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• Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. • Reduction of total cardiovascular events was greater at higher baseline Lp(a). The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (p interaction =0.08). Medication adherence and adverse event rates were similar in both sexes. Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a). [Display omitted] [ABSTRACT FROM AUTHOR]

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Background and Aims: ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial.Methods and Results: The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively.Conclusion: The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment.Clinicaltrials: Gov Identifier: NCT02476006. [ABSTRACT FROM AUTHOR]

• RDW independently associates with risk of MACE and death in patients with recent ACS. • RDW adds to information provided by other risk factors and biomarkers, such as hs-CRP. • RDW is an existing component of the complete blood count. • As such, RDW provides useful predictive information after ACS at no incremental cost. Elevated red blood cell distribution width (RDW) is associated with increased risk for major adverse cardiovascular events (MACE) and death in patients with cardiovascular disease. The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. This post hoc analysis determined whether RDW independently predicts risk of MACE and death in patients after recent ACS, whether RDW influences MACE reduction with alirocumab, and whether alirocumab treatment affects RDW. Associations of baseline RDW with risk of MACE and death were analyzed in the placebo group in adjusted proportional hazards models. Interactions of RDW and treatment on the risk of MACE and death were evaluated. An increasing quartile of RDW was associated with characteristics that predicted risk of MACE and death including age, hypertension, diabetes, atherosclerotic conditions and events, revascularizations, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. After adjusting for baseline characteristics associated with the risk of MACE or death, baseline RDW remained independently associated with the risk of MACE and death in the placebo group (hazard ratios [95% confidence intervals] 1.08 [1.02–1.15] and 1.13 [1.03–1.24] per 1% increase of RDW, respectively, both p <0.001). There was no interaction of RDW and treatment on MACE or death, nor did alirocumab affect RDW. RDW was associated with an increased risk of MACE and death, independent of established risk factors. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes. [Display omitted] • LPS perturbed renal function, oxidative stress, inflammatory and apoptotic biomarkers, histological picture. • LPS dysregulated Nrf2/HO-1; PCSK9; HMGB1/RAGE/TLR4/ MYD88; CX3CL1/CX3R1 and NF-ᴋB/NLRP3/Caspase-1 hubs. • Alirocumab elicited nephroprotective effects against LPS intoxication. • Alirocumab exerted modulatory effects on PCSK9; HMGB1/RAGE/TLR4/ MYD88; NF-ᴋB/NLRP3, CX3CL1/CX3R1 and apoptotic axes. [ABSTRACT FROM AUTHOR]

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

• Persistence to PCSK9i increased within an integrated specialty pharmacy care model. • Medication access was not a main contributor to PCSK9 inhibitor non-persistence. • LDL-C values of persistent patients were similar to other real-world studies. • Specialty pharmacists are positioned to help increase persistence to PCSK9i therapy. Nearly 40% of patients do not continue proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapy after 6 months, despite their ability to lower low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events. Limited work has assessed persistence to PCSK9i therapy in an integrated specialty pharmacy model. To assess rates of persistence to PCSK9i therapy and report reasons for non-persistence in patients serviced within an integrated specialty pharmacy. We conducted a single-center, retrospective review of patients prescribed a PCSK9i at an academic health system between September 2015 and August 2018. Persistence was calculated as a binary measure (yes/no) of whether the patient was still receiving PCSK9i therapy at 3-, 12-, and 24-months; frequency distributions described reasons for non-persistence and descriptive statistics described the change in LDL-C from baseline to 24 months. 477 patients met inclusion criteria, 53% were male with median age of 63 years [IQR 56-70]. Median LDL-C at baseline was 157mg/dL and 86% had an atherosclerotic cardiovascular disease indication. Persistence at 3-, 12-, and 24-months was 94%, 80%, and 68%, respectively. Of the 262 patients persistent on PCSK9i therapy at 24 months with LDL-C values available, median LDL-C was 65 mg/dL. The most common reasons for non-persistence at 24 months included medication adverse effects (54%) and loss to follow-up (17%). High rates of persistence to PCSK9i were seen in patients receiving care within an integrated specialty pharmacy model compared with rates in previous studies, suggesting specialty pharmacists may play a role in mitigating many common reasons for PCSK9i non-persistence. [ABSTRACT FROM AUTHOR]

Trials of the fully human monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9) alirocumab in hypercholesterolemia demonstrated substantial low-density lipoprotein cholesterol (LDL-C) lowering, reduction in cardiovascular (CV) events and outcomes, and a generally acceptable safety and tolerability profile. The impact of maintaining low LDL-C levels on higher order brain function is unclear, with reports of neurocognitive disorders with other lipid-lowering therapies. Patients (n = 2176) with heterozygous familial hypercholesterolemia (HeFH) or non-FH, at high or very-high CV risk despite maximally tolerated statin therapy, randomly received subcutaneous alirocumab 75/150 mg or placebo every 2 weeks in this double-blind, placebo-controlled trial. The primary outcome was prospectively evaluated every 24 weeks over 96 weeks by Cambridge Neuropsychological Test Automated Battery (CANTAB). Among 2086 patients with CANTAB cognitive domain Spatial Working Memory Strategy (SWMS) assessments, change from baseline to Week 96 in SWMS z-score (primary outcome) achieved noninferiority between alirocumab and placebo (least squares [LS] mean change at Week 96, −0.180 vs −0.200; LS mean difference vs placebo [95% confidence interval]: −0.020 [−0.094 to 0.055], p = 0.6055). Exploratory outcome measures, which further assessed neurocognitive function in the CANTAB domains, did not differ significantly over 96 weeks and achieved nominal noninferiority between treatment groups. Alirocumab resulted in nominally significant reductions in LDL-C and other lipid parameters, and was generally well tolerated. Confirming previous PCSK9 inhibitor data, alirocumab showed no effect on neurocognitive function over 96 weeks' treatment, substantially reduced LDL-C and was generally well tolerated in patients with HeFH or non-FH at high or very-high CV risk. [Display omitted] • Maintaining low LDL-C levels for CV benefit may impact neurocognitive function • Prospective 96-week study, alirocumab or placebo in 2176 high-risk HeFH/non-FH patients • Confirming prior PCSK9i data, alirocumab showed no effect on neurocognitive function • Non-inferior ΔCANTAB cognitive domain SWMS z-score between alirocumab and placebo • Alirocumab was generally well tolerated and significantly reduced LDL-C/other lipids [ABSTRACT FROM AUTHOR]

