Case Report: Difficulties in the Treatment of a 12-Year-Old Patient With Homozygous Familial Hypercholesterolemia, Compound Heterozygous Form − 5 Years Follow-Up

The literature review we conducted reveals the limited use of proprotein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) in children with familial hypercholesterolemia (FH). In 2015, a 10-year-old boy presented with round, xanthochromic lesions on his right knee and elbow. The values of total and LDL-cholesterol (LDL-C)−18 and 15 mmol/l, respectively—along with normal triglycerides and HDL-cholesterol (HDL-C) confirmed the lesions were xanthomas. The data suggested a homozygous form of FH. The level of lipoprotein (a) was high: 270 mg/dl. Initial treatment, based on European recommendations, included Atorvastatin 20 mg and Ezetimibe 10 mg and led to a decrease in LDL-C by 46% for 5 months; however, the patient developed severe statin intolerance. Atorvastatin was replaced with Rosuvastatin 10 mg, but the symptoms persisted. Success was achieved by switching to an intermittent regimen: Rosuvastatin 10 mg three times a week with a daily intake of Ezetimibe 10 mg. However, the results were far from the desired LDL target. LDL-apheresis was advisable, but unfortunately, it is not performed in Bulgaria. In May 2017, a genetic analysis [two pathological mutations within the LDLR gene: c.1519A>G; p.(Lys507Glu) and c.2403_2406del; p.(Leu802Alafs*126)] confirmed the initial diagnosis: the patient had homozygous FH with compound heterozygosity indeed. Having turned 12 in September 2017, the patient was eligible for treatment with a PCSK9i: Evolocumab 140 mg. The mean reduction of LDL-C with the triple combination reached a reduction of 52.17% for the whole 2-year period. The LDL target was reached in January 2020. The triple therapy significantly reduced Apolipoprotein B by 29.16%. No statistically significant difference was found in Lp (a) levels (p > 0.05) Our clinical case demonstrates that the triple lipid-lowering combination in a patient with compound heterozygous FH is a good therapeutic option for reaching the LDL-target.

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Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

European Heart Journal ◽

10.1093/ehjci/ehaa946.3009 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R.S Wright ◽

D Kallend ◽

F.J Raal ◽

R Stoekenbroek ◽

W Koenig ◽

...

Keyword(s):

Statin Therapy ◽

Therapeutic Option ◽

Lipid Lowering ◽

Funding Source ◽

Lipid Lowering Therapy ◽

Statin Intolerance ◽

Private Company ◽

Phase 3 ◽

Absolute Reduction ◽

Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p<0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

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Abstract 18995: Statins in Familial Hypercholesterolemia - Effects on Coronary Artery Disease and All-cause Mortality

Circulation ◽

10.1161/circ.132.suppl_3.18995 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Joost Besseling ◽

Gerard K Hovingh ◽

John J Kastelein ◽

Barbara A Hutten

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Lipid Lowering ◽

Premature Coronary Artery Disease ◽

Lipid Lowering Therapy ◽

Time Varying ◽

All Cause Mortality ◽

Artery Disease

Introduction: Heterozygous familial hypercholesterolemia (heFH) is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary artery disease (CAD) and death. Reduction of CAD and mortality by statins has not been properly quantified in heFH. The aim of the current study is to determine the effect of statins on CAD and mortality in heFH. Methods: All adult heFH patients identified by the Dutch FH screening program between 1994 and 2014 and registered in the PHARMO Database Network were eligible. Of these patients we obtained hospital, pharmacy (in- and outpatient), and mortality records in the period between 1995 and 2015. The effect of statins (time-varying) on CAD and all-cause mortality was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, antihypertensive and antidiabetic medication (all time-varying). Furthermore, we used inverse probability for treatment weighting (IPTW) to account for differences between statin-treated and untreated patients regarding history of CAD before follow-up, age at start of follow-up and age of screening, as well as body mass index, LDL-C and triglycerides. Results: Of the 25,479 identified heFH patients, 11,021 gave informed consent to obtain their medical records, of whom 2,447 could be retrieved. We excluded 766 patients younger than 18. The remaining 1,681 heFH patients comprised our study population and these had very similar characteristics as compared to the 23,798 excluded FH patients, e.g. mean (SD) LDL-C levels were 214 (74) vs. 203 (77) mg/dL. Among 1,151 statin users, there were 133 CAD events and 15 deaths during 10,115 statin treated person-years, compared to 17 CAD events and 9 deaths during 4,965 person-years in 530 never statin users (combined rate: 14.6 vs. 5.2, respectively, p<0.001). After applying IPTW to account for indication bias and correcting for use of other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.61 (0.40 - 0.93). Conclusions: In heFH patients, statins lower the risk for CAD and mortality by 39%.

