Role of PCSK9 Inhibitors in High Risk Patients with Dyslipidemia: Focus on Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is characterized by substantially increased Low-Density Lipoprotein Cholesterol (LDL-C) levels. Patients with FH have a significantly higher risk for Cardiovascular (CV) events, and the timely reduction of LDL-C is of paramount importance to ameliorate the risk for CV disease. Among the available lipid-lowering therapies, the novel Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have emerged as a very promising class of drugs for the management of such patients. Objective: The purpose of this review is to present available data on the efficacy and safety of the two available PCSK9 inhibitors in patients with FH, and importantly to discuss potential differences between the two drugs. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the impact of evolocumab or alirocumab on lipid and CV parameters in patients with FH. Results: Several studies have assessed the lipid-lowering profile of PCSK9 inhibitors in patients with FH. Both evolocumab and alirocumab were found to significantly reduce LDL-C by more than 50-60% in FH patients. Furthermore, data also support a lower rate of lipid apheresis in FH patients receiving a PCSK9 inhibitor. In terms of CV outcomes, both drugs were found to possess CV-ameliorating effects of the same extent in patients with CV disease. However, alirocumab reduced all-cause mortality, as well, a finding not observed with evolocumab. Several differences in the study population characteristics might explain this and other mild differences observed in the CV trials of these drugs. Conclusion: Available evidence suggests similar potency of alirocumab and evolocumab in reducing lipids and CV events.

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Real-world use of PCSK9 inhibitors: A single-center experience

Journal of International Medical Research ◽

10.1177/0300060518800595 ◽

2018 ◽

Vol 47 (1) ◽

pp. 265-270 ◽

Cited By ~ 1

Author(s):

Sinan Sarsam ◽

Abeer Berry ◽

George Degheim ◽

Robby Singh ◽

Marcel Zughaib

Keyword(s):

Cardiovascular Disease ◽

Lipid Profile ◽

Real World ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Atherosclerotic Cardiovascular Disease ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

The Impact

Objective Hyperlipidemia is an important risk factor for atherosclerotic cardiovascular disease. Many patients are intolerant to or have limited benefit from statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been approved for treating hyperlipidemia in these patients. We sought to investigate the impact of these medications in a real-world cardiology practice. Methods This was a retrospective study of 17 patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) levels above the treatment target despite maximally tolerated statins. Baseline lipid profile was compared with a repeat lipid profile obtained 4 to 6 weeks after initiating treatment with a PCSK9 inhibitor. Results The average duration of PCSK9 inhibitor treatment was 10.7 months. Lipid profile comparison showed that total cholesterol decreased from 243 ± 72 to 148 ± 39 (mg/dL) (39% reduction), triglycerides decreased from 185 ± 86 to 149 ± 62 (mg/dL) (19.5% reduction), high-density lipoprotein cholesterol increased from 56 ± 20 to 62 ± 26 (mg/dL) (10.7% increase), and LDL-C decreased from 154 ± 30 to 57 ± 32 (mg/dL) (63% reduction) from baseline. Conclusions PCSK9 inhibitors as add-on therapy to maximally tolerated statins resulted in an approximately 63% reduction in LDL-C.

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PCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report

Journal of the Endocrine Society ◽

10.1210/js.2019-00070 ◽

2019 ◽

Vol 3 (8) ◽

pp. 1461-1464 ◽

Cited By ~ 1

Author(s):

Carlo Pirazzi ◽

Federica Tavaglione ◽

Åsa Tivesten ◽

Stefano Romeo

Keyword(s):

Familial Hypercholesterolemia ◽

Low Density Lipoprotein ◽

Genetic Diagnosis ◽

Density Lipoprotein ◽

Statin Treatment ◽

Lipoprotein Cholesterol ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

Lipid Clinic ◽

High Doses

Abstract In female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively. The 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient’s LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.

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The LDLR c.501C>A is a disease-causing variant in familial hypercholesterolemia

Lipids in Health and Disease ◽

10.1186/s12944-021-01536-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Haochang Hu ◽

Ruoyu Chen ◽

Yingchu Hu ◽

Jian Wang ◽

Shaoyi Lin ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Lipid Level ◽

Density Lipoprotein ◽

Hek293 Cells ◽

Lipid Lowering ◽

Therapeutic Effects ◽

Autosomal Dominant Disorder ◽

Pcsk9 Inhibitor ◽

Inhibitor Treatment

Abstract Background As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. Methods The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. Results All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. Conclusions LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

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Use of PCSK9 Inhibitor in a Mexican Boy with Compound Heterozygous Familial Hypercholesterolemia: A Case Report