The effects of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on endothelial function as assessed by flow-mediated dilation (FMD) in patients with acute myocardial infarction (AMI) are unknown. Therefore, we aimed to investigate the effects of the PCSK9 inhibitor alirocumab added to high-intensity statin on FMD, and its association with coronary atherosclerosis in non-infarct related arteries using intracoronary intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT). This was a pre-specified substudy among patients recruited at Bern University Hospital, Switzerland, for the randomized-controlled, double-blind, PACMAN-AMI trial, which compared the effects of biweekly alirocumab 150 mg vs. placebo added to rosuvastatin. Brachial artery FMD was measured at 4 and 52 weeks, and intracoronary imaging at baseline and 52 weeks. 139/173 patients completed the substudy. There was no difference in FMD at 52 weeks in the alirocumab (n = 68, 5.44 ± 2.24%) versus placebo (n = 71, 5.45 ± 2.19%) group (difference = −0.21%, 95% CI −0.77 to 0.35, p = 0.47). FMD improved throughout 52 weeks in both groups similarly (p < 0.001). There was a significant association between 4 weeks FMD and baseline plaque burden (IVUS) (n = 139, slope = −1.00, p = 0.006), but not with lipid pool (NIRS) (n = 139, slope = −7.36, p = 0.32), or fibrous cap thickness (OCT) (n = 81, slope = −1.57, p = 0.62). Among patients with AMI, the addition of alirocumab did not result in further improvement of FMD as compared to 52 weeks secondary preventative medical therapy including high-intensity statin therapy. FMD was significantly associated with coronary plaque burden at baseline, but not with lipid pool or fibrous cap thickness. [Display omitted] • This randomized trial assessed the effect of alirocumab/statin vs. placebo/statin on flow mediated dilation (FMD) in acute myocardial infarction (AMI). • FMD improved throughout 1 year after AMI with medical therapy similarly in alirocumab/statin vs. placebo/statin treated patients. • FMD at baseline was significantly inversely associated with coronary plaque burden on intravascular ultrasound. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce cardiovascular events, but their effects on atherosclerotic plaque remain elusive. Using serial magnetic resonance imaging (MRI), we studied changes in carotid plaque lipid content and neovasculature under PCSK9 inhibition with alirocumab. Among patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl but ineligible for high-dose statin therapy, those with lipid core on carotid MRI were identified to receive alirocumab 150 mg every 2 weeks. Follow-up MRI was performed at 3, 6, and 12 months after treatment. Pre- and post-contrast MRI were acquired to measure percent lipid core volume (% lipid core). Dynamic contrast-enhanced MRI was acquired to measure the extravasation rate of gadolinium contrast (K trans ), a marker of plaque neovasculature. Of 31 patients enrolled, 27 completed the study (mean age: 69 ± 9; male: 67%). From 9.8% at baseline, % lipid core was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months (p = 0.014 for trend), which was accompanied by a progressive increase in % fibrous tissue (p = 0.009) but not % calcification (p = 0.35). K trans was not reduced until 12 months (from 0.069 ± 0.019 min−1 to 0.058 ± 0.020 min−1; p = 0.029). Lumen and wall areas did not change significantly during the study period. Regression in plaque composition and neovasculature were observed under PCSK9 inhibition on carotid MRI, which provides unique insight into the biological process of plaque stabilization with disease-modifying therapies. [Display omitted] • Carotid MRI can quantify plaque lipid content (% lipid core) and neovasculature (K trans ). • With PCSK9i, % lipid core was reduced progressively and seen as early as 3 months. • K trans , a marker of plaque neovasculature, was not reduced until 1 year. • Changes in serum lipids and imaging markers did not correlate at the individual level. [ABSTRACT FROM AUTHOR]

Treatment with proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), in addition to statin therapy, reduces LDL-cholesterol (LDL-c) in some patients to extremely low levels (i.e.< 20 mg/dl or < 0.52 mmol/l). There is concern that at such low levels, the physiologic role of cholesterol may be impaired, e.g. the adrenal cortisol stress response might be compromised. We therefore evaluated the effect of PCSK9i therapy on the cortisol response to ACTH in patients with LDL-c down to extremely low levels. Nineteen patients on PCSK9i therapy and 18 controls matched for age, gender and comorbidities were included. The cortisol response to adrenocorticotropic hormone (ACTH) was tested after application of 250 μg ACTH. LDL-c levels ranged from 0.42 to 3.32 mmol/l (mean 1.38 ± 0.84 mmol/l) in the PCSK9i group and 0.81–4.82 mmol/l (mean 2.10 ± 0.97) in the control group. By analysis of covariance (ANCOVA), the PCSK9i group had significantly lower cortisol response compared to the control group (- 97.26 nmol/l, −178.60 to −15.93, p = 0.02) after 60 min. There was a significant positive correlation between the duration of PCSK9i treatment and cortisol levels (r = 0.59, p = 0.009). Extremely low LDL-c levels down to 0.42 mmol/l were not associated with lower stimulated cortisol levels. Patients on PCSK9i therapy showed a significantly lower cortisol response to ACTH. Stimulated cortisol levels were lower in the first months of PCSK9i treatment, suggesting an adaptive phenomenon. We conclude that the adrenal stress response in patients on PCSK9 inhibitor therapy is reduced. [Display omitted] • Adrenal stress response in patients on PCSK9i therapy was significantly reduced. • Stimulated cortisol levels were lower in the first months of PCSK9i treatment. • LDL-c down to 0.42 mmol/l was not associated with a reduced adrenal stress response. • No difference was found between patients on Alirocumab and Evolocumab. [ABSTRACT FROM AUTHOR]

