab and Cardiovascular Outcome in Patients With Homozygous Familial Hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. Twelve patients, 5 females and 7 males (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

BackgroundHomozygous familial hypercholesterolemia (HoFH) is characterized by early-onset atherosclerotic cardiovascular disease due to the high low-density lipoprotein cholesterol (LDL-C) burden. Patients with null-null low-density lipoprotein receptor (LDLR) variants respond poorly, if at all, to statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which act by upregulating LDLR expression. The 24-week double-blind treatment period (DBTP) of the phase 3 ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial hypercholesterolemia; NCT03399786) study demonstrated significant LDL-C reductions in patients with HoFH; LDL-C reductions were also observed in those with null-null LDLR mutations. ObjectivesThe purpose of this study was to evaluate longer-term efficacy and safety of evinacumab in patients with HoFH from the ELIPSE HoFH study. MethodsPatients with HoFH on stable lipid-lowering therapies (LLTs) ± lipoprotein apheresis and screening LDL-C ≥70 mg/dL who completed the DBTP entered the 24-week open-label treatment period (OLTP) and received intravenous evinacumab 15 mg/kg every 4 weeks. OLTP results were summarized descriptively. ResultsA total of 64 patients completed the DBTP and received open-label evinacumab. Despite multiple LLTs, the mean baseline LDL-C at DBTP entry was 250.5 ± 162.3 mg/dL. From baseline to week 48 (end of OLTP), evinacumab reduced mean LDL-C by 46.3% (mean reduction, 134.3 ± 117.3 mg/dL), with similar mean LDL-C reductions for patients with null-null (47.2%) and non-null variants (45.9%). Adverse events occurred in 47 (73.4%) patients; 4 (6.3%) patients experienced adverse events considered evinacumab-related (drug hypersensitivity, infusion-related reaction and asthenia, generalized pruritis, and muscle spasms). ConclusionsIn patients with HoFH, evinacumab demonstrated substantial and sustained LDL-C reduction regardless of LDLR function, and was generally well tolerated.

OR24-02 Case Series Of Canadian Patients With Homozygous Familial Hypercholesterolemia Treated With ANGPTL3 Inhibitor Evinacumab

Abstract Disclosure: I. Shamsudeen: None. B.W. McCrindle: Consulting Fee; Self; Jansen Pharmaceuticals, Amryt, Ultragenyx, Chiesi, Esperion. R.A. Hegele: Advisory Board Member; Self; Amgen Inc, HLS Pharmaceuticals, Novartis Pharmaceuticals. Consulting Fee; Self; Akcea Therapeutics, Ultragenyx, Medison, Acasti, Amgen Inc, Novartis Pharmaceuticals, Amryt, Amgen Inc, Pfizer, Inc., Arrowhead, Sanofi, HLS Pharmaceuticals, Regeneron Pharmaceuticals. Background: Homozygous familial hypercholesterolemia (HoFH) is an ultrarare, life-threatening condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) due to biallelic LDL receptor variants. Patients have an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Traditional lipid-lowering agents are minimally effective and the gold standard treatment is serial apheresis. Recently, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, evinacumab, was introduced as a promising new treatment for HoFH. It was FDA-approved in 2021, but is currently available in Canada only through clinical trials or special access programs. Case Presentations: The first five Canadian HoFH patients to receive evinacumab via special access are presented. Their mean age is 24.6 years (SD = 13.9). As of December 2022, they have received evinacumab 15 mg/kg intravenously every four weeks for a mean of 12.2 months (SD = 11.3). Their mean incremental LDL-C reduction is 49.4% (SD = 8.9) on evinacumab along with reduced apheresis frequency for those on serial apheresis. Safety labs for all patients are normal. Brief case summaries are as follows: (a) Patient A is a 36-year-old man with severe ASCVD who has been on evinacumab for 30 months, in addition to a statin, ezetimibe, evolocumab and LDL-apheresis. His time-averaged LDL-C has decreased by 46.2%, from 4.76 to 2.56 mmol/L (184 to 99 mg/dL), on evinacumab. (b) Patient B is a 17-year-old male with elevated LDL-C levels despite being on a statin, ezetimibe and LDL-apheresis. After 14 months on evinacumab, his time-averaged LDL-C reduced by 40.3%, from 8.75 to 5.22 mmol/L (338 to 202 mg/dL). (c) Patient C is a 30-year-old woman with ASCVD and xanthomas on a statin and ezetimibe, but not apheresis. She has been on evinacumab for 12 months with a 57.7% reduction in LDL-C, from 11.43 to 4.83 mmol/L (442 to 187 mg/dL). (d) Patient D is a 36-year-old man with ASCVD on a statin, ezetimibe, evolocumab and lomitapide in addition to plasmapheresis. He started evinacumab 2 months ago and has already had a 42.6% decrease in time-averaged LDL-C, from 4.34 to 2.49 mmol/L (168 to 96 mg/dL). (e) Patient E is a 4-year-old boy with HoFH and xanthomas on a statin, ezetimibe and plasmapheresis. After 3 months of treatment with evinacumab, his time-averaged LDL-C decreased by 59.9%, from 9.45 to 3.79 mmol/L (365 to 147 mg/dL). Concurrently, he has developed unexplained intermittent abdominal pain, with temporary suspension of evinacumab pending further assessment. Discussion: Five HoFH patients with distinctive histories, baseline treatments and ASCVD have all shown marked improvement in LDL-C levels with a mean reduction of 49.4% on evinacumab on top of existing therapy. Overall, observations from our case series suggest that evinacumab is an effective new treatment for HoFH, a life-threatening condition with few therapeutic options. Presentation: Saturday, June 17, 2023

