Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors Alirocumab Research Articles

'A case of autoimmune hepatitis associated with the PCSK9 inhibitor alirocumab'.

This is a case of a 61-year-old lady who presented to the lipid clinic with possible familial hypercholesterolaemia (Simon Broome Criteria). She was commenced on atorvastatin; however, 4weeks later, she developed hepatitis, and therefore her atorvastatin was discontinued. Following that, her liver function tests normalized, and she was diagnosed with statin-induced hepatitis. Three years later, she was seen again in the lipid clinic with an uncontrolled lipid profile, and she was commenced on alirocumab, a Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitor. A few days later, she developed hepatitis, and subsequently, the alirocumab was discontinued. She underwent a liver biopsy, which confirmed that she had Autoimmune Hepatitis (AIH) with presumed superimposed drug injury. This is the first reported case of autoimmune hepatitis associated with alirocumab.

Effect of alirocumab on quantitative flow ratio and diameter stenosis in non-infarct related arteries from patients with acute myocardial infarction: a PACMAN-AMI randomized clinical trial substudy

Abstract Introduction Treating hypercholesterolemia with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on top of statins leads to plaque regression and stabilization. The effects of PCSK9 inhibitors on coronary physiology and angiographic diameter stenosis (DS%) are unknown. Quantitative Flow Ratio (QFR) is a novel method to assess coronary hemodynamics. Purpose We aimed to investigate the effects of the PCSK9 inhibitor alirocumab on QFR and 3D-Quantitative Coronary Angiography (3D-QCA) DS% in non-infarct-related arteries (non-IRA) among acute myocardial infarction (AMI) patients. Methods This was a pre-specified substudy of the PACMAN trial, a randomized, double-blind, placebo-controlled trial comparing alirocumab vs. placebo on top of high-intensity rosuvastatin among AMI patients. QFR and 3D-QCA were assessed at baseline and 1-year follow-up in any non-infarct related artery (non-IRA) with ≥2.0mm diameter and >25% 3D-QCA DS%. The pre-specified primary endpoint was the number of patients with mean QFR increase from baseline to follow-up, and the secondary endpoint the change in 3D-QCA DS%. Results Of 300 enrolled patients, 265 had serial follow-up, of which 193 underwent serial QFR/3D-QCA analysis in 282 non-IRA. Baseline mean QFR was 0.96[IQR 0.91-0.98] and mean DS% 36.96±7.88% in the alirocumab group vs. 0.96[IQR 0.91-0.99] (p=0.593) and 36.63±8.46% (p=0.742) in the placebo group. At 1-year, QFR increased in 50/94 (53.2%) patients with alirocumab vs. 40/99 (40.4%) with placebo (Δ12.8%; OR=1.7, 95%CI 0.9-3.0; p=0.076). When excluding non-IRA with QFR >0.95, QFR increased in 37/57 (64.9%) patients with alirocumab vs. 22/50 (44.0%) with placebo (Δ20.9%; OR=2.4, 95%CI 1.1-5.2; p=0.031). DS% decreased by -1.03±7.28% with alirocumab and increased by +1.70±8.27% with placebo (Δ-2.54%, 95%CI -4.51 to -0.57; p=0.012). Conclusions Treatment of AMI patients with alirocumab vs. placebo for 1 year resulted in a significant regression in angiographic DS%. While no overall improvement of coronary hemodynamics was observed with alirocumab as compared to placebo, potential benefits were found in alirocumab treated patients with baseline QFR ≤0.95.Figure 1.Flowchart and primary endpointFigure 2.Secondary endpoint

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Effect of alirocumab on cataracts in patients with acute coronary syndromes

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

Impact of alirocumab added to high-intensity statin therapy on platelet function in AMI patients: a pre-specified substudy of the randomized, placebo-controlled PACMAN-AMI trial