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The previously published ODYSSEY ESCAPE trial demonstrated a significant reduction in the use of lipoprotein apheresis for heterozygous familial hypercholesterolemia (HeFH) patients when placed on alirocumab 150 mg every 2 weeks. In patients with HeFH who have consistently elevated levels of low-density lipoprotein cholesterol (LDL-C) despite maximally tolerated statin therapy, current lipid guidelines recommend apheresis. Although apheresis reduces LDL-C levels by 50%–75%, it must be repeated, as frequently as every 1–2 weeks. To assess clinical experience with apheresis and alirocumab for patients in a real-world practice setting. This retrospective review included patients from 5 apheresis centers who were treated with apheresis and had started alirocumab therapy. In addition to LDL-C levels, total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, and particle numbers were evaluated if data were available. Eleven of the 25 (44%) patients discontinued apheresis completely after initiation of alirocumab therapy, having achieved LDL-C <70 mg/dL or >50% reduction from baseline levels. Among the 14 patients who remained on apheresis, seven decreased the frequency of apheresis sessions. No significant safety problems were reported. Alirocumab lowered LDL-C levels by an average of 55.5% in patients receiving apheresis for elevated LDL-C. Seventy-two percent of patients on alirocumab therapy discontinued or reduced the frequency of apheresis treatment. However, some patients continued to require apheresis due to elevated lipoprotein(a), extremely elevated LDL-C, or if alirocumab therapy was discontinued due to less than anticipated LDL-C reduction. • Lipoprotein apheresis is effective in lowering high LDL-C • Alirocumab, a PCSK9 antibody, is also effective in lowering LDL-C • Alirocumab can decrease the use or frequency of apheresis in high-risk patients [ABSTRACT FROM AUTHOR]

The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin. The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen. This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at Week 12 if Week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at Week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5%–71.9% over Weeks 20–24 in patients on 300 mg Q4W and 57.2%–63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache. Data provide further insight on alirocumab's mode of action in terms of relationship between alirocumab, PCSK9, and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions. • Alirocumab, PCSK9, and LDL-C relationships were assessed with alirocumab 300 mg Q4W. • >80% of patients (including those on statins) achieved low-density lipoprotein cholesterol (LDL-C) goals with 300 mg Q4W. • Greater target-mediated clearance of alirocumab suggested in statin-treated patients. • Change to 150 mg Q2W more likely in statin-treated or higher baseline LDL-C patients. • Results provide further insight on alirocumab's mode of action. [ABSTRACT FROM AUTHOR]

Background: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.Objectives: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.Methods: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.Results: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.Conclusions: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402). [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402). [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. NCT01604824; clinicaltrials.gov. • For the apolipoprotein B (APOB) loss-of-function mutations (LOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 55.3% at Week 8. • For the proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 73.1% at Week 8. • At Week 8, alirocumab levels were lower in APOB LOFm vs PCSK9 GOFm carriers. • PCSK9 suppression by alirocumab was greater in APOB LOFm vs PCSK9 GOFm carriers. • Treatment-emergent adverse events occurred in 94.1% and 83.3% of PCSK9 GOFm and APOB LOFm groups, respectively. [ABSTRACT FROM AUTHOR]

Background: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.Objectives: This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).Methods: Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003).Results: In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]).Conclusions: Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402). [ABSTRACT FROM AUTHOR]

Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined. This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy. Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1% to 1.0%), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%). In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402) [ABSTRACT FROM AUTHOR]

Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were −25.6% vs. −2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and −21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p= 0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79–1.01; p= 0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p -interaction vs. Lp(a) < 50 mg/dL: 0.0549). In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels. Image 1 • Analysis of 10 phase 3 ODYSSEY trials, alirocumab (ALI) vs. placebo or ezetimibe. • Median lipoprotein(a) [Lp(a)] reductions: ALI (21.4–25.6%) vs. control (0.0–2.5%). • Adjusted by baseline characteristics, 12% RRR in MACE per 25% reduction in Lp(a); p = 0.0254. • Adjusted by LDL-C reductions, RRR was not significant; hazard ratio = 0.89, p = 0.0780. • Fully adjusted RRR significant if baseline Lp(a) ≥ vs. < 50 mg/dL; p -interaction 0.0549. [ABSTRACT FROM AUTHOR]

Hyperlipidemia plays a crucial role in the underlying pathogenesis of multiple cardiovascular diseases (CVD), including coronary artery disease, peripheral arterial disease, carotid stenosis, and heart failure. The risk of developing such diseases in the diabetic population is relatively high. Diabetes mellitus (DM) is an independent risk factor for premature atherosclerosis. The hallmark of DM dyslipidemia is a demonstrably high level of atherogenic triglyceride rich lipids including very low-density lipoprotein, chylomicrons, and small dense low-density lipoprotein (LDL). Moderate to high intensity statins, targeting LDL cholesterol reduction, remain the cornerstone in the management of this unique disorder. Many 'non-statin' drugs have recently been studied in the DM patients who were either on a 'maximally tolerated statin' or 'statin intolerant'. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are particularly important and were incorporated in the recent guidelines by the European Society of Cardiology, American College of Cardiology, American Heart Association, and American Diabetes Association. Icosapent Ethyl has garnered huge interest this year following publication of the REDUCE-IT trial. There are several newer hypolipidemic drugs, including Bempedoic acid, Inclisiran and RVX-208, that are in different phases of clinical trials. In this article, we review the underlying pathophysiology of DM dyslipidemia, existing guidelines related to its management, and the potential of newer hypolipidemic and anti-inflammatory drugs being incorporated in the management of DM. [ABSTRACT FROM AUTHOR]

Chaque année, des secteurs isolés de la thérapeutique bénéficient de l'arrivée de médicaments sur le marché. Un tout nouveau concept de traitement des hypercholestérolémies a vu le jour, alors que d'autres spécialités récentes en allergologie, rhumatologie et neurologie sont le fruit d'innovations amorcées déjà depuis quelques années. Every year, lower-profile medical fields benefit from the arrival of new drugs on the market. A brand-new concept for the treatment of high cholesterol has been developed, while other recent specialities in allergology, rheumatology and neurology are the fruit of innovations first initiated a few years ago. [ABSTRACT FROM AUTHOR]