Clinical Benefit of Bempedoic Acid in Randomized Clinical Trials

Bempedoic acid is a selective inhibitor of the adenosine triphosphate citrate lyase that reduces low-density lipoprotein cholesterol (LDLc) levels by 17% to 28%. Although the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (CLEAR-OUTCOMES) trials demonstrated the efficacy on cardiovascular outcomes there is a controversy related to the possible net clinical benefit. Thereafter, we performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6months. The mean baseline LDLc was 129.4 (22.8)mg/100ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6)mg/100ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm.

Protein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies (PCSK9mab) in Clinical Practice at Secondary Care - Real World Multicentre Experience.

Background and Aims Protein convertase subtilisin/Kexin type 9 monoclonal antibodies (PCSK9mab) are a novel addition to the therapeutic options for managing hyperlipidemia. Various guidelines have advocated the addition of these agents if the target low-density lipoprotein-cholesterol ( LDL-C) is not achieved by maximum lipid-lowering therapy. They have shown a robust and consistent reduction in LDL-C in clinical trials. However, the translation of these results in a real-world setting is limited and confined mainly to tertiary lipid centers. This service evaluation aimed to assess their efficacy in a real-world outpatient setting of secondary care centers. Methods Data was collected retrospectively from four hospitals in the North-West of England. Patients were required to attend a lipid clinic for follow-up investigations to continue with the prescription of PCSK9mab. Results A total of 175 patients were identified. Efficacy outcomes were measured in 169 patients. 6 discontinued the agent within 3 months of initiation and were excluded from the efficacy outcomes. 19.5% (n=33) had confirmed familial hypercholesterolemia. 61% (n=103) of the patients were intolerant to statins. 53.2% (n=90) of the patients have been prescribed Alirocumab. Mean LDL-C reduction was 50.6% at 6-month which was sustained at 48.9% at 12 months. There was no difference in % reduction of LDL-C between Alirocumab and Evolocumab. LDL-C reduction was more significant in patients who were on concomitant statins. 9.1% of patients experienced side effects, and 5.1% discontinued the PCSK9mab during treatment. Conclusion The efficacy of lipid reduction and the side effect profile of PCSK9mab from these secondary care services are similar to randomized clinical trials and real-world observational studies from tertiary lipid centers.