Abstract Background Previous small observational studies have suggested a potential association of proprotein convertase subtilisin kexin type 9 (PCSK9) and platelet reactivity. However, the role of the PCSK9 inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. Purpose We investigated the effect of alirocumab on P2Y12 reaction unit (PRU) on top of high-intensity statin therapy among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). Methods This was a pre-specified, powered, pharmacodynamic substudy nested within the PACMAN (effects of the PSCK9 antibody AliroCuMab on coronary Atherosclerosis in patieNts with Acute Myocardial Infarction) trial, a randomized, double-blind trial comparing biweekly alirocumab (150mg) versus placebo in AMI patients undergoing percutaneous coronary intervention (PCI). Patients recruited at Bern University Hospital, receiving DAPT with either ticagrelor or prasugrel at 4 weeks and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The VerifyNow P2Y12 point-of-care assays were used to measure PRU at baseline (i.e. before first study drug administration), 4 weeks, and 52 weeks after study drug administration (higher PRU levels indicating greater platelet aggregation). The primary endpoint was PRU at 4 weeks. Results Among 139 randomized patients (mean age 58.2 years [SD, 9.5], 21 [15.0%] women, mean LDL-C level 150.6mg/dL [SD, 30.9]), baseline characteristics were well balanced between groups including baseline PRU (50.0 [IQR, 120.0] in the alirocumab group vs. 62.0 [IQR, 122.0] in the placebo group, P=0.75). At 4 weeks, mean LDL-C was significantly lower in the alirocumab group (23.5 [SD, 23.7] mg/dL vs. 74.4 [SD, 30.5] mg/dL, P&amp;lt;0.001). The majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] vs. 69 [94.5%], P=0.14). There were no significant differences in PRU at 4 weeks (12.5 [IQR, 27.0] vs. 19.0 [IQR, 30.0], P=0.26) and at 52 weeks (25.0 [IQR, 37.0] vs. 34.0 [IQR, 59.0], P=0.07) (Figure). Consistent results were observed in 126 patients treated with ticagrelor (i.e. after excluding 13 patients treated with prasugrel) at 4 weeks (13.0 [IQR, 20.0] vs. 18.0 [IQR, 27.0], P=0.28). Conclusion Among AMI patients receiving DAPT with potent P2Y12 inhibitors, alirocumab had no significant effect on platelet function as assessed by PRU. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Bern University Hospital

Alirocumab and Lipid Levels, Inflammatory Biomarkers, Metabolomics, and Safety in Patients Receiving Maintenance Dialysis: The ALIrocumab in DIALysis Study (A Phase 3 Trial to Evaluate the Efficacy and Safety of Biweekly Alirocumab in Patients on a Stable Dialysis Regimen)

Rationale & ObjectiveThe proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab is used in the general population to treat dyslipidemia, but little is known about the effects of alirocumab on lipid levels, biomarkers, the metabolome, and safety in individuals receiving maintenance dialysis.Study DesignPatients receiving maintenance dialysis for at least 3 months and with a low-density lipoprotein cholesterol level of >70 mg/dL were treated with alirocumab for 12 weeks. Laboratory measurements, drug levels, and safety assessments were obtained at baseline and every 4 weeks during the trial.Setting & ParticipantsIn an outpatient setting, 14 patients completed the trial.InterventionThe patients were treated with alirocumab at a full dose of 150 mg every 2 weeks for 12 weeks. The patients were asked to report any adverse events every 2 weeks.OutcomesThere were no unexpected adverse events or laboratory abnormalities in this population receiving dialysis. The drug levels were the same as those for a population not receiving dialysis.ResultsAlirocumab resulted in a 45% reduction in the low-density lipoprotein cholesterol level (P = 0.005) and a 35% reduction in the apolipoprotein B level (P = 0.06). There were no significant decreases in the levels of triglycerides, C-reactive protein, fibrinogen, or other inflammatory biomarkers tested. There were significant decreases in the levels of 7 ceramide, 5 sphingomyelin, and 5 cholesterol ester species.LimitationsThis study was performed in only 14 patients who were administered alirocumab for only 12 weeks. This study did not address alirocumab treatment in patients with chronic kidney disease not receiving maintenance dialysis.ConclusionsIndividuals receiving maintenance dialysis had a similar response to the PCSK9 inhibitor alirocumab as patients not receiving dialysis. The levels of inflammatory biomarkers were not clearly decreased by alirocumab, but the levels of ceramides, sphingomyelins, and cholesterol esters were significantly reduced.Trial RegistrationClinical Trials.gov as NCT03480568.