Journal of the Endocrine Society ◽

10.1210/jendso/bvz018 ◽

2019 ◽

Vol 4 (2) ◽

Cited By ~ 3

Author(s):

José Juan Ceballos-Macías ◽

Ramón Madriz-Prado ◽

Norma Alejandra Vázquez Cárdenas ◽

Carlos Aguilar-Salinas ◽

Maria Teresa Tusié-Luna ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Receptor Gene ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Compound Heterozygous ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

Functional Studies ◽

Dietary Plan

Abstract We report on the case of an 8-year-old Mexican male, with a 3-year-old clinical diagnosis of familial hypercholesterolemia, and the difficulties encountered in his treatment while in our care. His treatment started with a regimen consisting of ezetimibe/simvastatin, cholestyramine, and a dietary plan of 1600 calories, with a limited intake of 200 mg of cholesterol per day. Problems arose when the patient’s low-density lipoprotein cholesterol (LDL) levels did not meet ideal targets, which prompted the use of LDL cholesterol apheresis (not available in Mexico) for 6 months. As a last resort, PCSK9 inhibitors were administered but the LDL levels remained in the 600 mg/dL range. AmbryGenetics conducted a genetic test employing the Sanger method. The results suggested that there were 2 different mutations for each allele of the same LDL receptor gene (c.249delTinsGG and p.(Cys109Arg)), located in exons 3 and 4, respectively. We identified compound heterozygous mutations in our index case, with him having both the p.C109R mutation (from the maternal lineage), as well as a c.249delTinsGG mutation (from the paternal lineage). The p.C109R mutation has been previously reported, not only in Mexico, but in European regions (Germany, Czech Republic, Ireland, Italy) as well. Functional studies indicated a residual enzymatic activity of 15% to 30% for heterozygotes. To date, the variant c.249delTinsGG has not been reported. This case study illustrates the fact that in Mexico there are limited options available for treatment in such a scenario. As medical professionals, we are limited by the tools at our disposal.

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Adoption of PCSK9 Inhibitors Among Patients With Atherosclerotic Disease

Journal of the American Heart Association ◽

10.1161/jaha.120.019331 ◽

2021 ◽

Author(s):

Elias J. Dayoub ◽

Lauren A. Eberly ◽

Ashwin S. Nathan ◽

Sameed Ahmed M. Khatana ◽

Srinath Adusumalli ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Pcsk9 Inhibitors ◽

Pcsk9 Inhibitor ◽

Number Of Patients

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors represent a promising class of lipid‐lowering therapy, although their use has been limited by cost concerns. Methods and Results A retrospective cohort study was conducted using a nationwide commercial claims database comprising patients with atherosclerotic cardiovascular disease (ASCVD), aged 18 to 64 years. We identified the number of patients with ASCVD started on a PCSK9 inhibitor from the dates of US Food and Drug Administration approval in quarter 3 2015 through quarter 2 2019. Secondary objectives identified the proportions of patients started on a PCSK9 inhibitor in various ASCVD risk groups based on statin use and baseline low‐density lipoprotein cholesterol. We identified 126 419 patients with ASCVD on either PCSK9 inhibitor or statin therapy. Among these patients, 1168 (0.9%) filled a prescription for a PCSK9 inhibitor. The number of patients initiating a PCSK9 inhibitor increased from 2 patients in quarter 3 2015 to 119 patients in quarter 2 2019, corresponding to an increase from 0.05% to 2.5% of patients with ASCVD already on statins who started PCSK9 inhibitor therapy. Of patients with ASCVD with high adherence to a high‐intensity statin, 13 643 had low‐density lipoprotein cholesterol ≥70 mg/dL, and in this subgroup, 119 (0.9%) patients initiated a PCSK9 inhibitor. Conclusions Few patients started PCSK9 inhibitors from 2015 through mid‐2019, despite increasing trial evidence of efficacy, guidelines recommending PCSK9 inhibitors in high‐risk patients with ASCVD, and price reductions during this period. The magnitude of price reductions may not yet be sufficient to influence use management strategies aimed to limit PCSK9 inhibitor use.