Lipid-lowering efficacy and safety of alirocumab in a real-life setting in France: Insights from the ODYSSEY APPRISE study

BackgroundRecently, a multicentre, prospective, single-arm, phase 3b, open-label trial was conducted to determine the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting. This study enrolled patients at high cardiovascular risk, with heterozygous familial hypercholesterolaemia (HeFH) or non-familial hypercholesterolaemia (non-FH). Results showed that alirocumab was well tolerated and resulted in a clinically significant reduction in low-density lipoprotein cholesterol (LDL-C). AimThis ancillary analysis aimed to describe the characteristics of the French patients enrolled in the study, the main results observed in this population according to their familial hypercholesterolaemia status, and adherence to treatment. MethodsFrench data were analysed separately from the original dataset of the study. ResultsAmong 215 French patients in the ODYSSEY APPRISE trial, 63.7% had non-FH, with a mean LDL-C concentration of 5.0±1.8mmol/L at baseline. The mean duration of alirocumab exposure was 72.4±42.5 weeks, with only 48.4% of patients receiving statins concomitantly. At week 12, a mean reduction in LDL-C of 56.5±17.8% was observed: 51.2±22.8% in HeFH; 59.5±13.2% in non-FH. This improvement in LDL-C started from week 4 and remained stable and sustained until week 120 in both populations. The overall incidence of severe treatment-emergent adverse events (TEAEs) was 33.5%. The most frequent TEAEs were myalgia (15.8%) and asthenia (15.3%). No tolerance or efficacy differences were observed between patients with or without established coronary artery disease or other cardiovascular disease, whatever the age of these events or considering the concomitant use of other lipid-lowering therapies. ConclusionsIn the French setting, alirocumab was well tolerated, safe and highly effective at reducing LDL-C. These findings support the use of alirocumab to manage hypercholesterolaemia in patients at high cardiovascular risk.

Abstract 10451: Efficacy and Safety of Ebronucimab, a Monoclonal Antibody Against Pcsk9, in Patients With Hyperlipidemia: Result From a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

Introduction Elevated low-density lipoprotein cholesterol (LDL-C) is a well-recognized risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to Low-density lipoprotein receptors (LDL-R) and triggers their degradation. Inhibiting PCSK9 activity results in lowering LDL-C levels and further reduceing the risk of cardiovascular events. Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. Objectives To evaluate the safety, efficacy of ebronucimab and further identify the optimal dosing scheme in patients with hyperlipidemia. Methods A total of 260 Chinese patients with hyperlipidemia (≧18 years, male or female) were planned to be enrolled, and randomized to receive ebronucimab 450 mg every 4 weeks (q4w), 300 mg q4w, 150 mg q2w, 75 mg q2w or matching placebo via subcutaneous injection. The patients were treated up to 12 weeks (day 85). Serum samples were collected at preselected timepoints to analyze the lipid profiles. Results Efficacy Ebronucimab showed significant and dose-dependent LDL-C reductions from baseline. At week 12, the mean reductions in LDL-C were 65.48 %, 48.14%, 63.69% and 37.39% for 450 mg q4w, 300 mg q4w, 150 mg q2w and 75 mg q2w dose groups, respectively. Patients in the 450 mg q4w and 150 mg q2w groups achieved higher and more sustained LDL-C reduction compared with other dose groups. Similar trend was observed in serum levels of total cholesterol (TC), apolipoprotein B (ApoB), lipoprotien (a) (LP[a]). Safety A total of 49.6% (130/262) patients experienced at least 1 treatment-emergent adverse event (TEAE), 109 patients (109/210 [51.9%]) in ebronucimab groups and 21 patients (21/52 [40.4%]) in the placebo group. Most TEAEs were mild and moderate. No adverse events were apparently dose dependent with ebronucimab. The overall incidence of serious adverse events (SAEs) was 3.4 % (9/262). Conclusions Ebronucimab was generally safe and well tolerated in Chinese patients with hyperlipidemia. Patients treated with ebronucimab achieved a significant reduction in serum levels of LDL-C and other lipids, especially in 450 mg q4w and 150 mg q2w treatment groups.