Effect of alirocumab on incidence of atrial fibrillation after acute coronary syndromes: insights from ODYSSEY OUTCOMES

Abstract Background Atrial fibrillation (AF) is a marker of risk in patients presenting with acute coronary syndromes (ACS). The potential effect of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) on the incidence of AF is unknown. Methods The ODYSSEY OUTCOMES trial compared randomized treatment with the PCSK9 inhibitor alirocumab or placebo in patients with recent ACS and residual dyslipidaemia despite optimal statin therapy. The current analysis determined: 1) whether alirocumab treatment influenced incident AF; 2) whether a history of AF influenced the risk of major adverse cardiovascular events (MACE); and 3) whether there was interaction between AF at baseline and randomized treatment on MACE. AF was determined from the medical history and investigator reports of adverse events. Results Of 18,924 participants, 662 (3.5%) had a history of AF at randomization and 18,262 (96.5%) had no history of AF. Of the latter category, 499 (2.7%) had incident AF. Older age, randomization in South America or Eastern Europe, history of heart failure or myocardial infarction, and higher body mass index were factors associated with incident AF. Treatment with alirocumab or placebo did not influence incident AF (2.2% vs 2.6%, respectively; hazard ratio 0.90, 95% confidence interval 0.75–1.08; Figure). Patients with a history of AF had a greater burden of comorbidities, including cerebrovascular disease, peripheral artery disease, hypertension and heart failure; they also had higher rates of MACE (Table). There was no significant interaction between AF and randomized treatment on risk of MACE (P interaction=0.78) Conclusions Although treatment with alirocumab did not significantly modify the risk of incident AF after ACS in this analysis, future studies with more sensitive and systematic methods of ascertainment may be warranted. History of AF is a strong predictor of risk of recurrent MACE after ACS. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Regeneron Pharmaceuticals, Inc

Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial.

AimsStatins reduce cardiovascular risk in patients with acute coronary syndrome (ACS) and normal-to-moderately impaired renal function. It is not known whether proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide similar benefit across a range of renal function. We determined whether effects of the PCSK9 inhibitor alirocumab to reduce cardiovascular events and death after ACS are influenced by renal function.Methods and resultsODYSSEY OUTCOMES compared alirocumab with placebo in patients with recent ACS and dyslipidaemia despite intensive statin treatment. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 was exclusionary. In 18 918 patients, baseline eGFR was 82.8 ± 17.6 mL/min/1.73 m2, and low-density lipoprotein cholesterol (LDL-C) was 92 ± 31 mg/dL. At 36 months, alirocumab decreased LDL-C by 48.5% vs. placebo but did not affect eGFR (P = 0.65). Overall, alirocumab reduced risk of the primary outcome (coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization) with fewer deaths. There was no interaction between continuous eGFR and treatment on the primary outcome or death (P = 0.14 and 0.59, respectively). Alirocumab reduced primary outcomes in patients with eGFR ≥90 mL/min/1.73 m2 (n = 7470; hazard ratio 0.784, 95% confidence interval 0.670–0.919; P = 0.003) and 60 to <90 (n = 9326; 0.833, 0.731–0.949; P = 0.006), but not in those with eGFR < 60 (n = 2122; 0.974, 0.805–1.178; P = 0.784). Adverse events other than local injection-site reactions were similar in both groups across all categories of eGFR.ConclusionsIn patients with recent ACS, alirocumab was associated with fewer cardiovascular events and deaths across the range of renal function studied, with larger relative risk reductions in those with eGFR > 60 mL/min/1.73 m2.

Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50-60% and lipoprotein(a) (Lp(a)) by 20-30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab. This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%. Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance. A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance.

Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial.

Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C. This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a). At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events. In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11). After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Sanofi and Regeneron Pharmaceuticals.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial.

Aims The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI.Methods and results Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI.Conclusion After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.

Proprotein convertase subtilisin/kexin type 9 inhibitors for reduction of cardiovascular events.

The efficacy, safety, and place in therapy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid lowering are reviewed. PCSK9 inhibitors are injectable monoclonal antibodies that increase the availability of low-density lipoprotein (LDL) receptors, resulting in a reduction in serum LDL cholesterol (LDL-C). The currently available PCSK9 inhibitors alirocumab and evolocumab were shown to reduce LDL-C concentrations by approximately 55-60% relative to placebo use when used as monotherapy or added to other lipid-lowering therapies. A large randomized controlled trial of evolocumab demonstrated a reduction in cardiovascular events that translated to a 16% relative risk reduction per 1-mmol/L (39-mg/dL) reduction in LDL-C over 2 years, nearly identical to risk reductions reported with use of statins for LDL-C lowering. Another large outcome trial with alirocumab is ongoing. PCSK9 inhibitors are well tolerated, and minor injection-site reaction is the only known adverse effect. Routine use of these agents in all patients with cardiovascular disease is not cost-effective at the current annual cost of therapy of approximately $14,000 in the United States and $7,000 in other Western countries. Careful patient selection may increase the benefit-to-cost ratio of these agents. The PCSK9 inhibitors alirocumab and evolocumab, as adjuncts to oral lipid-lowering agents or as monotherapy, lower serum LDL-C concentrations and reduce the risk of cardiovascular events. These agents are safe and well tolerated, but high cost and lack of cost-effectiveness limit their routine use.

