Effectiveness and safety of PCSK9 inhibitor therapy in patients with familial hypercholesterolemia within a therapeutic program in Poland: Preliminary multicenter data.

BACKGROUND: In Poland, treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has become available free of charge in a therapeutic program. Assessed herein, is the efficacy and safety of alirocumab and evolocumab in patients with heterozygous familial hypercholesterolemia (FH). METHODS: Data of 55 adult FH patients who participated in the program were analyzed upon meeting the criteria established by the Ministry of Health (low density lipoprotein cholesterol [LDL-C] above 160 mg/dL on max. tolerated statin dose and ezetimib). The efficacy of PCSK9 inhibitors in reducing LDL-C with drug administration every 2 weeks was assessed after 3 months and 1 year of therapy. A safety profile evaluation was performed at each visit. 48 patients completed the 3-month and 21 for the 1-year observation periods (34 patients treated with alirokumab and 14 with evolocumab). RESULTS: The mean concentration of direct-measured LDL-C decreased from the initial level of 215.1 ± 74.5 mg/dL to 75.3 ± 64.1 mg/dL, i.e., by 65 ± 14% following 3 months of treatment. This effect was stable in 1-year observation (77.7 ± 72.8 mg/dL). Adverse effects were flu-like symptoms (13.0%), injection site reactions (11.1%), fatigue (5.6%) and musculoskeletal symptoms (5.6%). Seven patients failed to complete the 3-month treatment period due to side effects or non-compliance, and 1 patient failed to complete the 1-year treatment due to myalgia. CONCLUSIONS: This study confirmed high effectiveness of PCSK9 inhibitors in reducing LDL-C levels in patients with FH. Due to restrictive inclusion criteria with LDL-C threshold level > 160 mg/dL (> 4.1 mmol/L) required for participation in the therapeutic program, a relatively small number of FH patients were eligible for treatment.

Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic lipid disorder leading to accelerated atherosclerosis, premature cardiovascular disease and death. Microvascular endothelial dysfunction is one of the earliest vascular pathology manifestations and may precede symptomatic atherosclerosis. METHODS: In this paper, microvascular endothelial function was assessed in FH patients and healthy controls using flow mediated skin fluorescence (FMSF), based on measurements of nicotinamide adenine dinucleotide fluorescence intensity during brachial artery occlusion (ischemic response, IR) and immediately after occlusion (hyperemic response, HR). Low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were used to assess its relation with microvascular parameters evaluated in vivo. RESULTS: LDL-C levels were significantly correlated to both HRmax (r = -0.548, p = 0.001) and HRindex (r = -0.514, p = 0.003). Similarly, there was a significant inverse correlation of TC levels and both HRmax (r = -0.538, p = 0.002) and HRindex (r = -0.512, p = 0.003). All FMSF parameters were found lower in FH patients compared to age- and sex-matched healthy controls. Hyperemic response (HRmax) was significantly higher in FH patients examined on statins compared to those without any lipid-lowering treatment (19.9 ± 3.1 vs. 16.4 ± 4.2 respectively, p = 0.022). CONCLUSIONS: This study shows that, in patients with FH, microvascular endothelial-dependent hyperemic response is impaired and inversely correlated to plasma cholesterol levels. Microvascular function was found better in FH patients receiving statins.

Cardiovascular risk factor profiles in familial hypercholesterolemia patients with and without genetic mutation compared to a nationally representative sample of adults in a high-risk European country.