Low-density lipoprotein cholesterol reduction with evolocumab and its use in clinical practice: evidence from Swedish national register data

Abstract Background/Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce low density lipoprotein cholesterol (LDL-C) levels by around 50% to 60%, and the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) in randomized clinical trials. Data on LDL-C reduction with PCSK9 inhibitors and its use in clinical practice is lacking. Purpose Assess LDL-C reduction with the PCSK9 inhibitor evolocumab and its use in clinical practice in Sweden. Methods Population-based, retrospective, longitudinal, observational study of patients initiating evolocumab treatment between July 2015 and May 2020. Patients undergoing lipoprotein apheresis were excluded. Patient level data was obtained from national diagnosis and pharmaceutical registers (covering 100% of the Swedish population), and electronic health records (covering 60% of the Swedish population). The use of evolocumab was assessed based on persistence with and adherence to treatment. Patients were defined as being persistent if they were still taking evolocumab 12 months after treatment initiation. Medication gaps were allowed until a last gap of ≥56 days. Patients were defined as being adherent if the proportion of days covered (PDC) by the drug was ≥80% during that same period. Mean LDL-C reduction was estimated 3 months after evolocumab treatment initiation, using a Generalized Least Squares regression model. Results Overall, 2341 patients were included in the analysis, with a median follow-up of 376 days. Median age was 65 years, 43% were women, 79% had a history of ASCVD and, among them, 94% had had a coronary event and 24% had diabetes. 44% of the patients had LDL-C available. Median LDL-C was 4.1 mmol/L and 64% of the patients were receiving oral lipid-lowering treatment (LLT). After 12 months of treatment, 76% of the patients were persistent with evolocumab. In these patients, median PDC over 12 months was 93%, with 86% of these patients being adherent (PDC ≥80%). In the overall population (n=724), the estimated mean LDL-C reduction with evolocumab at 3 months was 48% (2.1 mmol/L, from 4.4 mmol/L at baseline). In patients who were adherent to evolocumab during the first 6 months (n=567), LDL-C reduction was 53% (2.2 mmol/L, from 4.3 mmol/L at baseline) (see figure). In patients who were adherent to both evolocumab and oral LLT (PDC ≥80% over a period of 3 months before and after evolocumab initiation) (n=186), LDL-C reduction was 59% (2.1 mmol/L, from 3.6 mmol/L at baseline). The estimated mean LDL-C reduction remained stable over a 6-month period. Conclusions Persistence with and adherence to evolocumab treatment were high over 12 months. LDL-C reduction with evolocumab in clinical practice was similar to that observed in randomized clinical trials and remained stable over 6 months. At evolocumab treatment initiation, many patients had high LDL-C levels and underused oral LLT, potentially due to statin intolerance. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen

Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials

Background. Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) –61.3 - –47.2; p&lt;0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI –57.9 - –47.8; p&lt;0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.

How to bridge residual distance to target low-density-lipoprotein cholesterol in acute coronary syndrome patients after initial statin therapy?