The Role of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors in the Management of Dyslipidemia.

Treatment with statins substantially reduces cardiovascular morbidity and mortality both in patients with and without established cardiovascular disease. Accordingly, statins represent the cornerstone of lipid-lowering treatment. However, there are still unmet clinical needs in the management of dyslipidemia. Indeed, it is difficult to achieve low-density lipoprotein cholesterol (LDL-C) targets in many patients, particularly in those at very high cardiovascular risk or in those with very high baseline LDL-C levels [e.g. with heterozygous familial hypercholesterolemia (FH)]. Moreover, a sizable proportion of patients are not able to tolerate high doses of statins, mostly due to muscle-related adverse effects. In these patient populations, inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) with monoclonal antibodies appears to represent a useful tool for achieving LDL-C targets. In the present review, we summarize the current knowledge on the effects of the PCSK9 inhibitors alirocumab and evolocumab on lipid levels in various populations and discuss the role of these agents in the management of dyslipidemia. In addition to a substantial reduction in LDL-C levels (by 50-60%), PCSK9 inhibitors also lower triglyceride, non-high-density lipoprotein cholesterol (non-HDL-C) and lipoprotein (a) levels and increase HDL-C levels. Preliminary data suggest that PCSK9 inhibitors are safe. However, ongoing randomized, placebo-controlled trials will provide definitive evidence on the safety of these novel agents and on their effects on cardiovascular morbidity and mortality. Given the high cost of PCSK9 inhibitors, their use should be restricted to carefully selected, veryhigh risk patients until the results of these trials are available.

Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed-effects modeling technique. A 2-compartment model with first-order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero-order synthesis rate decreased by the antibodies and a first-order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.

PCSK9-Inhibitoren – Durchbruch bei der LDL-Cholesterin-Senkung?

The proprotein convertase subtilisin / kexin type 9 (PCSK9) plays an important role in LDL cholesterol (LDL-C) metabolism. Subjects harboring loss-of-function mutations in the gene encoding for PCSK9 display markedly reduced LDL-C plasma levels. PCSK9 is secreted by the liver, binds to the LDL receptor and, following endocytosis, induces lysosomal degradation of the receptor together with the bound LDL-C. Current PCSK9 inhibitors are monoclonal antibodies that specifically absorb PCSK9. Subsequently, instead of being degraded the receptor can dissociate from LDL-C and recycle, consecutively resulting in an increased hepatocyte LDL receptor density and higher LDL-C clearance. In clinical trials, the PCSK9 inhibitors alirocumab and evolocumab induced reductions in LDL-C of up to 70 % in statin-treated as well as statin-naïve patients. So far, serious side effects (requiring cessation of drug treatment) occurred only in rare cases. Since this new class of lipid lowering drugs promises a high potential benefit, they have been approved by the EMA even before completion of the studies addressing clinically relevant endpoints like cardiovascular events and mortality. Therefore, the expected publication of these study results in 2017 may allow a better assessment of the efficacy and safety of PCSK9 inhibitors.

