Abstract Familial hypercholesterolemia (FH) is the most common genetic disorder causing premature cardiovascular disease and death. Heterozygous FH conservatively affects approximately 1:500 ...Canadians, and the more serious homozygous form affects approximately 1:1,000,000 Canadians, although these numbers might be underestimated. Of approximately 83,500 Canadians estimated to have FH, most are undiagnosed, which represents a simultaneous public health deficit and opportunity, because early treatment of heterozygous FH can normalize life expectancy. Diagnostic algorithms for FH incorporate increased plasma low-density lipoprotein cholesterol, pathognomonic clinical features, and family history of early cardiovascular disease and hyperlipidemia. DNA-based detection of causative mutations in FH-related genes can help with diagnosis. Maximizing diagnosis and treatment of FH in Canada will involve a multipronged approach, including: (1) increasing awareness of FH among health care providers and patients; (2) creating a national registry for FH individuals; (3) setting standards for screening, including cascade screening in affected families; (4) ensuring availability of standard-of-care therapies, in particular optimization of plasma low-density lipoprotein cholesterol levels and timely access to future validated therapies; (5) promoting patient-based support and advocacy groups; and (6) forming alliances with international colleagues, resources, and initiatives that focus on FH. This document aims to raise awareness of FH nationally, and to mobilize knowledge translation, patient support, and availability of treatment and health care resources for this underrecognized, but important medical condition.
Elevated lipoprotein(a) Lp(a) is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to ...proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Objective Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Guidelines recommend initiating statins early to reduce low-density ...lipoprotein cholesterol (LDL-C). Studies have evaluated rosuvastatin in children aged ≥10 years, but its efficacy and safety in younger children is unknown. Methods Children with HeFH and fasting LDL-C >4.92 mmol/L (190 mg/dL) or >4.10 mmol/L (>158 mg/dL) with other cardiovascular risk factors received rosuvastatin 5 mg daily. Based on LDL-C targets (<2.85 mmol/L <110 mg/dL), rosuvastatin could be uptitrated to 10 mg (aged 6–9 years) or 20 mg (aged 10–17 years). Treatment lasted 2 years. Changes in lipid values, growth, sexual maturation, and adverse events (AEs) were assessed. Results The intention-to-treat analysis included 197 patients. At 24 months, LDL-C was reduced by 43, 45, and 35% vs baseline in patients aged 6–9, 10–13, and 14–17 years, respectively ( P < .001 for all groups). Most AEs were mild. Intermittent myalgia was reported in 11 (6%) patients and did not lead to discontinuation of rosuvastatin treatment. Serious AEs were reported by 9 (5%) patients, all considered unrelated to treatment by the investigators. No clinically important changes in hepatic biochemistry were reported. Rosuvastatin treatment did not appear to adversely affect height, weight, or sexual maturation. Conclusions In HeFH patients aged 6–17 years, rosuvastatin 5–20 mg over 2 years significantly reduced LDL-C compared with baseline. Treatment was well tolerated, with no adverse effects on growth or sexual maturation.
Background Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein ...cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)–containing high-density lipoprotein–mimetic particle, on carotid artery wall dimensions in patients with HoFH. Methods and results Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR , APOB , PCSK9 , or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm2 ( P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). Conclusions In HoFH, 12 biweekly infusions with an apoA-I–containing high-density lipoprotein–mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein–lowering therapy. This finding supports further clinical evaluation of apoA-I–containing particles in patients with HoFH.
Lipoprotein(a) Lp(a) is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase ...subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (−30.3% vs −0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.
Background Statin therapy is recommended for children with familial hypercholesterolemia (FH), but most children do not reach treatment targets. Objective Here we present the design and results at ...baseline of the ongoing CHARON study, to evaluate the safety and efficacy of rosuvastatin. Methods This study comprises an international 2-year open label, titration-to-goal study in 198 children with heterozygous FH aged 6 to 18 years, with rosuvastatin in a maximum dose of 10 mg (<10 years of age) or 20 mg (older children). In addition, 64 unaffected siblings were enrolled as controls. The primary efficacy outcome is the change from baseline in low-density lipoprotein cholesterol, and the secondary outcome is the change in carotid intima-media thickness (c-IMT) in patients with FH compared with their siblings. The primary safety outcomes are growth and sexual maturation; secondary outcomes are the change in other lipoprotein levels and the incidence of adverse events, discontinuation rates, and abnormal laboratory values. Results At baseline, mean age of patients with FH was 12.1 ± 3.3 years, 44% were boys, and mean low-density lipoprotein cholesterol levels were 6.1 ± 1.3 mmol/L (235.9 ± 48.7 mg/dL). Mean c-IMT was 0.399 mm (95% CI, 0.392–0.406 mm) in children with FH versus 0.377 (95% CI, 0.366–0.388 mm) in unaffected siblings ( P = .001). Conclusions At baseline, as expected according to on previous observations, children with FH proved to have a greater c-IMT than their healthy siblings. These differences had already occurred at a very young age, which emphasizes the importance of considering early statin initiation in this high-risk population.
Abstract Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers ...prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This “omic” approach recently resulted in new targets for reducing CVD events.
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