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Current guidelines recommend intensive low-density-lipoprotein cholesterol (LDL-C) lowering by ≥50% to target LDL-C &amp;lt;1.4mmol/L after acute coronary syndrome (ACS). Residual distance to LDL-C target can help select treatment strategy after initial statin therapy. PURPOSE We aimed to evaluate residual distance to guideline recommended target LDL-C and the proportion of ACS patients who are projected to reach target LDL-C by different statin and non-statin lipid lowering strategies. METHODS We retrospectively analyzed 46,114 patients admitted with ACS who survived 1 year from 18 acute hospitals in Hong Kong between Jan 2014 and Dec 2018. Patients were divided into (i) high potency (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg); (ii) non-high potency (NHP-S; other statin doses) statin users and (iii) no statin therapy. We calculated the mean distance and percentage LDL-C reduction required to reach dual LDL-C targets (&amp;gt;50% reduction from baseline and &amp;lt;1.4mmol/L). We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by approximately 5-10%; addition of ezetimibe 15-20% and PCSK-9 inhibitor 50-60%. RESULTS Of 46,114 patients (60.7% males, mean age 76.2 ± 13.3 years), 80.4% (n = 10945/13614) had LDL-C ≥1.4mmol/L at 12-months after index ACS with 60.2% (n = 18319/30450), 31.9% (n = 9726/30450) and 8.0% (2405/30450) of patients on no statin, NHP-S and HP-S, respectively. 86% of HP-S and 93% of NHP-S users did not reach dual LDL-C targets at 12-months. Among patients on NHP-S and HP-S, the mean LDL-C at 12-months was 2.0 ± 0.7 and2.1 ± 0.9 mmol/L; mean residual distance to target 0.64 ± 0.7 and0.66 ± 0.9 mmol/L; and mean percentage LDL-C reduction required to reach dual LDL-C targets was 22.4 ± 33% and 18.8 ± 36%, respectively. 13% of statin users required &amp;gt;50% further LDL-C reduction to reach targets. Projected proportion of NHP-S users to reach LDL-C targets is 11% (n = 430/3966) by up-titrating to HP-S, 21% (n = 828/3966) by up-titration to HP-S plus ezetimibe and 100% (n = 3966/3966) with PCSK-9 inhibitor plus HP-S and ezetimibe. Projected proportion of HP-S users to reach LDL-C targets is 13% (n = 143/1099) by ezetimibe and 100% (n = 1099/1099) with addition of PCSK-9 inhibitor. CONCLUSION The use of high-potency statin was low and almost all statin users did not reach dual LDL-C targets at 12-months after index ACS. High potency statin plus ezetimibe is projected to bridge about a fifth of these patients to target LDL-C. PCSK-9 inhibitor is likely needed in the majority of patients who have not achieved target LDL-C at 12-months after ACS to reach guideline recommendations.

Evinacumab Markedly Reduces Low-density Lipoprotein Cholesterol in Adolescent Patients With Homozygous Familial Hypercholesterolemia†

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Regeneron Pharmaceuticals, Inc. Background/Synopsis Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease, underscoring the need for early and aggressive treatment. Evinacumab, an angiopoietin-like protein 3 inhibitor, is an effective LDL-C lowering drug in adult HoFH patients. Objective/Purpose The primary objective of the study is to evaluate the safety and tolerability of intravenous evinacumab 15 mg/kg every 4 weeks in adolescent patients with HoFH. Methods This is an interim analysis of an evinacumab open-label phase 3 trial (NCT03409ba744) in adolescent patients (aged 12 to <18 years) with HoFH. Patients who participated in a previous study (NCT03399786) or who were evinacumab-naive received intravenous evinacumab 15 mg/kg every 4 weeks. All patients were genotyped. Results In total, 13 patients (8 male; mean [range] age 14 [12-17] years) were treated for a mean (range) duration of 34.5 (4-61) weeks. At baseline, mean (standard deviation [SD]) LDL-C was 310.3 [97.3] mg/dL; 8 patients (61.5%) received lipoprotein apheresis. Treatment-emergent adverse events (TEAEs) occurred in 6 (46.2%) patients; no TEAEs were reported in more than 1 patient. One patient reported 2 serious adverse events, both considered unrelated to study drug. LDL-C data were available for 9 patients at week 24. Overall, evinacumab reduced mean LDL-C by 52.4% (mean [SD], 183.4 [101.6] mg/dL; Figure) from baseline to week 24. In patients with null-null (n=4) and non-null (n=5) LDL-receptor variants, evinacumab reduced mean LDL-C levels by 67.2% and 40.6%, respectively. Conclusions In this small sample of adolescent patients with HoFH, evinacumab markedly reduced LDL-C irrespective of genotype or background treatment in patients with HoFH. Evinacumab was generally well-tolerated with few TEAEs. Nothing to disclose.

Sex Differences in Low-Density Lipoprotein Cholesterol Reduction With PCSK9 Inhibitors in Real-world Patients: The LIPID-REAL Registry.