Abstract Background Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9-I) reduce low-density lipoprotein (LDL) cholesterol in human studies. Previous studies suggest that PCSK9-I may also affect very-low-density lipoproteins (VLDL). We therefore studied VLDL size and composition in a "real-world" study population with the use of β-quantification. Subjects and methods 350 patients (62 ± 11 years old, 58% men, 22% with diabetes mellitus) with different concomitant lipid lowering therapies, and in whom PCSK9-I treatment was indicated, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). The major lipoprotein fractions were separated by β-quantification and lipid and apolipoprotein compositions were determined before and 4 weeks after initiation of PCSK9-I treatment. Results After 4 weeks of PCSK9-I treatment, the ratio of triglycerides to apolipoprotein B in VLDL particles (VLDL-TG/apoB ratio) increased by 40% (p <.0001). VLDL-associated apolipoproteins E, CII, and CIII were reduced by 29.4%, 16.4%, and 12.4%, respectively (all p <.0001). Conclusion PCSK9-I treatment increased VLDL size (estimated by an increased VLDL-TG/apoB ratio) and reduced VLDL-associated apolipoproteins in a heterogeneous "real-world" study-population, reflecting a higher clearance of small atherogenic VLDL remnant particles by PCSK9-I. This may potentially lower cardiovascular risk in clinical routine patients beyond low-density cholesterol (LDL-C) reduction. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins. To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke. Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, alirocumab dose, and control (placebo or ezetimibe). Baseline LDL-C, non–high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%–62.9%) and without (43.6%–58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C–lowering efficacy of alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%–84.8% and 63.7%–74.7%, respectively. The safety profile of alirocumab was generally similar regardless of prior MI/ischemic stroke status. Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke. • Analysis of alirocumab ODYSSEY trials by MI/ischemic stroke status (with/without). • Alirocumab reduced LDL-C in patients with or without MI/ischemic stroke. • Alirocumab reduced lipoprotein(a) regardless of MI/ischemic stroke status. • Most patients with/without prior MI/ischemic stroke attained LDL-C goals. • Alirocumab's safety profile was generally similar regardless of prior MI/ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in the cholesterol metabolism by negatively regulating the low-density lipoprotein receptor (LDLR). Lipid metabolic and ovarian disorders are the common clinical manifestation of polycystic ovary syndrome (PCOS). Here, we intended to elucidate the role of PCSK9 in the pathogenesis of PCOS conducted on a human population in case-control design and animal part in an interventional study. Methods We firstly investigated the serum levels of PCSK9 in 46 PCOS patients compared with 49 healthy women as controls, and then developed a PCOS mouse model induced by dehydroepiandrosterone (DHEA) and a high-fat diet (HFD) to determine the role of PCSK9 in abnormal lipid metabolism and ovarian dysfunction of PCOS in four groups (n = 40 per group): control, PCOS mice, PCOS plus alirocumab group, and PCOS plus vehicle group. The expression of PCSK9 in their serum, hepatic and ovarian tissues, serum lipid profiles and hormones were measured. Additionally, mRNA and protein expression levels of LDLR in hepatic and ovarian tissues, ovarian morphology and function were determined. Finally, we used freshly isolated theca-interstitial cells (TICs) and granulosa cells (GCs) from prepubertal normal mice to explore the effect of PCSK9 on LDL uptake of the cells. Results Serum PCSK9 concentrations were higher in PCOS patients than normal controls (P < 0.05). The PCOS model mice exhibited significantly increased serum levels of total cholesterol (TC), LDL-C and high-density lipoprotein-cholesterol (HDL-C; P < 0.001, P < 0.001, P = 0.0004, respectively). Moreover, the serum PCSK9 protein level was significantly increased in PCOS mice (P = 0.0002), which positively correlated with serum LDL-C (r = 0.5279, P = 0.0004) and TC (r = 0.4151, P = 0.035). In both liver and ovary of PCOS mice, PCSK9 mRNA and protein levels were significantly increased (P < 0.05), but LDLR levels were significantly decreased (P < 0.05). Furthermore, alirocumab inhibiting PCSK9 partly increased in LDLR expression in both liver and ovary in PCOS mice, also ameliorated the lipid metabolic disorders and pathological changes of ovarian morphology and function and serum reproductive hormones but not in the PCOS plus vehicle group. In vitro experiment, recombinant PCSK9 decreased LDL uptake in TICs and GCs (P < 0.001, P = 0.0011, respectively), which were partly reversed by alirocumab (P < 0.001, P = 0.012, respectively). Conclusion Abnormal high expression of PCSK9 in the blood, liver and ovary may be involved in the pathogenesis of PCOS by affecting lipid metabolism and ovarian function, and the inhibition of PCSK9 may partly reverse the pathological changes of PCOS. Our research suggests a possibility of PCSK9 as a new attractive target for diagnosis and treatment of PCOS. Highlights • Serum PCSK9 concentrations were higher in PCOS patients than normal controls. • The expression of PCSK9 increased in the serum, livers and ovaries of PCOS mice. • PCSK9 directly affects ovarian lipid metabolism in PCOS mice. • Alirocumab inhibiting PCSK9 improves lipid metabolism in PCOS mice. • Alirocumab treatment partly reverses ovarian function disorders in PCOS mice. [ABSTRACT FROM AUTHOR]

Highlights • ALTAIR: Phase IV, open-label, randomized, parallel-group, single-center study. • Alirocumab arm: alirocumab 75 mg every 2 weeks added to rosuvastatin 10 mg/day. • Standard-of-care arm: rosuvastatin 10 mg/day. • Optical coherence tomography (OCT) imaging at baseline and at week 36 (post-treatment). • Main outcome measure: change in thickness of the fibrous cap (blinded OCT analysis). Abstract Background Although a recent clinical trial demonstrated that alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, significantly reduces the incidence of acute coronary events, the impact of alirocumab on plaque stabilization remains uncertain. The Efficacy of ALirocumab for Thin-cap fibroatheroma in patients with coronary Artery disease estImated by optical coherence tomogRaphy (ALTAIR) study will investigate the effect of alirocumab on thin-cap fibroatheroma (TCFA) in Japanese patients who underwent recent percutaneous coronary intervention (PCI). Methods and design ALTAIR is a phase IV, open-label, randomized, parallel-group, single-center study involving blinded optical coherence tomography (OCT) image analysis in Japanese adults hospitalized for PCI and having suboptimal control of low-density lipoprotein cholesterol (LDL-C) levels (>70 mg/dL) despite statin therapy. Patients will be randomized (1:1) to the alirocumab arm (alirocumab 75 mg every 2 weeks added to rosuvastatin 10 mg/day) or the standard-of-care arm (rosuvastatin 10 mg/day, with initiation and/or dose adjustment of non-statin lipid-lowering to achieve an LDL-C target of <70 mg/dL). OCT imaging will be conducted at baseline and at week 36 (post-treatment). The primary objective is to compare the alirocumab and standard-of-care arms regarding the change in TCFA fibrous-cap thickness after 9 months of treatment. Conclusion The outcomes of ALTAIR (ClinicalTrials.gov identifier: NCT03552432) will provide insights into the effect of alirocumab on plaque vulnerability following PCI in patients with suboptimal LDL-C control despite stable statin therapy. [ABSTRACT FROM AUTHOR]

