PCSK9: From discovery to therapeutic applications

SummaryThe proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism mainly by targeting the low-density lipoprotein receptor (LDLR) for degradation in the liver. Gain-of-function mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolaemia. Conversely, loss-of-function mutations are associated with lower concentrations of LDL cholesterol (LDL-C) and reduced coronary heart disease. As these loss-of-function mutations are not associated with apparent deleterious effects, PCSK9 inhibition is an attractive new strategy for lowering LDL-C concentration. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. A dramatic decrease in LDL-C up to 70% can be obtained with the most efficacious doses. Efficacy has been evaluated so far in addition to statins in hypercholesterolaemic patients with or without familial hypercholesterolaemia, in patients with intolerance to statin therapy and in monotherapy. Large phase III programmes are ongoing to evaluate the long-term efficacy and safety of these very promising new agents

Severe familial hypercholesterolaemia: Current and future management

SummaryFamilial hypercholesterolaemia is an inherited disorder, leading to accumulation of low-density lipoprotein (LDL) particles in plasma and premature cardiovascular disease. Although the phenotype of the rare homozygous form is always severe, the phenotypic expression of the common heterozygous familial hypercholesterolaemia can vary considerably. Beyond the magnitude of the LDL-cholesterol elevation and the type of mutation, additional genetic, metabolic and environmental cardiovascular risk factors lead to the substantial variations in the clinical manifestations and severity of atherosclerotic disease. Heterozygous familial hypercholesterolaemia is often under-diagnosed and under-treated, and there is an unmet need in terms of management of severe heterozygous forms. Homozygous and severe heterozygous familial hypercholesterolaemia should receive more intensive treatment and alternative therapeutic approaches are needed for these high-risk patients. In this article, we review the recommendations for diagnosis and treatment of severe familial hypercholesterolaemia and the agents currently available or under development

Low incidence of paradoxical reductions in HDL-C levels in dyslipidemic patients treated with fenofibrate alone or in combination with ezetimibe or ezetimibe/simvastatin

<p>Abstract</p> <p>Background</p> <p>Fibrates have been reported to cause paradoxical decreases in HDL-C in certain patients.</p> <p>Design and methods</p> <p>This post-hoc analysis explored the frequency/magnitude of HDL-C reductions in a pooled database of mixed dyslipidemic patients (LDL-C:3.4-5.7 mmol/L;TG:1.7-5.7 mmol/L) receiving placebo (PBO), fenofibrate (FENO), ezetimibe plus FENO (EZE+FENO), or EZE/simvastatin plus FENO (EZE/SIMVA+FENO) for 12 weeks.</p> <p>Results</p> <p>PBO-treated patients had the highest incidence of HDL-C reductions from baseline (45%) compared with patients taking FENO (14%), EZE+FENO (9%), or EZE/SIMVA+FENO (9%). Reductions <30% reflected natural variability since the largest reduction in HDL-C approached 30% in the PBO group. Only 3 patients exhibited HDL-C reductions ≥30% (i.e., 2 patients in the FENO group and 1 in the EZE+FENO group). There were no differences in demographic/biochemical characteristics between patients with and without HDL-C reductions.</p> <p>Conclusions</p> <p>The incidence of paradoxical HDL-C reductions was low in mixed dyslipidemic patients receiving FENO alone or combined with EZE or EZE/SIMVA.</p> <p>Trial registrations</p> <p>Clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00092560">NCT00092560</a> and <a href="http://www.clinicaltrials.gov/ct2/show/NCT00092573">NCT00092573</a></p

Ezetimibe/Simvastatin 10/20 mg versus Rosuvastatin 10 mg in high-risk hypercholesterolemic patients stratified by prior statin treatment potency

<p>Abstract</p> <p>Objective</p> <p>This <it>post-hoc </it>analysis compared the lipid-altering efficacy of Ezetimibe/Simvastatin 10/20 mg (EZ/Simva) versus Rosuvastatin 10 mg (Rosuva) in patients stratified by statin potency/dose prior to randomization.</p> <p>Methods</p> <p>Patients with elevated low-density lipoprotein cholesterol (LDL-C) despite prior statin treatment (n = 618) were randomized 1:1 to EZ/Simva 10/20 mg or Rosuva 10 mg for 6 weeks. Percent change from baseline in lipids and attainment of lipid targets were assessed within each subgroup (low potency n = 369, high potency n = 249). Consistency of the treatment effect across subgroups was evaluated by testing for treatment-by-subgroup interaction. No multiplicity adjustments were made.</p> <p>Results</p> <p>Significant treatment-by-subgroup interaction occurred for LDL-C (p = 0.013), total cholesterol (p = 0.025), non-HDL-C (p = 0.032), and apolipoprotein B (p = 0.016) with greater between-treatment differences in favor of EZ/Simva observed in patients from the high potency stratum vs low potency stratum. Individual and triple target attainment was higher for Eze/Simva compared with Rosuva in both strata.</p> <p>Conclusions</p> <p>Compared with Rosuva, switching to EZ/Simva provided greater reductions in LDL-C, total cholesterol, non-HDL-C and apolipoprotein B and higher target attainment in patients on prior statin treatment, regardless of potency, although patients treated with higher potency statins prior to randomization experienced greater between treatment differences in favor of EZ/Simva.</p> <p>Trial Registration</p> <p>Registered at ClinicalTrials.gov: NCT00479713</p