Previous evidence supports that monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 50%-65%, regardless of baseline treatments. We tested possible sex differences in a multicentre registry of real-world patients treated with PCSK9 inhibitors. This is a multicentre and retrospective study of 652 patients initiating treatment with any PCSK9 inhibitor in 18 different hospitals. Before-treatment and on-treatment LDLc and medical treatments, clinical indication, and clinical features were recorded. Women represented 24.69% of the cohort. The use of statins was similar in both sexes, but women were receiving most frequently ezetimibe. Before-treatment median LDLc was 135 (interquartile range 115-166) mg, and it was higher in women. The median on-treatment LDLc was 57 (interquartile range 38-84) mg/dL, which represented a mean 54.5% reduction. On-treatment LDLc was higher in women, and the mean LDLc reduction was lower in women (47.4% vs. 56.9%; P = 0.0002) receiving evolocumab or alirocumab. The percentage of patients who achieved ≥50% LDLc reduction was higher in men (71.36% vs. 57.62%; P = 0.002). According to LDLc before-treatment quartiles, LDLc reduction was statistically lower in women in the 2 highest and a significant interaction of women and baseline LDLc >135 mg/dL was observed. Women were negatively associated with lower rates of LDLc treatment target achievement (odds ratio: 0.31). Differences were also observed in women with body mas index >25 kg/m2. Only 14 patients (2.14%) presented side effects. This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction.

Abstract 12756: Long-Term Efficacy and Safety of Evinacumab in Adult and Adolescent Patients With Homozygous Familial Hypercholesterolemia

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare genetic lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease, underscoring the need for early and aggressive treatment. Evinacumab, an angiopoietin-like 3 inhibitor, significantly reduced LDL-C in patients with HoFH in a pivotal Phase 3 trial (NCT03399786). The current study assesses long-term safety and efficacy of evinacumab in patients with HoFH. Methods: This is an interim analysis of an evinacumab open-label Phase 3 trial (NCT03409744) in adult and adolescent(12-&lt;18 years) patients with HoFH. Patients who previously received evinacumab or who were evinacumab-naïve both received intravenous evinacumab 15 mg/kg every 4 weeks. Results: A total of 115 patients (50.4% male; mean [range] age 39 [12-75] years; 11.3% adolescent) were enrolled and treated for a mean (range) duration of 53 (4-132) weeks. At baseline, mean (standard deviation [SD]) LDL-C was 261.8 (160.5) mg/dL; 44 (38.3%) patients were receiving concomitant lipoprotein apheresis. At Week 24, data were available for 81 patients. From baseline to Week 24, evinacumab reduced mean LDL-C for all patients by 43.7% (mean [SD], 133.0 [125.9] mg/dL); mean LDL-C reduction for adult (n=72) and adolescent (n=9) subgroups was 42.6% (mean [SD], 126.7 [127.9] mg/dL) and 52.4% (mean [SD], 183.4 [101.6] mg/dL), respectively. Treatment-emergent adverse events (TEAEs) occurred in 76 (66.1%) patients; one patient reported pregnancy which led to discontinuation of study treatment per protocol. Serious TEAEs were reported by 16 (13.9%) patients; two (1.7%) patients experienced a TEAE resulting in death, none of which were considered related to study treatment. Conclusions: In this large cohort of patients with HoFH, evinacumab markedly reduced LDL-C irrespective of age. Evinacumab was generally well tolerated, and the efficacy and safety of evinacumab was sustained over the long term.

Treatment adherence and effect of concurrent statin intensity on the efficacy and safety of alirocumab in a real-life setting: results from ODYSSEY APPRISE.