Highlights • Alirocumab 150 mg Q4W dosing is efficacious in reducing low-density lipoprotein cholesterol. • Alirocumab 150 mg Q4W or Q2W is well tolerated in Japanese hypercholesterolemic patients. • Alirocumab 150 mg Q4W offers an alternative, flexible dosing, regimen for Japanese patients. Abstract Background Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, given every 2 weeks (Q2W), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in Japanese hypercholesterolemic patients on background statin. We evaluated alirocumab 150 mg every 4 weeks (Q4W) in patients on lowest-dose statin or non-statin lipid-lowering therapy (LLT). Methods ODYSSEY NIPPON was a double-blind study conducted in Japanese patients with LDL-C ≥100 mg/dL (heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia with coronary heart disease) or ≥120 mg/dL (non-familial hypercholesterolemia, Japan Atherosclerosis Society category III) on atorvastatin 5 mg/day or non-statin LLT. Patients were randomized (1:1:1) to subcutaneous alirocumab 150 mg Q4W, alirocumab 150 mg Q2W, or placebo for the 12-week double-blind treatment period (DBTP), followed by a 52-week open-label treatment period (OLTP). At entry into the OLTP, patients received alirocumab 150 mg Q4W, with possible up-titration to 150 mg Q2W at Week 24. Results Least-square mean percent change in LDL-C from baseline at Week 12 (primary efficacy endpoint) was −43.8% for alirocumab Q4W, −70.1% for Q2W, and −4.3% for placebo. During the OLTP, mean LDL-C change from baseline was −45.1% at Week 20, with a further reduction at Week 36, with achieved levels maintained to Week 64. Percent of patients with ≥1 adverse event (DBTP) was 51.9% with alirocumab Q4W, 47.2% with Q2W, and 46.4% with placebo. Most common adverse events were infections and infestations (25.9%, 22.6%, 17.9%, respectively), gastrointestinal disorders (13.0%, 9.4%, 12.5%), nervous system disorders (5.6%, 7.5%, 10.7%), and general disorders and administration-site conditions (3.7%, 11.3%, 5.4%). Conclusions Hypercholesterolemic Japanese patients who tolerate only lowest-strength dose statin or non-statin LLT can achieve robust LDL-C reduction with alirocumab 150 mg Q4W, in addition to their current LLT. Alirocumab 150 mg Q4W dosing was efficacious and generally well tolerated without new safety concerns. (ClinicalTrials.gov number: NCT02584504) [ABSTRACT FROM AUTHOR]

Access to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that lower low-density lipoprotein cholesterol in patients at high risk of atherosclerotic cardiovascular disease events has proven challenging. Methods to overcome access barriers are needed to fully realize the benefits of these novel agents. This study evaluated medication access rates in patients prescribed a PCSK9 inhibitor at a health care system with integrated specialty pharmacy services. We performed a single-center, ambispective cohort study of patients prescribed a PCSK9 inhibitor between September 2015 and December 2016 at Vanderbilt University Medical Center outpatient clinics. The primary end point was the percentage of PCSK9 inhibitor prescriptions resulting in access of the total prescriptions triaged to Vanderbilt Specialty Pharmacy. Secondary end points assessed among patients approved for therapy included time between benefits investigation and insurance approval, financial assistance use, and treatment initiation rates. Two hundred ninety-nine patients met inclusion criteria (average age = 63 years). Forty-six percent were female, 57% held commercial insurance, and 70% had an atherosclerotic cardiovascular disease indication. Overall, 96% of prescriptions resulted in access to a PCSK9 inhibitor. Most patients were approved with an initial prior authorization (58%) or after one appeal (29%). The median time to approval was 8 days. Among patients approved for therapy, 53% received financial assistance and 94% initiated therapy. An integrated specialty pharmacy service model in outpatient clinics produced high rates of PCSK9 inhibitor therapy access and initiation. This high level of access supports this model as a best practice for prescribing PCSK9 inhibitor therapy. • High rates of PCSK9 inhibitor access and initiation are possible. • An integrated specialty pharmacy successfully facilitates treatment access. • ASCVD and government insurance were negatively associated with time to access. [ABSTRACT FROM AUTHOR]

Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.Results: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS. [ABSTRACT FROM AUTHOR]

Background Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. Objective The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. Methods After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. Results During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). Conclusions In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels. Graphical abstract Highlights • Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) by 63.1% at Week 8 of LONG TERM trial (HeFH cohort). • Alirocumab 75 mg Q2W reduced LDL-C by 47.3% at Week 8 of OLE (same cohort, n = 214). • Choice of alirocumab dose allowed for an individualized approach to LDL-C lowering. • Alirocumab provided steady LDL-C reductions over ≤3 years of treatment. • Treatment-emergent adverse events leading to treatment discontinuation occurred in 4 patients (1.9%) [ABSTRACT FROM AUTHOR]

In conclusion, the present systematic review and meta-analysis showed that in patients with previous cardiovascular events, the risk of stroke was significantly reduced in patients with and without previous stroke treated with PCSK9 inhibitors irrespective of the baseline LDL-C levels. Keywords: Lipid-lowering; Statin; PCSK9 inhibitor; Evolocumab; Alirocumab; Stroke EN Lipid-lowering Statin PCSK9 inhibitor Evolocumab Alirocumab Stroke 130 132 3 03/03/21 20210301 NES 210301 Dear Editor, over the last decades lipid-modifying strategies made a pivotal change in cardiovascular prevention especially in patients with previous coronary artery disease or ischemic stroke. The beneficial effect of PCSK9 inhibitors in patients with previous cardiovascular events and stroke was not related to an increase of hemorrhagic stroke rates, irrespectively of the LDL-C levels. [Extracted from the article]