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Abstract P183: Lipid Control in Veterans Following Percutaneous Intervention

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.4.suppl_2.ap183 ◽

2011 ◽

Vol 4 (suppl_2) ◽

Author(s):

Sloane A McGraw ◽

Chris Healy ◽

Burhan Mohamedali ◽

Anupama Shivaraju ◽

Adhir Shroff

Keyword(s):

Total Cholesterol ◽

Therapeutic Option ◽

Coronary Intervention ◽

Lipid Lowering ◽

Lipid Management ◽

Beneficial Effects ◽

The Mean ◽

Lipid Control ◽

Statin Use

Background: Management of lipids is vital in patients with underlying coronary artery disease (CAD). According to the American College of Cardiology (ACC) guidelines, all patients with CAD should have low density lipoproteins (LDL) goals to be less than 100 mg/dl with the therapeutic option of treatment to less than 70 mg/dl. This can be achieved using multiple lipid lowering agents, however statin use is encouraged in CAD patients due to its multiple beneficial effects. Methods: We conducted a retrospective cohort study focusing on lipid management and statin use in 857 veterans undergoing percutaneous coronary intervention (PCI) between September 2004 and December 2009 at the Jesse Brown Veterans Hospital in Chicago, IL. Values were collected both pre-intervention as well as at six month follow up. Results: Both pre and post PCI, focus was maintained on the total cholesterol as well as the LDL levels. The mean total cholesterol prior to intervention was 166mg/dl and decreased to150mg/dl at six month follow up. The LDL mean pre-PCI was 98mg/dl and at six months the mean LDL decreased to 86mg/dl. With regards to ACC guidelines, the percent at goal for LDL less than 100mg/dl increased from 59% pre-PCI to 74% post-PCI Furthermore, treatment to less than 70mg/dl increased from 22 to 32% at six months. Lastly, the use of statins increased from 72 to 89%. Conclusions: There were in improvements in both total cholesterol and LDL values at six months post-PCI. There were also improvements in the percentage of patients who met the ACC recommended goal of LDL cholesterol less than 100mg/dl and the suggested goal of 70mg/dl. At six months, there was also an increase in usage of statin therapy.

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Complex lipid-lowering treatment options in patients with a history of acute coronary syndrome

Orvosi Hetilap ◽

10.1556/oh.2011.29036 ◽

2011 ◽

Vol 152 (8) ◽

pp. 296-302 ◽

Cited By ~ 1

Author(s):

Győző Dani ◽

László Márk ◽

András Katona

Keyword(s):

Acute Coronary Syndrome ◽

Serum Lipid ◽

Ldl Cholesterol ◽

Hdl Cholesterol ◽

Lipid Lowering ◽

Coronary Syndrome ◽

Target Values ◽

History Of ◽

Lipid Parameters

Authors aimed to assess how target values in serum lipid concentrations (LDL- and HDL-cholesterol, triglyceride) can be achieved in patients with a history of acute coronary syndrome during follow up in an outpatient cardiology clinic. Methods: 201 patients with a history of acute coronary syndrome were included and were followed up between January 1 and May 31, 2007.Authors analyzed serum lipid parameters of the patients and the lipid-lowering medications at the time of the first meeting and during follow up lasting two years. Results: During the enrollment visit only 26.4% of the patients had serum LDL cholesterol at target level, whereas high triglycerides and low HDL cholesterol levels were observed in 40.3% and 33.3% of the patients, respectively. Only 22 patients (10.9%) achieved the target levels in all three lipid parameters. Of the 201 patients, 179 patients participated in the follow up, and data obtained from these patients were analyzed. There was a positive trend toward better lipid parameters; 42.5% of the patients reached the desired LDL-cholesterol target value and 17.3% of the patients had HDL-cholesterol and triglycerides target values. Conclusions: These findings are consistent with those published in the literature. Beside the currently used therapeutic options for achieving optimal LDL-cholesterol, efforts should be made to reduce the so-called “residual cardiovascular risk” with the use of a widespread application of combination therapy. Orv. Hetil., 2011, 152, 296–302.