IntroductionThe phase IIIb open-label ODYSSEY APPRISE study prospectively assessed the safety and efficacy of alirocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in a real-life setting in high cardiovascular risk patients with heterozygous familial hypercholesterolemia or low-density lipoprotein cholesterol (LDL-C) not at goal despite maximally tolerated dose statins ± other lipid-lowering therapies (NCT02476006). This post-hoc analysis assessed patient adherence to statins and alirocumab, plus alirocumab efficacy and safety, according to concomitant statin intensity and prior ezetimibe usage.Material and methodsPatients received alirocumab 75 or 150 mg (dose adjustment based on physician’s judgment) every 2 weeks (for ≥ 3 to ≤ 30 months).ResultsOf 994 enrolled and treated patients, 58.4% received concomitant high-intensity statins, 18.2% received moderate/low-intensity statins, and 23.4% received no statin; 55.9% received prior ezetimibe. Mean alirocumab adherence (percent adherence defined as injections received/theoretical injections × 100) was 96.6% over 72.4 weeks’ mean treatment duration. Mean LDL-C reduction from baseline at Week 12 was similar between statin intensity subgroups (53.6–55.7%). More patients achieved LDL-C < 1.8 mmol/l and/or ≥ 50% reduction from baseline in the ≥ 100% versus < 100% adherent to alirocumab subgroup; high-intensity and low/moderate-intensity subgroups versus no statin subgroup; and prior ezetimibe versus no prior ezetimibe subgroup. Treatment-emergent adverse events occurred in 65.2–75.1% and 68.0–76.3% of patients across statin and ezetimibe subgroups, respectively.ConclusionsIn a real-life setting, patient adherence to alirocumab was high. Alirocumab provided clinically significant reductions in LDL-C, with most patients achieving LDL-C treatment targets across background statin therapy and prior ezetimibe therapy subgroups.

LDLc reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with coronary heart disease that are not candidates for PCSK9 inhibitors treatment

Abstract Background Statin plus ezetimibe combination has a recommendation class IIa, level of evidence B, for low-density lipoprotein cholesterol (LDLc) reduction. Since LDLc treatment target for patients with coronary heart disease (CHD) has been recently reduced to &amp;lt;55 mg/dl most patients might need lipid-lowering drugs combinations and fixed-dose combinations are known to increase adherence. Current indications for PCSK9 inhibitors accepted for reimbursement in Spain in patients with CHD are LDL &amp;gt;100 mg/dl despite maximal dose tolerated of statins or any of previous patients with statin intolerance and LDL &amp;gt;100 mg/dl. Methods Investigator-initiated retrospective analysis of patients with coronary heart disease that received fixed-dose combination with rosuvastatin-ezetimibe between 2019 and 2020 in a specialized unit for patients with CHD. Inclusion criteria were: CHD and LDLc &amp;lt;100 mg/dl despite statin treatment or &amp;gt;100 mg/dl without previous lipid-lowering treatments. We also analysed patients in whom treatment was initiated at discharge from and acute coronary syndrome (ACS) or with chronic coronary syndrome (CCS) Results We analyzed 137 patients, 79.4% males, mean age 62. (12.3) and 24.1% with ACS. Statin treatment before initiation fixed-dose combination was higher in patients with CCS (71.2% vs. 8.2%; p&amp;lt;0.01). Mean LDLc before treatment was 103.0 (30.5) mg/dl and it was higher in patients with ACS (121.3 (40.2) vs. 97.4 (24.4); p&amp;lt;0.001). Median time to second blood test was 203 days (IQR 122–300); mean post-treatment LDLc was 60.8 (21.2) mg/dl and no difference (p=0.18) was found in patients with ACS vs CCS: 56.0 (26.1) vs. 62.4 (19.2) mg/dl. Mean LDLc reduction was 38.5% and it was higher in was higher in ACS patients (49.9% vs. 34.7%) (figure). LDLc &amp;lt;55 mg/dl was achieved in 42.1% of the patients, more frequently in patients with ACS: 59.3% vs. 36.3% (p=0.036). No increase in transaminases was detected and a reduction in triglycerides was found (149.1 (100.4) to 124.7 (82.3) mg/dl; p=0.041). Conclusions Treatment with a fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD not candidate for PCSK9 inhibitors is effective and safe for LDLc reduction especially in patients discharged after an ACS. Funding Acknowledgement Type of funding sources: None.