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Risk of Recurrent Coronary Events in Patients With Familial Hypercholesterolemia; A 10-Years Prospective Study

Frontiers in Pharmacology ◽

10.3389/fphar.2020.560958 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kjell-Erik Arnesen ◽

Ann Vinh Phung ◽

Karoline Randsborg ◽

Irene Mork ◽

Marlene Thorvall ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Statin Treatment ◽

Term Treatment ◽

Lipid Lowering ◽

Treat To Target ◽

Atherosclerotic Cardiovascular Disease ◽

Pcsk9 Inhibitors ◽

Long Term Treatment

Background and Aim: Real world evidence on long term treatment of patients with familial hypercholesterolemia (FH) is important. We studied the effects of intensive lipid lowering medication (LLM) and optimized lifestyle in the study TTTFH–Treat To Target FH.Materials and Methods: Adults with a first known total cholesterol of mean (95% CI) 9.8 mmol/L (9.5, 10.1) were included consecutively in their routine consultation during 2006. Of the patients 86.4% had a pathogenic FH-mutation and the remaining were clinically diagnosed. We included 357 patients and 279 met for follow-up after median 10.0 (min 8.1, max 12.8) years.Results: Mean (95% CI) low density lipoprotein (LDL-C) was reduced from 3.9 (3.8, 4.1) to 3.0 (2.9, 3.2). More men than women used high intensity statin treatment, 85.2 and 60.8%, respectively. Women (n = 129) had higher LDL-C; 3.3 mmol/L (3.0, 3.5), than men; (n = 144) 2.8 mmol/L (2.6, 3.0), p = 0.004. Add-on PCSK9 inhibitors (n = 25) reduced mean LDL-C to 2.0 (1.4, 2.6) mmol/L. At enrollment 57 patients (20.4%) had established atherosclerotic cardiovascular disease (ASCVD), and 46 (80.4%) of them experienced a new event during the study period. Similarly, 222 (79.6%) patients had no detectable ASCVD at enrollment, and 29 of them (13.1%) experienced a first-time event during the study period.Conclusion: A mean LDL-C of 3.0 mmol/L was achievable in FH, treated intensively at a specialized clinic with few users of PCSK9 inhibitors. LDL-C was higher (0.5 mmol/L) in women than in men. In patients with ASCVD at enrollment, most (80.7%) experienced a new ASCVD event in the study period. The FH patients in primary prevention had more moderate CV risk, 13% in ten years.

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Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

Current Atherosclerosis Reports ◽

10.1007/s11883-021-00972-x ◽

2021 ◽

Vol 23 (12) ◽

Author(s):

Angela Pirillo ◽

Alberico L. Catapano ◽

Giuseppe D. Norata

Keyword(s):

Monoclonal Antibodies ◽

High Risk ◽

Familial Hypercholesterolemia ◽

Plasma Levels ◽

Low Density Lipoprotein ◽

Genetic Defect ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Low Density ◽

Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

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The Impact of Changes in Population LDL-C Levels on LDL-C Control in Patients After PCI in China: A Retrospective Cohort Study

10.21203/rs.3.rs-101538/v1 ◽

2020 ◽

Author(s):

Huan Liu ◽

Zhipeng Zhou ◽

Yanqing Wu ◽

Jingsong Xu

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Blood Lipid ◽

Coronary Intervention ◽

Lifestyle Changes ◽

Treatment Goal ◽

Lipid Lowering ◽

Lipid Control ◽

The Impact

Abstract BANKGROUND: Mortality from coronary artery disease continues to rise, and secondary prevention and treatment are particularly important. OBJECTIVE: The objective of this study is to evaluate low-density lipoprotein cholesterol (LDL-C) levels in patients after percutaneous coronary intervention (PCI), to describe how treatment outcomes for individual patients changed over time and to examine the potential impact of lipid control rates through population LDL-C levels changes.METHODS: This retrospective study was conducted in patients who underwent PCI between July 2017 and June 2019. The main results included LDL-C levels after PCI. To assess the outcome of prevention, three separate measures of LDL-C were considered: baseline, first follow-up, and final follow-up, and LDL-C control rates were analyzed according to different guidelines. we examine the impact of 0.1mmol/l decreases or increases in population LDL-C levels on LDL-C control.RESULTS: Data were analyzed for 423 patients (mean age, 62 ±10 years), and the baseline LDL-C level was 3.11 ± 0.99 mmol/l. 51.5% of the patients achieved the Chinese Lipids Guidelines treatment goal, 22% and 11.6% of the patients achieved the 2016 ESC Lipids Guidelines and 2019 ESC Lipids Guidelines treatment goal at the final follow-up period respectively. LDL-C levels fluctuated during the follow-up period, and the long-term maintenance results could not be guaranteed after PCI. Population LDL-C levels changes in lifestyle could have a very large impact on LDL-C control in China.CONCLUSION: LDL-C control with statins is not ideal in patients after PCI, which is far from the requirements of the latest guidelines. Although clinicians understand the lipid-lowering effect of statins, they should not give up active lifestyle changes, and should strengthen the comprehensive management of blood lipid control.