A 48-year-old man presented to our lipid clinic with statin intolerance and elevated serum creatine kinase levels, being affected by mitochondrial myopathy because of heteroplasmic mitochondrial DNA missense mutation in MTCO1 gene (m.7671T>A). He had just been treated with a coronary artery bypass 4 years before because of acute coronary syndrome, and he had consistently high levels of both low-density lipoprotein cholesterol and triglycerides. Dyslipidemia was successfully treated using 75 mg of alirocumab subcutaneously every 2 weeks, 10 mg of ezetimibe daily, 2 g of marine omega-3 fatty acids daily, and 145 mg of micronized fenofibrate every 2 days. Although muscle weakness persisted, myalgia did not reoccur and serum creatine kinase levels remained almost stable over the time. • Lipid-lowering management of patients with mitochondrial myopathy is challenging. • In patients with inherited myopathies, statins have to be used with caution. • Treatment with proprotein convertase subtilisin/kexin type 9 inhibitors does not interact with muscle metabolism. • Proprotein convertase subtilisin/kexin type 9 inhibitors can be safely used in patients with mitochondrial myopathy. [ABSTRACT FROM AUTHOR]

Une meilleure connaissance des voies du métabolisme des lipides a conduit à l'émergence de deux nouvelles classes d'hypocholestérolémiants : les inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 et les inhibiteurs de la protéine trifonctionnelle mitochondriale. Ces composés réservés aux dyslipidémies sévères ouvrent la voie à d'autres thérapies innovantes telles que les inhibiteurs de l'angiopoïétine like 3, de l'apolipoprotéine CIII ou de l'apolipoprotéine B100. A better understanding of the pathways of lipid metabolism has led to the emergence of two new classes of cholesterol-lowering drugs: subtilisine/kexin type 9 convertase protein inhibitors and mitochondrial trifunctional protein inhibitors. These compounds for severe dyslipidemia pave the way for other innovative therapies such as angiopoietin like 3, apolipoprotein CIII or apolipoprotein B100 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Background and aims ODYSSEY OLE (open-label extension; NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolemia (HeFH), receiving maximally tolerated statins, who had completed one of four Phase 3 double-blind parent studies (all 18 months' duration), with the aim to assess longer-term safety and efficacy of alirocumab. Methods Patients received starting dose alirocumab 75 mg every 2 weeks (Q2W; patients from FH I, FH II, and LONG TERM) or alirocumab 150 mg Q2W (patients from HIGH FH). Low-density lipoprotein cholesterol (LDL-C) levels were blinded to the patient and physician until Week 8; from Week 8, LDL-C levels were communicated to physicians. From Week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa , was possible per physician's clinical judgment according to patient's LDL-C levels. Results Patients who had received alirocumab (n = 655) compared with placebo (n = 330) in the parent studies exhibited similar rates of treatment-emergent adverse events (TEAEs; 87.3% vs. 83.9%) during OLE (2.5 years median alirocumab exposure). Overall, 33 patients (3.4%) experienced TEAEs leading to permanent treatment discontinuation. At Week 8, alirocumab reduced mean LDL-C by 44.2% (reduction from 151.9 mg/dL at parent study baseline to 84.9 mg/dL); reduction in LDL-C was consistent to Week 96 of OLE. Reductions in lipid parameters were similar regardless of treatment allocation in the parent study. Conclusions In patients with HeFH, no unexpected long-term safety concerns were observed with alirocumab compared with previously published data; durability of LDL-C-lowering over 3 years (including 1.5 years of parent trials) was demonstrated. Graphical abstract Image 1 Highlights • In total, 985 patients with HeFH received alirocumab (median duration 2.5 years). • TEAE rates unaffected by parent study treatment allocation (alirocumab vs placebo). • TEAEs leading to treatment discontinuation occurred in 33 patients (3.4%). • Unique to the ODYSSEY OLE trial, dose adjustment was per physician judgment. • At Week 96 alirocumab reduced LDL-C by 47.9%, maintained throughout OLE from Week 8. [ABSTRACT FROM AUTHOR]

Background ODYSSEY OLE (NCT01954394) was an open-label extension (OLE) study for patients with heterozygous familial hypercholesterolemia (HeFH) who had completed previous phase 3 clinical trials with alirocumab. Alirocumab dose could be increased or decreased as per physician judgment. Objective To assess how the alirocumab dosing strategy was used by physicians during OLE. Methods Patients who entered OLE on a starting dose of alirocumab 75 mg every 2 weeks (Q2W) were included in the analysis (those from FH I, FH II, and LONG TERM trials). Those who completed LONG TERM entered an 8-week washout period before receiving alirocumab 75 mg Q2W at the start of OLE. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible, based on the physician's clinical judgment. Results In total, 909 patients with HeFH completed the 3 parent studies and were treated during OLE for a duration of up to 40 months. Most patients (56.7%) were maintained on 75 mg Q2W throughout OLE, whereas 43.3% of patients had their dose increased to 150 mg Q2W. The dose was subsequently decreased in 7.4% of the patients in whom alirocumab was initially uptitrated. Overall, treatment-emergent adverse events were similar between those who had received placebo or alirocumab in the parent studies. Conclusions In the opinion of physicians, alirocumab 75 mg Q2W enabled over half of patients with HeFH to achieve sufficient low-density lipoprotein cholesterol lowering. Graphical abstract Highlights • In total, 909 patients with heterozygous familial hypercholesterolemia received alirocumab (median duration 2.5 years). • Alirocumab dose received (75 or 150 milligrams) based on clinical judgment of physician. • Seventy-five milligram dose considered enough for low-density lipoprotein cholesterol control for 56.7% of patients by physicians. • During open-label extension, 5.9% of patients reported local injection-site reaction adverse events. • Physician's decision to increase alirocumab dose was primarily due to high low-density lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). Methods Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy. Results Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions versus controls. Conclusions Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG). Highlights • Patients with ASCVD and prior revascularization are at very-high risk of CV events. • Alirocumab efficacy/safety were compared in ASCVD with/without revascularization. • Data were pooled from eight placebo/ezetimibe-controlled Phase 3 ODYSSEY trials. • Alirocumab significantly reduced LDL-C/lipoproteins, regardless of prior PCI/CABG. • Alirocumab's safety profile was favourable regardless of revascularization status. [ABSTRACT FROM AUTHOR]