Gender differences low-density lipoprotein cholesterol reduction with PCSK9 inhibitors in real world patients

Abstract Background Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments, and are supposed to have a homogenous effect. We tested possible gender differences in a large multicenter registry of real-world patients treated with PCSK9 inhibitors. Methods Multicentre and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals from Spain. Before and on-treatment LDLc cholesterol was recorded as well as medical treatments, clinical indication and clinical features. Results A total of 562 patients were analysed, mean age 60.2 (9.6) years and 79.2% males. Most frequent indication for PCSK9 inhibitor treatment was established cardiovascular disease (CVD) with LDLc &amp;gt;100 mg/dl (58.1%) followed by familial hypercholesterolemia (23.4%) and statin intolerance (18.5%). Indications other than CVD were more frequent in women (53.3% vs. 39.1%; p=0.03). Women were more frequently ezetimibe (67.5% vs. 50.6%; p=0.001) before PCSK9 treatment; although no gender differences in statin use was observed (78.6% vs. 83.6%; p=0.93) in the whole cohort it was significantly lower in patients with coronary heart disease (91.4% vs. 98.9%; p=0.005). Before treatment LDLc was 148.7 (50.1) mg/dl and it was higher women vs. men (160.3 (59.3) vs. 145.6 (47.0); p=0.005). Evolocumab was initiated in 318 (56.6%) patients; 229 (40.7%) alirocumab 75 mg and 15 (2.7%) alirocumab 150 mg. No gender differences in PCSK9 inhibitors drug or dose were observed. Median time to second blood determination were 187.5 (IQR 101–242) days. Mean on-treatment LDLc was 66.7 (46.4) mg/dl and it was also higher in women vs. men (84.4 (58.6) vs. 61.9 (41.3); p&amp;lt;0.001). Mean LDLc reduction was 54.7% but it was higher in men as compared to women (57.0% vs. 46.1%; p=0.0003). Higher LDLc reductions were also observed in patients with CVD as compared to the other 2 indications (57.1% vs. 47.3%; p=0.002). Moreover, LDLc reduction with PCSK9 inhibitors treatment was also higher in men vs women among patients with CVD (58.9% vs. 48.0%; p=0.04) Conclusions This multicentre and retrospective registry of real-world patients treated with PCSK9 inhibitors highlights significant gender differences in LDLc reduction. Funding Acknowledgement Type of funding sources: None.

Impact of a preventive cardiology clinic focusing on lifestyle and nutrition counseling: A pilot analysis

Standard cardiology practice often defers preventive strategies to primary care providers. We aimed to evaluate the effectiveness of a preventive cardiology clinic focused on lifestyle and nutrition counseling combined with guideline-directed medical therapy on reducing cardiovascular disease (CVD) risk. We queried the University of Florida-Health database for patients enrolled in the preventive cardiology clinic, and a general and interventional cardiology clinic from January 2016 to October 2019. Mean change in weight and blood cholesterol including LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were compared in the three clinics in the initial cohort and stratified into primary and secondary prevention. A propensity score-matched analysis was done to adjust for CVD risk factors and statin use. Among a cohort of 239 patients, enrollment in the preventive clinic (n = 99) was associated with greater weight loss at 6 months compared to other clinics (n = 140) (mean −1.7 vs +0.1 kg, p 0.007). Preventive clinic was also associated with greater mean reduction in LDL-C (−24.8 vs −7.1 mg/dl, p 0.021), TC (−29.3 vs −2.0, p 0.003) and TG (−19.7 vs +13.3, p 0.002) at both initial and last follow-up (median time 6 and 16 months). The association with reduction in TG was observed in both primary and secondary prevention, but reduction in LDL-C and TC was only significant in secondary prevention. In a propensity-matched linear regression analysis, preventive clinic was independently associated with LDL-C reduction (b −14.7, r −0.3, p 0.038). A preventive cardiology clinic focused on patient education can be effective in reducing CVD risk.

A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9

PurposeAT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.MethodsThis phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77–196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.ResultsThe most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was −7.2% (95% CI [−10.4 to −3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.ConclusionsAlthough both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.Trial registrationEudraCT: 2015-001719-11. ClinicalTrials.govIdentifier: NCT02508896.

LDL Cholesterol Reduction Variability with Different Types and Doses of Statins in Monotherapy or Combined with Ezetimibe. Results from the Spanish Arteriosclerosis Society Dyslipidaemia Registry.

Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10mg (32.5 ± 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40mg (58.7 ± 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10mg combined with ezetimibe (50.6 ± 24.6%) and rosuvastatin 40mg combined with ezetimibe (71.6 ± 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.