Familial hypercholesterolaemia (FH) is an autosomal-dominant disorder associated with high low-density lipoprotein cholesterol (LDL-C). Left untreated, 50% of men with FH will develop coronary heart ...disease by the age of 50 and 30% of women by the age 60 1,2. It is estimated that the prevalence may be as high as one in 250 people, with most undiagnosed.
This article explores the development of advocacy in FH patient organisations, citing examples from Canada, the Netherlands, Spain, the US and the UK as well as the pan-European patient organisation, FH Europe. The article demonstrates that for patient advocacy, the link with medical and scientific expertise is essential to ensure that advocacy for familial hypercholesterolaemia is well-founded and credible and that patient associations are prepared to take a long-term view on achieving improvements in identification and treatment.
•Familial hypercholesterolaemia (FH) is mostly an unidentified disease that does not discriminate.•More awareness is required to increase the number of FH patients identified.•Patient empowerment and the patient voice is paramount in raising awareness and getting system change to identify and optimally treat all FH cases.•Patient organisations and healthcare professionals work together to find all FH patients worldwide, the earlier the better.•Networking by and between FH patient organisations is important to share information and learning.
Familial hypercholesterolemia (FH) is a relatively common genetic disorder associated with elevated atherosclerotic risk. Dietary interventions can modulate processes associated with cardiovascular ...risk and potentiate the impact of pharmacological lipid-lowering therapies. This review evaluates recent findings of dietary patterns and their components on risk biomarkers in people with FH.
Diets lower in saturated fatty acids (SFA) may reduce low-density lipoprotein-cholesterol (LDL-C); however, their effects seem to be modest. A Mediterranean style diet apparently exerts more robust effects on plasma LDL-C, apolipoprotein B and C reactive protein concentrations than one restricted in SFA. Supplementation of plant sterols and stanols reduces LDL-C especially in children with FH. Caloric restricted diets may reduce weight and improve triglyceride levels in individuals with FH and excess body weight.
Despite the strong impact of genetic variants, dietary patterns mostly low in SFA and especially the Mediterranean diet may influence risk biomarkers in FH. However, most available studies are limited by cross-sectional design, small number of study subjects and short-term follow-ups. Robust interventional studies are necessary to test the impact of dietary patterns in people with FH.
We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial ...hypercholesterolemia (HoFH).
SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined.
Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02).
HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.
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•The SAFEHEART shows the high genetic and phenotypic variability in HoFH.•New lipid-lowering therapies on top of statins have significantly improved LDL-C reduction in long-term follow-up.•An increased survival free of cardiovascular events was observed in the long-term follow-up.•Patients carrying defective pathogenic variants show a better prognosis.
Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been ...poorly studied in FH.
This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP).
In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135–250) and 161 (133–193) mg/dL; 141 (109–181) and 103 (88–134) mg/dL; and 1.6 (0.8–4.0) and 0.8 (0.4–1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies.
Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.
•The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH.•Dyslipidemia and inflammation were higher in Brazilian FH patients.•Spanish FH patients had greater adherence to a Mediterranean diet.•Adherence to a Mediterranean diet was associated with less dyslipidemia and inflammation.•Diet may influence cardiovascular risk in FH.
Abstract
Aims
Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density ...lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting.
Methods and results
Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL interquartile range (IQR), 123–177, 3.8 mmol/L (IQR 3.2–4.6). After a median follow up of 3.7 years (IQR 2.3–4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43–88), 1.6 mmol/L (IQR 1.1–2.23); 61 mg/dL (IQR 44–82), 1.6 mmol/L (IQR 1.1–2.1); 57.6% (IQR 39.5–69); and 58% (IQR 44–68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable.
Conclusion
Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting.
Trial registration
ClinicalTrials.gov number NCT02693548.
Graphical Abstract
Graphical Abstract
Persistence with long-term PCSK9 inhibitors treatment and its effectiveness in familial hypercholesterolaemia.
Healthy lifestyle habits are the cornerstone in the management of familial hypercholesterolaemia (FH). Nevertheless, dietary studies on FH-affected populations are scarce. The present study analyses ...dietary habits, adherence to a Mediterranean diet pattern and physical activity in an adult population with FH and compares them with their non-affected relatives.
Cross-sectional study.
Data came from SAFEHEART, a nationwide study in Spain.ParticipantsIndividuals (n 3714) aged ≥18 years with a genetic diagnosis of FH (n2736) and their non-affected relatives (n 978). Food consumption was evaluated using a validated FFQ.
Total energy intake was lower in FH patients v. non-affected relatives (P<0·005). Percentage of energy from fats was also lower in the FH population (35 % in men, 36 % in women) v. those non-affected (38 % in both sexes, P<0·005), due to the lower consumption of saturated fats (12·1 % in FH patients, 13·2 % in non-affected, P<0·005). Consumption of sugars was lower in FH patients v. non-affected relatives (P<0·05). Consumption of vegetables, fish and skimmed milk was higher in the FH population (P<0·005). Patients with FH showed greater adherence to a Mediterranean diet pattern v. non-affected relatives (P<0·005). Active smoking was lower and moderate physical activity was higher in people with FH, especially women (P<0·005).
Adult patients with FH report healthier lifestyles than their non-affected family members. They eat a healthier diet, perform more physical activity and smoke less. However, this patient group's consumption of saturated fats and sugars still exceeds guidelines.