Background and aims Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, significantly reduces low-density lipoprotein cholesterol (LDL-C). We evaluated the efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus (T2DM) with versus without mixed dyslipidaemia (MDL, defined as baseline LDL-C ≥70 mg/dL [1.8 mmol/L] and triglycerides ≥150 mg/dL [1.7 mmol/L]). Methods Data from 812 individuals with T2DM, from the placebo-controlled, 78-week, Phase 3 ODYSSEY LONG TERM trial of alirocumab 150 mg every 2 weeks (Q2W), on a background of maximally tolerated statins ± other lipid-lowering therapies, were pooled according to MDL status. Efficacy endpoints included percentage change from baseline to Week 24 in calculated LDL-C and other lipids/lipoproteins. Results In individuals with T2DM who received alirocumab 150 mg Q2W, mean LDL-C changes from baseline to Week 24 were −62.6% ( vs . −6.0% with placebo) in those with MDL and −56.1% ( vs . 5.6%) in those without MDL, with no significant between-group difference ( p -interaction = 0.0842). Risk-based LDL-C goals (<70 [1.8 mmol/L] or <100 mg/dL [2.6 mmol/L]) were achieved by 69.1% and 72.4% of alirocumab-treated individuals with and without MDL, respectively. Mean reductions in non-high-density lipoprotein cholesterol (49.2% and 47.8%) and apolipoprotein B (50.2% and 49.1%) with alirocumab were also similar in those with and without MDL, respectively. Treatment-emergent adverse event rates were comparable between alirocumab-treated individuals with T2DM, with and without MDL. Conclusions Reductions in LDL-C and other lipids with alirocumab, as well as safety and tolerability, were comparable between individuals with T2DM and with versus without MDL. [ABSTRACT FROM AUTHOR]

The discovery of proprotein convertase subtilisin kexin-type 9 (PCSK9) and the development of inhibitors of PCSK9 function appear to mark an epochal advance in clinical lipidology. PCSK9 is a circulating protein that binds to low-density lipoprotein (LDL) receptors and facilitates their lysosomal degradation following internalization in cells. Blocking PCSK9 thus increases the recycling of LDL receptors and results in more receptors on the cell surface, particularly in the liver, thereby lowering LDL levels. In this Roundtable, we discuss the recent large cardiovascular outcomes trials in which evolocumab and alirocumab, monoclonal antibodies directed against PCSK9, successfully reduced major cardiovascular events. We discuss the safety of these drugs as well as the safety of maintaining very low LDL cholesterol levels. Finally, we address pragmatic considerations affecting the use of PCSK9 inhibitors in clinical practice. [ABSTRACT FROM AUTHOR]

Background Serial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. Methods ODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [≥100 mg/dL (2.6 mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of-care (SOC). The alirocumab arm will receive alirocumab 75 mg every 2 weeks (Q2W) added to statin therapy (atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day), with a dose increase to 150 mg Q2W in patients whose LDL-C value remains ≥100 mg/dL at week 12. The SOC arm will receive atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day, with dose adjustment to achieve LDL-C <100 mg/dL. Post-treatment IVUS imaging will be done at week 36 ± 2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. Conclusion ODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy. ClinicalTrials.gov number : NCT02984982 . [ABSTRACT FROM AUTHOR]

Background The alirocumab expanded use program provided open-label access to alirocumab before its commercial availability to patients with severe hypercholesterolemia not controlled with maximally tolerated doses of standard-of-care lipid-lowering therapy. Objective To describe the safety and lipid-lowering efficacy of alirocumab in high-risk patients who were likely to be early users of proprotein convertase subtilisin/kexin type 9 inhibitors after approval. Methods Patients with heterozygous familial hypercholesterolemia (HeFH) and/or coronary heart disease (CHD) and baseline low-density lipoprotein cholesterol (LDL-C) of ≥160 mg/dL on maximally tolerated lipid-lowering therapy were enrolled and received alirocumab 150 mg every 2 weeks for 24 weeks. Patients were permitted use of all available statins; those not taking any dose of statin could also be enrolled. Results Of 100 enrolled patients, 93 were white, 62 were women, and overall mean age was 58 years; 61 had HeFH, 3 had unknown type of familial hypercholesterolemia, 66 had CHD, and 30 had both familial hypercholesterolemia and CHD. Sixty-four patients were identified by their providers to have some level of statin intolerance; of these, 47 were not on statin. Alirocumab reduced LDL-C on average from 221 mg/dL at baseline to 102 mg/dL by week 24 (−55%). Treatment-emergent adverse events were experienced in 61% of patients and treatment-emergent adverse events leading to permanent treatment discontinuation in 3% of patients; no deaths occurred. Conclusions Safety and efficacy observations from the open-label alirocumab expanded use program of very high-risk patients with HeFH and/or CHD and baseline LDL-C of ≥160 mg/dL uncontrolled by maximally tolerated lipid-lowering therapy were consistent with those in the placebo/ezetimibe-controlled ODYSSEY trials. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease.Objectives: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older).Methods: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations.Results: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person.Conclusions: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices. [ABSTRACT FROM AUTHOR]

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C metabolism has been discovered in 2003, there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human PCSK9 antibodies evolocumab and alirocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and they have been shown to decrease LDL-C by ∼50 to 70%. Rates of achieving LDL-C goals are up to 87–98% of treated subjects. Multiple phase 3 studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016. Both, alirocumab and evolocumab have been approved in 2015 for the treatment of hypercholesterolemia in the European Union and in the United States. Preliminary meta-analytic data show an improvement in cardiovascular morbidity and mortality by ∼50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy. [ABSTRACT FROM AUTHOR]