BACKGROUND: There is a paucity of data on the distribution of cardiovascular risk factors in patients with familial hypercholesterolemia (FH) as compared to the general population. The aim of the study was to compare cardiovascular risk factors in a cohort of FH patients to the representative sample of adults in Poland who represent a high-cardiovascular risk European region. METHODS: We compared the distribution of risk factors in 1,382 individuals with FH phenotype referred for genetic testing between 2006 and 2014 to the National Centre of Familial Hypercholesterolemia in Gdansk, Poland. The cohort was comprised of 637 positive FH(+) and 745 negative FH(-) patients who were compared to a nationally representative sample of 2,413 adults age 18-79, standardized by age and sex, from the NATPOL 2011 study (NATPOL). We analyzed patients' distribution of history of atherosclerotic cardiovascular disease (ASCVD) and standard risk factors including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure (SBP, DBP), body mass index, smoking, and diabetes. RESULTS: FH(+) patients (mean age 45.6 years) had the highest LDL-C of 241.7 mg/dL (95% CI 234.8-248.5) compared to 206.1 mg/dL (200.5-211.7) in FH(-) patients (mean age 48.2) and 126.2 mg/dL (124.8-127.6) in NATPOL. Mean SBP was the lowest in FH(+) patients at 128.7 mm Hg (126.7-130.7) compared to 133.4 mm Hg (132.6-134.3) in NATPOL and 134.4 mm Hg (132.3-136.5) in FH(-). No differences were found in the prevalence of diabetes and body mass index. Smoking was less common in FH(+) at 12.4% (9.4-15.4) compared to both FH(-) and NATPOL: 20.4% (16.6-24.1) and 28.4% (26.6-30.2), respectively. The prevalence of individuals with a history of ASCVD in both FH(+) and FH(-) was nearly 3-fold higher compared to NATPOL: 26% (21.8-30.1) and 26.6% (22.2-30.9) versus 9.5% (8.3-10.7), respectively. CONCLUSIONS: The FH(+) patients had significantly higher mean LDL-C, but the levels of nonlipid factors were lower or similar compared to the other groups. Both FH(+) and FH(-) were characterized by a heavy burden of ASCVD. This suggests that cholesterol, and no other risk factors, is a key contributor to cardiovascular risk in patients with FH, especially those with genetic mutation.

Efficacy of clinical diagnostic criteria for familial hypercholesterolemia genetic testing in Poland.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH), which leads to premature cardiovascular events, still remains underrecognized and undertreated in most countries. Untreated FH individuals aged 20-39 years are at 100-fold higher risk of mortality from coronary heart disease compared to those of a general population. Therefore, special efforts should be implemented to diagnose FH patients at early stages of life. The aim of this study was to evaluate the efficacy of the revised Dutch Lipid Clinic Network (DLCN) criteria proposed by the Polish Lipid Experts Forum to select index FH patients for DNA mutational analysis in Poland. METHODS: The study included 193 unrelated adult patients (mean age 48 ± 13 years) with clinical diagnosis of FH based on the revised DLCN score, tested sequentially for mutations in LDLR and APOB genes using bidirectional Sanger sequencing and MLPA techniques. The cut-off points of the clinical FH criteria score were assessed by ROC statistics to identify patients with the highest probability of carrying an FH-causing mutation. RESULTS: The causal heterozygous LDLR or APOB mutation was identified in 41% (80/193) of probands. Adults aged <40 years were more likely to carry an FH-causing mutation compared to subjects aged ≥40 years (65% vs. 33%; p < 0.001). LDL-C thresholds for the molecular diagnosis of FH were 5.79 mmol/l for individuals aged<40 and 6.7 mmol/l for subjects ≥40 years old. The threshold values of the clinical diagnostic score for efficient selection of patients for genetic testing were 5 and 7 points for individuals aged <40 and ≥40 years, respectively. CONCLUSIONS: The study validated the efficacy of proposed clinical FH criteria for the disease diagnosis in Poland. The clinical criteria score thresholds for positive FH molecular diagnosis differ depending on age (<40 and ≥40 years). We propose that in the healthcare systems with limited genetic testing resources individuals younger than 40 years, who fulfill the clinical criteria for possible, probable or definite FH should qualify for the FH mutation testing. The index patients aged ≥40 years with clinical diagnosis of probable or definite FH should also qualify for the genetic testing.