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Association Between Dietary Intake and Lipid-lowering Therapy: Prospective Analysis Using a Quantile Regression Approach (OR22-03-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz028.or22-03-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Adelle Gadowski ◽

Natalie Nanayakkara ◽

Stephane Heritier ◽

Dianna Magliano ◽

Jonathan Shaw ◽

...

Keyword(s):

Dietary Intake ◽

Quantile Regression ◽

Daily Intake ◽

Lipid Lowering ◽

Current Evidence ◽

Lipid Lowering Therapy ◽

Food Groups ◽

Dietary Behaviours ◽

Lowering Therapy

Abstract Objectives Lipid-lowering therapy (LLT) is ideally accompanied by dietary guidance for cardiovascular risk reduction, however current evidence suggests sub optimal dietary behaviours in those on pharmacological interventions. This study examines associations between daily intake of major food groups (vegetable, fruit, cereal, protein and dairy) and LLT use in Australian adults. Methods Data were analysed from 5895 participants of the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) aged ≥ 25 years. Medical history and dietary intake was obtained at baseline (1999–00) and follow up (2004–05). LLT use was categorised as: LLT users, commenced LLT, ceased LLT, and non-users. The association between dietary intake and LLT use was examined using quantile regression, at the 25th, 50th and 75th quantile of dietary intake. Analysis was adjusted for known risk factors. Results A total of 446 participants remained on LLT from baseline to follow up; 565 participants commenced LLT; 71 participants ceased LLT and 4813 were non-users. Less than 1% of the cohort met recommended intakes of all food groups at baseline and follow up, with no difference by LLT status. Median daily dietary intake at follow up among LLT users was 2.2 serves of vegetables, 1.4 serves of fruit, 2.8 serves of cereal, 2.0 serves of protein and 1.4 serves of dairy. Dietary intake was similar across all LLT groups. LLT use was not significantly associated with dietary intake at the 25th, 50th and 75th quantile. Conclusions Adjusted quantile regression analysis showed no differences in median daily intake of key food groups in LLT users, compared to non-users. The dietary behaviours observed suggest that all adults, regardless of their medication regimen, need additional education on improving their dietary intake. These findings emphasise the importance of addressing adherence to dietary guidelines, for people with chronic disease, with special focus on people requiring LLT. Funding Sources Nil Supporting Tables, Images and/or Graphs

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Lp (a) >50 mg/dl predicts atherosclerotic cardiovascular events in patients with heterozygous familial hypercholesterolemia who achieved LDL-C <2.6 mmol/l

European Heart Journal ◽

10.1093/ehjci/ehaa946.2991 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Funabashi ◽

Y Kataoka ◽

M Hori ◽

M Ogura ◽

K Matsuki ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Coronary Revascularization ◽