A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of cholesterol-lowering medications that provide significant reductions in lipids but at a large cost relative to statins. With 2 such drugs now on the market, alirocumab and evolocumab, comparing the evidence base for these drugs is necessary for informed decision making. To compare the benefits and harms of the PCSK9 inhibitors alirocumab and evolocumab. The databases Ovid MEDLINE, Cochrane Library, SCOPUS, and ClinicalTrials.gov were used to search for randomized controlled trials of alirocumab or evolocumab with any relevant comparator reporting health outcomes, lipid outcomes, or harms through September 2015, and information was requested from manufacturers. Results were reviewed according to standard review methods. The database searches revealed 17 fair- and good-quality trials; however, none had primary health outcomes or directly compared PCSK9 inhibitors. Alirocumab (75 mg to 150 mg subcutaneously every 2 weeks) resulted in significantly greater reductions in low-density lipoprotein cholesterol (LDL-C; -8% to -67%) at 12-24 weeks in patients with (a) heterozygous familial hypercholesterolemia and (b) patients at high or varied cardiovascular (CV) risk who were not at LDL-C goals with statin therapy. The highest strength evidence was for patients with high CV risk not at LDL-C goals. Alirocumab also resulted in high-density lipoprotein cholesterol (HDL-C) increases of 6%-12%. Low- and moderate-strength evidence for adjudicated CV events at 52-78 weeks for a priori analyses indicated no benefit. Low- and moderate-strength evidence also found no differences in harms except possibly slightly more injection-site reactions. Evolocumab (120 mg subcutaneously every 2 weeks to 420 mg every 4 weeks) resulted in significantly greater reductions in LDL-C (-32% to -71%) at 12-52 weeks in patients with heterozygous or homozygous familial hypercholesterolemia, patients intolerant of statins, and patients with varied CV risk not at LDL-C goal with statin therapy. The highest strength evidence was for heterozygous familial hypercholesterolemia and patients not at LDL-C goals. Moderate-strength evidence showed HDL-C increases in the range of 4.5%-6.8%. Harms were not different between groups, except possibly slightly greater overall adverse event reporting. Evidence on adjudicated CV outcomes was insufficient to draw conclusions because of sparseness of events, study limitations, and inability to assess consistency of findings. Alirocumab and evolocumab have evidence of large improvements in lipid levels. The strength of the evidence is greater for alirocumab than evolocumab in patients with high CV risk who were not at LDL-C target goals, while evidence for evolocumab is stronger in patients with heterogeneous familial hypercholesterolemia and patients with varied CV risk who were not at LDL-C target goals. Evidence on adjudicated CV outcomes for a priori analyses is unable to show benefit for alirocumab and is insufficient to draw conclusions for evolocumab. Important questions remain about the comparative effects on long-term health outcomes. This project was funded by The Drug Effectiveness Review Project. Project participants reviewed the manuscript but had no role in conducting the work or writing the manuscript. Any comments received from the participants during the course of the review were taken at the discretion of the authors independently. All authors had access to the data and a role in writing the manuscript. McDonagh, Peterson, and Holzhammer declare no conflict of interest or financial interest in any therapy discussed in this article. Fazio declares receiving compensation from Sanofi for a presentation on his science to a group of their advisors and has served as a consultant to MSD, BASF, NHP, Sanofi, Ionis Pharmaceuticals, and Kowa. Study concept and design were primarily contributed by McDonagh, along with Peterson and Holzhammer, with assistance from Fazio. Holzhammer took the lead in data collection, with assistance from McDonagh and Peterson. Data interpretation was performed by McDonagh, Peterson, and Fazio. The manuscript was written by McDonagh, Peterson, and Fazio, with assistance from Holzhammer, and revised by all the authors.

Familial Hypercholesterolemia: new therapeutic approaches

Familial Hypercholesterolemia (FH) is caused by a mutation in the gene that encodes the low-density lipoprotein (LDL) receptor, resulting in very high levels of circulating LDL-cholesterol and endothelial damage during time. Apoprotein B, activated by LDL receptor, and PCSK9 (proprotein convertase subtilisin / kexin type 9 serine Protease), that impairs the clearance of LDL receptors, are important additional mechanisms that lead to increase LDL-cholesterol. The prevalence of Homozigous form (HoFH) is estimated to be 1 per 1 million individuals and, if untreated, proximal coronary disease or aortic valve disease frequently occurs during childhood and most affected patients suffer from fatal coronary disease before the age of 30. Heterozygous condition (HeFH) occurs in about 1/380-500 individuals. The levels of LDL-cholesterol in this form may greatly vary but the disease is always asymptomatic until adult age when there is a high risk of early cardiovascular disease. Lifestyle intervention and maximal statin therapy are the mainstays of treatment. In patients that not achieve LDL-C targets, primarly HoFH patients, adjunctive lipoprotein apheresis is recommended where available. Biological agents represents to date a new therapeutic approach for this not so rare condition. The PCSK9 pathway is one of the best examples of how genetics has led to identification of a new target for cholesterol management. Different PCSK9 inhibitors (alirocumab, evolocumab) are now available [1]. Mipomersen is an antisense oligonucleotide (ASO) that targets apoliporotein B-100 mRNA and disrupts its function: it is distributed mainly to the liver where it silences apoB mRNA, thereby reducing hepatic apoB-100 and giving rise to reductions in plasma total cholesterol, LDL-cholesterol, and apoB concentrations [2]. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor. MTP resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apo B–containing lipoproteins in enterocytes and hepatocytes. This inhibition leads to a reduction in the synthesis of chylomicrons and very low–density lipoprotein, resulting in a reduction in plasma LDL levels [3].