Background and aims The effect of LDLc lowering with PCSK9 antibodies on tendon xanthomas (TX) is unknown. Methods TX was measured in 24 heterozygous familial hypercholesterolemia (HeFH) cases and in 24 HeFH controls with or without PCSK9 inhibitors for at least one year. Results Exposure to PCSK9 inhibitors in cases was 2.96 ± 1.33 years. LDLc decreased 80.8 ± 7.66% in cases and 56.9 ± 11.1% in controls. There was a decrease in maximum (−5.03%) and mean (−5.32%) TX in cases but not in controls (+3.97%, +3.16, respectively, p = 0.01). PCSK9 inhibitor treatment was independently associated with TX reduction. Conclusion Addition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and TX after 3 years of treatment. [ABSTRACT FROM AUTHOR]

Background and aims Familial hypercholesterolemia (FH) is a high cardiovascular risk condition. Less than 20% of patients achieve the LDL targets. Although PCSK9 inhibitors improve control and reduce cardiovascular events, official recommendations for their use are restrictive. We aim to assess the number of FH patients suitable for PCSK9 inhibition according to the European guidelines. Methods A total of 2685 FH patients, with a minimum follow-up of 6 months, included in the Dyslipidemia Registry of the Spanish Arteriosclerosis Society, were sorted according to the intensity of their lipid-lowering therapy (LLT) and LDL cholesterol levels achieved. The number of patients who met the recommendations for PCSK9 inhibition treatment according to the European Atherosclerosis Society (ESC/EAS), Spanish Arteriosclerosis Society and the European Medicines Agency was calculated. Results In total, 1573 patients were on high-intensity LLT; 607 were on moderate-intensity statins; 82 were on low-intensity LLT, and 423 were neither on statins nor on ezetimibe in the last visit registered. The mean LDL reduction among those on high-intensity LLT was 54%. Ninety-one percent of patients on high-intensity LLT had an LDL below 5.2 mmol/L, 53% below 3.4 mmol/L, and 23% below 2.6 mmol/L. Only 12% of FH patients with cardiovascular disease achieved 1.8 mmol/L. Despite this, only 17% of patients qualified for PCSK9 inhibition according to ESC/EAS guidelines. Conclusions For patients with a condition that exposes them to high cardiovascular risk and who have extreme difficulties in achieving LDL targets, wider access to PCSK9 inhibitor therapy is warranted. [ABSTRACT FROM AUTHOR]

Background Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection). Objective The objective of the study was to assess long-term adherence to alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia. Methods Data were pooled from 6 ODYSSEY trials (n = 4212) with double-blind treatment durations of 52 to 104 weeks. Adherence was reported as percentage of days receiving injections according to dosing schedule and categorized into 100% adherence, below-planned dosing, above-planned dosing, and both below- and above-planned dosing. Overall adherence was calculated as 100 − (percentage of days with below-planned dosing + percentage of days with above-planned dosing). Safety of alirocumab and effect on LDL-C levels were also evaluated. Results Adherence was analyzed for 4197 patients (n = 2786 alirocumab; n = 1411 control). Mean overall adherence was high (alirocumab 98.0%; control 97.8%). Among patients receiving alirocumab, 45.7% were 100% adherent, 20.4% had below-planned dosing, 2.9% had above-planned dosing, and 31.1% had both below- and above-planned dosing. Mean percentage reduction in LDL-C (baseline to Week 52) was 45.8% to 61.9%, depending on alirocumab dose, and was comparable across adherence categories. Treatment-emergent adverse events leading to alirocumab discontinuation were infrequent and included myalgia and injection-site reactions (<1% each). Conclusions Alirocumab injections were associated with a high level of adherence over ≥1 year. Infrequent below- or above-planned dosing had minimal impact on LDL-C reductions. [ABSTRACT FROM AUTHOR]

An Expert Panel convened by the National Lipid Association was charged with updating the recommendations on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy that were provided by the 2015 National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part 2. Recent studies have demonstrated the efficacy of these agents in reducing low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol and have confirmed their excellent safety profile. A cardiovascular outcomes study has shown that these agents reduce incident atherosclerotic cardiovascular disease (ASCVD) events in patents with stable ASCVD and concomitant risk factors. The current update provides the Expert Panel's evidence-based recommendations on the clinical utility of PCSK9 inhibitors in patients with stable ASCVD, progressive ASCVD, LDL-C ≥ 190 mg/dL (including polygenic hypercholesterolemia, heterozygous familial hypercholesterolemia and the homozygous familial hypercholesterolemia phenotype) and very-high-risk patients with statin intolerance. [ABSTRACT FROM AUTHOR]

Background PCSK9 inhibition with alirocumab significantly reduced LDL-C levels in trials of up to 78 weeks' duration in patients with heterozygous familial hypercholesterolemia (HeFH). We report results from 3 years of an ongoing open-label treatment extension ( NCT01576484 ) to a 12-week double-blind trial in HeFH patients ( NCT01266876 ). Methods Patients who completed the parent study and were receiving stable daily statin ± ezetimibe could enter the open-label extension, where they received alirocumab 150 mg every 2 weeks (Q2W) subcutaneously (n = 58). The primary endpoint was safety (treatment-emergent adverse events, TEAEs). Efficacy endpoints included the percentage change in LDL-C from baseline at Week 24. Safety and efficacy data were available up to Weeks 156 and 148, respectively. Results Mean baseline LDL-C was 150.7 mg/dL (3.9 mmol/L), despite all patients being on a statin (76% on high-intensity statin; 72% also receiving ezetimibe). Over 156 weeks, 54 (93.1%) patients experienced a TEAE, 12 (20.7%) experienced a serious TEAE, and two (3.4%) discontinued due to a TEAE. Injection site reactions occurred in 21 (36.2%) patients. Mean (SD) reduction in LDL-C from baseline to Week 24 was 65.4 (21.1)%, with reductions maintained through 148 weeks (Week 148 reduction: 56.0 [23.8]%). Mean apolipoprotein B reduction was 50.9% and median lipoprotein (a) reduction was 22.5% at Week 24 (46.1% and 25.6% at Week 148, respectively). Conclusions Open-label treatment for 3 years with alirocumab 150 mg Q2W, administered with background statin ± ezetimibe, was generally well-tolerated and had a safety profile comparable with that seen in the overall alirocumab clinical trial program. Alirocumab provided significant, sustained LDL-C reductions. [ABSTRACT FROM AUTHOR]