Statistical Significance ◽

Lipid Lowering ◽

Current Guideline ◽

Potential Therapeutic Target ◽

Heterozygous Familial Hypercholesterolemia ◽

Significant Difference ◽

History Of ◽

Atherosclerotic Cardiovascular Diseases

Abstract Introduction Lipoprotein (a) [Lp (a)] is a plasma lipoprotein which exhibits atherogenic properties. Lp(a) ≥50 mg/dl has been recently shown to associate with a risk of atherosclerotic cardiovascular diseases (ASCVD) in patients with heterozygous familial hypercholesterolemia (HeFH). While current guideline recommends lowering LDL-C as a first-line therapeutic approach in HeFH subjects, it remains to be fully determined whether an elevated level of Lp(a) confers additional ASCVD risks in HeFH patients who achieved a lower LDL-C level. Purpose To investigate cardiovascular outcomes in HeFH subjects with a lower LDL-C but an elevated Lp(a) levels. Methods 182 HeFH patients with on-treatment LDL-C <2.6 mmol/l under lipid-lowering therapies were analyzed. Clinical characteristics and MACE (= a composite of all-cause death, ACS, stroke, PAD and coronary revascularization) were compared in HeFH subjects with Lp(a) ≥ vs. <50 mg/dl. Results The averaged LDL-C and Lp (a) levels were 1.9 mmol/l and 26.8 mg/dl, respectively. 19.2% of study subjects exhibited Lp(a)≥50 mg/dl. HeFH patients with Lp(a) ≥50 mg/dl were more likely to be older and have a history of hypertension, but these comparisons did not meet statistical significance. There was no significant difference in on-treatment LDL-C, HDL-C and Triglyceride level (Table). However, during the observational period (median=4.7 years), there was a 2.7-fold (95% CI, 1.41–5.02; p=0.004) greater likelihood of experiencing MACE in subjects with Lp(a) ≥50 mg/dl (picture). Even after adjusting clinical demographics, Lp(a) ≥50 mg/dl remained an independent predictor for the occurrence of MACE (hazard ratio=2.53, 95% CI: 1.29–4.82, p<0.001). Conclusions Despite achieving on-treatment LDL-C <2.6 mmol/l, an elevated risk of MACE was observed in HeFH patients with Lp(a) ≥50 mg/dl. Our findings suggest an increased level of Lp(a) as a risk stratification marker and a potential therapeutic target in patients with HeFH. Clinical outcome Funding Acknowledgement Type of funding source: None

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Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01999-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Laura D’Erasmo ◽

Antonio Gallo ◽

Angelo Baldassare Cefalù ◽

Alessia Di Costanzo ◽

Samir Saheb ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Treatment Algorithm ◽

Lipid Lowering ◽

Homozygous Familial Hypercholesterolemia ◽

Lipoprotein Apheresis ◽

Term Efficacy ◽

Threatening Condition ◽

Life Threatening

Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Italy (n = 30) and the other with LA in France (n = 29). Results The two cohorts differed significantly for genotype (p = 0.004), baseline lipid profile (p < 0.001), age of treatment initiation (p < 0.001), occurrence of cardiovascular disease (p = 0.003) as well as follow-up duration (p < 0.001). The adjunct of lomitapide to conventional lipid-lowering therapies determined an additional 58.0% reduction of last visit LDL-C levels, compared to 37.1% when LA was added (padj = 0.004). Yearly on-treatment LDL-C < 70 mg/dl and < 55 mg/dl goals were only achieved in 45.5% and 13.5% of HoFH patients treated with lomitapide. The long-term exposure to LDL-C burden was found to be higher in LA than in Lomitapide cohort (13,236.1 ± 5492.1 vs. 11,656.6 ± 4730.9 mg/dL-year respectively, padj = 0.002). A trend towards fewer total cardiovascular events was observed in the Lomitapide than in the LA cohort. Conclusions In comparison with LA, lomitapide appears to provide a better control of LDL-C in HoFH. Further studies are needed to confirm this data and establish whether this translates into a reduction of cardiovascular risk.

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Comparison between the Efficacy of Intense Pulsed Light (IPL) versus Photodynamic Therapy with Methylene Blue in the Treatment of Nail Psoriasis

QJM ◽

10.1093/qjmed/hcab093.012 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Maha Adel Shaheen ◽

Samah Ibrahim Hassen ◽

Azzahra Omar Dakhli

Keyword(s):