Subgroup Evaluation of Ezetimibe/Simvastatin Versus Rosuvastatin

SUMMARY Aims: This post hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) or rosuvastatin 10 mg (ROSUVA) in uncontrolled high-risk hypercholesterolemic patients with/without type 2 diabetes mellitus (T2DM) despite statin monotherapy. Methods: Patients (n = 618) at high risk for coronary vascular disease with elevated LDL-C ≥100 and ≤190 mg/dL despite use of statins were randomized 1:1 to double-blind EZE/SIMVA 10/20 mg or ROSUVA 10 mg for 6 weeks. Patients were classified as having T2DM based on ≥1 of the following: diagnosis of T2DM, antidiabetic medication, or FPG ≥126 mg/dL. This analysis evaluated percent changes from baseline in lipids among patients with (n = 182) and without T2DM (n = 434). Results: EZE/SIMVA was more effective than ROSUVA at lowering LDL-C, TC, non-HDL-C, and apo B in the overall study population and within both subgroups. Numerically, greater between-treatment reductions in LDL-C, TC, non-HDL-C, and apo B were seen in patients with T2DM versus those without T2DM. A significant interaction (P= 0.015) was seen for LDL-C indicating that patients with T2DM achieved larger between-group reductions versus those without T2DM. Conclusions: Switching to EZE/SIMVA 10/20 mg versus ROSUVA 10 mg provided superior lipid reductions in patients with/without T2DM

Safety and Efficacy of Long-Term Co-Administration of Fenofibrate and Ezetimibe in Patients With Mixed Hyperlipidemia

ObjectivesThis study sought to determine the long-term safety and efficacy of co-administered fenofibrate (FENO) and ezetimibe (EZE) in patients with mixed hyperlipidemia.BackgroundBoth EZE and FENO offer complementary benefits to the lipid profile of patients with mixed hyperlipidemia.MethodsAfter completing the 12-week randomized, double-blind base study that compared EZE 10 mg, FENO 160 mg, FENO 160 mg plus EZE 10 mg, and placebo in patients with mixed hyperlipidemia, patients continued into a double-blind, 48-week extension phase. Those patients in the FENO plus EZE and FENO groups continued on their respective base study treatment, and patients in the EZE and placebo groups were switched to FENO plus EZE and FENO, respectively.ResultsOf the 587 patients who completed the base study, 576 continued into the extension study (n = 340 in FENO plus EZE and n = 236 in FENO). The FENO plus EZE produced significantly greater reductions in low-density lipoprotein-cholesterol compared with FENO (−22% vs. −9%, respectively; p < 0.001). There were also significantly greater improvements in triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non–HDL-C, and apolipoprotein B with FENO plus EZE compared with FENO. Changes in apolipoprotein A-I and high-sensitivity C-reactive protein were similar between groups. Overall, FENO plus EZE was well tolerated during the extension study. The proportion of patients with consecutive elevations of alanine aminotransferase/aspartate aminotransferase ≥3 times upper limit of normal were similar between the FENO plus EZE (1.2%) and FENO (1.7%) groups. No cases of creatine phosphokinase elevations ≥10 times upper limit of normal or myopathy were observed in either group.ConclusionsLong-term, 48-week co-administration of FENO plus EZE was well tolerated and more efficacious than FENO in patients with mixed hyperlipidemia

Efficacy of Ezetimibe/Simvastatin 10/20 mg Versus Rosuvastatin 10 mg in High-Risk Patients With or Without Obesity

Introduction: This post-hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) or rosuvastatin 10 mg (ROSUVA) in high-risk hypercholesterolemic patients with/without obesity. Methods: Patients (n=618) at high-risk for coronary heart disease with elevated low-density lipoprotein cholesterol (LDL-C) ≥2.59 and ≤4.92 mmol/L, while on a statin, entered a 6-week open-label stabilization/screening period during which they continued on the same statin. Patients were then randomized 1:1 to double-blind EZE/SIMVA 10/20 mg or ROSUVA 10 mg for 6 weeks. Patients were classified as non-obese (n=437) or obese (n=180) based on body mass index 0.050 for all). Conclusions: In this post-hoc analysis of high-risk patients with elevated LDL-C, despite prior use of statin therapy, switching to EZE/SIMVA 10/20 mg versus ROSUVA 10 mg provided superior reductions in LDL-C, TC, and non-HDL-C in obese and non-obese patients