The association of components of a low saturated fat (SFA) and of a Mediterranean diet was tested with atherosclerosis biomarkers in 190 familial hypercholesterolemia adults (FH) from Brazil (BR) and ...Spain (SP). Median blood LDL-C, Apolipoprotein B (apoB), and C reactive protein (hs-CRP) concentrations were higher in BR than in SP: 179.0 vs.161 mg/dL; 141 vs. 103 mg/dL; and 1.6 vs. 0.8 mg/L respectively (all p < 0.001). In BR there was lower median total fat (22.3 vs. 38.3%) and SFA (8.1 vs. 12.5%) but higher cholesterol (283.3 mg vs.188.9 mg) and carbohydrate (57.1 vs. 42.5%) consumption (all p < 0.001). Inverse associations were encountered between fibers, mono, and polyunsaturated fats and their ratios to SFA with LDL-C and ApoB (all p < 0.001). There was a direct association respectively of cholesterol with lipid biomarkers and of carbohydrates and trans-fatty acids with hs-CRP while other fats showed inverse relations with the latter (p < 0.001).
•PCSK9 inhibitors reduce LDL-C by 58% in heterozygous familial hypercholesterolemia.•Response was significantly higher when maximally tolerated statin therapy is used.•Most patients reach an LDL ...cholesterol goal according guidelines.•PCSK9 inhibitors are highly effective in FH patients in clinical practice setting.
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PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose.
To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting.
SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020.
433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6–3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125–173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41–70) p<0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44–87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated.
PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.
Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH.
The objectives of the study were ...to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk.
SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs.
A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5–10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67–3.39) and 1.22 (0.54–2.93) at enrollment for ATV and RV, respectively (P < .001). There were no significant differences at the follow-up: 1.29 (0.54–2.82) and 1.22 (0.54–2.76) in the ATV and RV groups, respectively (P = .51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P = .58).
ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated.
•This study analyzes event rates of 2 high-potency statins in FH.•LDL-C goal attainment and risk were similar in both groups.•LDL-C reduction was greater with rosuvastatin. Events were similar in both groups.•Event rate was 1.1/100 patient-years with atorvastatin and 1.2 with rosuvastatin.
El estudio SAFEHEART se diseñó para analizar la situación y mejorar el conocimiento de la hipercolesterolemia familiar heterocigota (HFH) en España. Nuestro objetivo es determinar la tasa de ...incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento y su modificación, el empleo de tratamiento hipolipemiante y la consecución de objetivos de colesterol unido a lipoproteínas de baja densidad en pacientes con HFH.
El SAFEHEART es un estudio prospectivo de cohorte, abierto, multicéntrico, de escala nacional, con seguimiento protocolizado a largo plazo en una población de HFH caracterizada molecularmente. Se analizó a los pacientes mayores de 18 años con seguimiento completo.
El análisis en este estudio se hizo con 2.648 pacientes con HFH. La mediana de seguimiento fue de 6,6 (4,8-9,7) años. La tasa de incidencia general de eventos cardiovasculares fue de 1,3 eventos/100 pacientes-año. El riesgo estimado de sufrir un evento cardiovascular a 10 años se redujo en el seguimiento, y pasó del 1,6 al 1,3% (p <0,001). En el último seguimiento, el 20,6 y el 22,2% de los pacientes en prevención primaria y secundaria consiguieron un colesterol unido a lipoproteínas de baja densidad <100 y <70 mg/dl respectivamente.
En este estudio se muestra la tasa de incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento cardiovascular en la mayor población de pacientes con HF en España, así como su modificación, la consecución de objetivos en colesterol unido a lipoproteínas de baja densidad y su tratamiento. Aunque el riesgo cardiovascular de la HFH es elevado, un adecuado tratamiento reduce la probabilidad de sufrir un evento.
Estudio registrado en ClinicalTrials.gov (Identificador: NCT02693548).
The SAFEHEART study was designed to analyze the situation of familial heterozygous hypercholesterolemia (FHH) and improve knowledge of this disease in Spain. Our objective was to determine the incidence rate of cardiovascular events, the estimated risk of developing an event and its modification, the use of lipid-lowering treatment, and the achievement of low-density lipoprotein cholesterol targets in patients with FHH.
SAFEHEART is a prospective, open, multicenter, nationwide cohort study, with long-term protocol-based follow-up in a population of individuals with molecularly-characterized FHH. We analyzed patients older than 18 years with complete follow-up.
We included 2648 patients with FHH. The median follow-up was 6.6 (4.8-9.7) years. The overall incidence rate of cardiovascular events was 1.3 events/100 patient-years. After the follow-up, the 10-year estimated risk of developing a cardiovascular event was reduced from 1.6% to 1.3% (P <.001). In the last follow-up, 20.6% and 22.2% of the patients in primary and secondary prevention achieved low-density lipoprotein cholesterol values <100mg/dL and <70mg/dL, respectively.
This study was performed in the largest population of patients with FHH in Spain. We identified the incidence rate of cardiovascular events, the estimated risk of developing a cardiovascular event and its modification, the achievement of low-density lipoprotein cholesterol targets, and the therapeutic management in this population. Although the cardiovascular risk of FHH is high, appropriate treatment reduces the likelihood of an event.
Clinical trial registration: http://www.clinicaltrials.gov. Identifier: NCT02693548.
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