Methylene Blue ◽

Photodynamic Therapy ◽

Therapeutic Option ◽

Group Versus ◽

Treatment Session ◽

Intense Pulsed Light ◽

Pulsed Light ◽

Nail Psoriasis ◽

Significant Difference

Abstract Background Nail psoriasis is often refractory to traditional treatments, and patients with nail psoriasis usually demand a therapeutic option. Both photodynamic therapy (PDT) and intense pulsed light have been evaluated in nail psoriasis. Objective The objective of this study was to evaluate and compare the efficacy of IPL and methylene blue assisted photodynamic therapy in the treatment of nail psoriasis. Patients and Methods Twenty patients (15 males and 5 females) with mild to moderate psoriasis with nail affection were included in this study. Their age ranged from 24 to 71 years. The PDT used IPL as the light source and methylene blue as photosensitizer. Sessions were applied every 2 weeks for a maximum of 3 months, treating one hand with IPL and the other with PDT. The nails treated were evaluated at baseline, after 2 sessions, after 6 sessions and 3 months after the last treatment session according to the Nail Psoriasis Severity Index (NAPSI) score. Follow-up was performed after 2 sessions, after 6 sessions, and 3 months after the last treatment session. Results A decrease in NAPSI score was observed with both treatments and in both nail bed and nail matrix involvement. No statistically significant difference was found between PDT and IPL as regarding total NPASI score. However, total NAPSI score improved by 61% in MB-PDT group versus 47% in IPL group. Patient follow-up revealed the appearance of new lesions in 3 patients in the group of IPL, and in 1 patient in the MB-PDT after 6 months. Conclusion Intense pulsed light and methylene blue assisted PDT are a promising effective modalities of treatment of nail psoriasis, which are easy to use, safe, and nearly pain-free. This was confirmed by the improvement NAPSI score.

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Abstract P270: Associations of Lipoprotein-associated Phospholipase A 2 Mass and Activity with Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis (MESA)

Circulation ◽

10.1161/circ.127.suppl_12.ap270 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Nancy S Jenny ◽

Robyn McClelland ◽

Neal Jorgensen ◽

Parveen Garg ◽

Gregory Burke ◽

...

Keyword(s):

Coronary Artery ◽

Coronary Artery Calcium ◽

Cardiac Computed Tomography ◽

Prevalence Ratio ◽

Hdl Cholesterol ◽

Phospholipase A ◽

Lipid Lowering ◽

Agatston Score ◽

Ethnic Study

Background: Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is an inflammatory enzyme localized in atherosclerotic lesions. However, associations of Lp-PLA 2 with coronary artery calcium (CAC), used as a marker of lesion progression, have not been extensively studied and may vary by sex and type of Lp-PLA 2 assay. Methods: We examined these associations in 5486 White, Black, Chinese and Hispanic men and women in the Multi-Ethnic Study of Atherosclerosis (MESA). At baseline, mean age was 62 years; all were free of clinical cardiovascular disease. CAC, by cardiac computed tomography, was assessed at baseline (2000-02) and follow-up; half the cohort at exam 2 (2002-04), the remainder at exam 3 (2004-05). 2758 had CAC (Agatston score>0) at baseline; of those with no baseline CAC, 372 (13.6%) had incident CAC (CAC>0) at follow-up. Lp-PLA 2 mass and activity were measured by immunoassay and enzymatic assay, respectively. Longitudinal models were adjusted for age, sex, ethnicity, smoking, diabetes, obesity, total and HDL cholesterol, blood pressure, hypertension, lipid-lowering medications and time between CAC measures. Results: Each standard deviation (SD 36.5 nmol/min/ml) increase in Lp-PLA 2 activity was associated with CAC presence (prevalence ratio 1.03; p=0.01) in the whole group at baseline and incidence in those with no CAC at baseline (odds ratio 1.17; p=0.02). Activity was not associated with CAC progression (increase in Agatston score over time) in the whole group (β=1.32; p>0.4). Lp-PLA 2 mass was not associated with CAC presence or incidence (SD 45.6 ng/ml; associations p>0.2). The only association that differed significantly by sex was that for mass and progression (p interaction 0.01). Mass was associated with CAC progression in women (β=4.99; p=0.004) but not men (β=-0.20; p>0.9). Conclusions: In this multi-ethnic cohort, associations of Lp-PLA 2 with CAC varied by sex and Lp-PLA 2 assay type. Lp-PLA 2 activity was associated with CAC presence and incidence, but not progression. Mass was associated with CAC progression in women only. Additional research is needed to support the clinical utility of Lp-PLA 2 in monitoring atherosclerosis progression.

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