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Abstract 406: Achievement of Treatment Target in Korean Patients With Familial Hypercholesterolemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.406 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Chan Joo Lee ◽

Jaewon Oh ◽

Jung Sun Kim ◽

Sang-Hak Lee

Keyword(s):

Total Cholesterol ◽

Familial Hypercholesterolemia ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Treatment Target ◽

Evaluation Point ◽

The Mean ◽

Artery Disease ◽

Primary Evaluation

Background: In many cases of familial hypercholesterolemia (FH), there remains difficulty in achievement of treatment target. However, despite growing attention to FH, data on the treatment and its results in these patients are very limited. Methods: From nine sites in Korea, 122 consecutive unrelated men and women who were diagnosed with heterozygous FH by Simon Broome criteria were initially enrolled. Atorvastatin 20 mg or similar-potency drugs were prescribed and the dose was escalated every 2 months (for the first 6 months) or 6 months (thereafter) if needed. Forty one subjects were dropped and 81 subjects who underwent regular laboratory check-up were finally analyzed. The primary evaluation points were achievement rates of low-density lipoprotein cholesterol (LDL-C) <70 mg/dL, LDL-C<100 mg/dL, and LDL-C down to 50% of baseline levels at 12 month. The secondary evaluation point was % change of LDL-C at 12 month. Results: Patients’ mean age was 53 years and 59.3% were males. 21.0% were definite type FH and 28.4% had coronary artery disease (CAD). The mean total cholesterol and LDL-C were 319 mg/dL and 232 mg/dL, respectively. At 12 month, 7.4% received atorvastatin 10mg or similar, 21.0% received atorvastatin 20mg or similar, 16.0% received atorvastatin 40mg or similar, 4.9% received atorvastatin 80mg or similar, and 49.4% received atorvastatin (mean 57 mg) or similar plus ezetimibe 10mg. The mean follow-up total cholesterol and LDL-C were 201 mg/dL and 124 mg/dL, respectively. The mean % change of LDL-C was -45.6%. The achievement rates of LDL-C<70 mg/dL, <100 mg/dL, and LDL-C down to 50% of baseline were 1%, 21%, and 44%, respectively. The achievement rates were not significantly different between the patients without or with CAD (1.8%, 26.3%, 47.4% vs. 0%, 8.7%, 34.8%, respectively, all p values > 0.05). Conclusions: The achievement rate of treatment target in FH was low in Korea even after maximum tolerable dose of lipid lowering drugs. Improvement of awareness on this issue and more aggressive treatment are needed for this population.

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Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study

European Heart Journal ◽

10.1093/eurheartj/ehaa034 ◽

2020 ◽

Vol 41 (40) ◽

pp. 3900-3909 ◽

Cited By ~ 8

Author(s):

Ali Allahyari ◽

Tomas Jernberg ◽

Emil Hagström ◽

Margrét Leosdottir ◽

Pia Lundman ◽

...

Keyword(s):

Myocardial Infarction ◽

High Intensity ◽

Low Density Lipoprotein ◽

Monte Carlo Model ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Pcsk9 Inhibitors ◽

Recent Myocardial Infarction ◽

Lowering Therapy

Abstract Aims To estimate the proportion of patients with a recent myocardial infarction (MI) who would be eligible for additional lipid-lowering therapy according to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias, and to simulate the effects of expanded lipid-lowering therapy on attainment of the low-density lipoprotein cholesterol (LDL-C) target as recommended by the guidelines. Methods and results Using the nationwide SWEDEHEART register, we included 25 466 patients who had attended a follow-up visit 6–10 weeks after an MI event, 2013–17. While most patients (86.6%) were receiving high-intensity statins, 82.9% of the patients would be eligible for expanded lipid-lowering therapy, as they had not attained the target of an LDL-C level of <1.4 mmol and a ≥50% LDL-C level reduction. When maximized use of high-intensity statins followed by add-on therapy with ezetimibe was simulated using a Monte Carlo model, the LDL-C target was reached in 19.9% using high-intensity statin monotherapy and in another 28.5% with high-intensity statins and ezetimibe, while 50.7% would still be eligible for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. When use of alirocumab or evolocumab was simulated in those who were eligible for PCSK9 inhibitors, around 90% of all patients attained the LDL-C target. Conclusion Our study suggests that, even with maximized use of high-intensity statins and ezetimibe, around half of patients with MI would be eligible for treatment with PCSK9 inhibitors according to the 2019 ESC/EAS guidelines. Considering the current cost of PCSK9 inhibitors, the financial implications of the new guidelines may be substantial.

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