Familial hypercholesterolemia.

Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.

Managing dyslipidaemia in patients with chronic kidney disease.

Patients with CKD are at increased risk for cardiovascular events. Clinical studies suggest statins reduce all-cause mortality and cardiovascular events in patients with CKD. Lipid lowering therapy with statin with or without ezetemibe is recommended for most of the patients in patients with eGFR <60 mL/min and also in those who have an increased urinary albumin-to-creatinine ratio (≥3 mg/mmol) for at least 3 months. Evidence suggests that it should not be started for hemodialysis patients without evidence of ASCVD. Patients who were already taking statins or statin/ezetimibe combination at the time of dialysis should consider continuing these medications, especially if they have ASCVD. Fibrates should not be used in conjunction with statins in patients with CKD, and ezetimibe monotherapy is also not recommended. The role of PCSK9 inhibitors is evolving suggests that it is effective in lowering LDL cholesterol without affecting the renal outcomes.

Evinacumab-dgnb (Evkeeza-REGN1500), A Novel Lipid-Lowering Therapy for Homozygous Familial Hypercholesterolemia.

Chronically elevated low-density lipoprotein (LDL) has harmful effects on the vasculature including increased vasoconstriction and the formation of plaques which may rupture, causing coronary heart disease and stroke. In patients with familial hypercholesterolemia, adequate reduction of LDL is especially challenging. Although HMG-CoA reductase inhibitors (statins) are the mainstays for LDL lowering, other treatments such as proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, incliseran, lomitapide, and apheresis have been employed in an effort to achieve adequate LDL reduction in these patients. Despite these available therapies, many patients with familial hypercholesterolemia do not meet the LDL targets suggested in current guidelines. Evinacumab is a novel lipid-lowering therapy that exerts its LDL-lowering effect through inhibition of angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 inhibits the breakdown of triglyceride-rich lipoproteins, such as very low-density lipoprotein and chylomicrons. By inhibiting ANGPTL3, evinacumab allows these lipoproteins to be degraded, ultimately leading to reductions in LDL, high-density lipoprotein, and triglycerides. Clinical trials have demonstrated evinacumab to be safe and effective in reducing LDL. However, data are lacking regarding its potential to reduce risk of atherosclerotic cardiovascular disease. Evinacumab is generally well tolerated with the primary adverse effects comprising infusion reactions, nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. While evinacumab is an interesting therapy, until it is proven to reduce cardiovascular events, its high cost leaves its anticipated role in therapy somewhat ambiguous. In the meantime, it may be a useful therapy for those with homozygous familial hypercholesterolemia.

PCSK9 inhibitor use during pregnancy in a case of familial hypercholesterolemia complicated with coronary artery disease.

Limited data have been reported on the use of proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors during pregnancy in women with familial hypercholesterolemia (FH). Here, we present the first case of initiating evolocumab (PCSK9 inhibitor) in a compound heterozygous FH mother. The patient was a 34-year-old primipara with severe dyslipidemia and a history of coronary artery bypass surgery. An elevated low-density lipoprotein cholesterol (LDL-C) level of 420 mg/dL was detected in the first trimester and persistently increased throughout pregnancy. Evolocumab was administered at 31 and 35 weeks of gestation, showing a positive effect on stabilizing LDL-C levels. Planned delivery with labor analgesia was performed at 38 + 4 weeks. Both the mother and infant were discharged without any notable complications. Hence, evolocumab, an IgG2 monochromatic antibody with little placental permeability, may be an alternative medication with limited influence on infants. Further studies are needed to assess the safety of evolocumab administration during pregnancy.

PCSK9 ablation attenuates Aß pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice.

BACKGROUND: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aß pathology, neuroinflammation, and brain lipids. METHODS: For in vitro studies, U373 human astrocytoma cells were treated with Aß fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aß plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. RESULTS: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aß fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aß burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. CONCLUSIONS: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aß pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.

Effect of statins combined with PCSK9 inhibitors on the prognosis of patients with acute coronary syndromes after interventional therapy.

Acute coronary syndromes (ACS) are a leading cause of morbidity and mortality worldwide. It has been clinically confirmed percutaneous coronary intervention (PCI) can alleviate the symptoms of ACS, but there are still some patients with slow blood flow or no-reflow after surgery, which has adverse effects on the prognosis of patients. This study aimed to investigate the effect of statins combined with PCSK9 inhibitors on the prognosis of patients with ACS after interventional therapy. A total of 208 ACS patients treated in our hospital from January 2021 to December 2022 were separated into observation and control groups. Patients in the control group received oral rosuvastatin 20 mg/ day. Patients in the observation group received PCSK9 inhibitor elozumab (Repatha) 140 mg, subcutaneously injected twice a week. The levels of inflammatory factors, cardiac function indexes, clinical effectiveness rate, adverse events, and complications were compared before and after treatment. After 1 week of treatment and 4 weeks of follow-up, the levels of inflammatory indicators in the observation group declined relative to the control group (P < 0.05 and P < 0.01). After 4 weeks, LVEF in the observation group was elevated in comparison to the control group, while LVEDD in the observation group declined compared to the control group (P < 0.05). The incidence of adverse events after treatment in the observation group declined relative to the control group (P < 0.05). The incidence of complications in the observation group declined in contrast to the control group (P < 0.05). Statins combined with PCSK9 inhibitors significantly reduce LDL-C levels in ACS patients undergoing PCI without increasing cardiovascular events or major adverse clinical effects.

Familial hypercholesterolemia and its manifestations: Practical considerations for general practitioners.

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, affecting almost 1 in 250 individuals worldwide. It is usually inherited via the autosomal dominant way and is characterized by aberrantly high total and low-density lipoprotein cholesterol (LDL-C) concentrations from early childhood, predisposing to increased risk of premature atherosclerotic cardiovascular disease (ASCVD), mostly coronary heart disease (CHD). Despite its high prevalence in the general population and the high ASCVD risk, FH is often underdiagnosed and undertreated. Genetic diagnosis is not always necessary since specific criteria, taking into account the patient's individual and family history, clinical signs, and untreated LDL-C concentrations, may be used for prompt diagnosis. Except for CHD, which may be already evident at diagnosis, leading to increased mortality, other non-CHD morbidities, such as stroke, peripheral artery disease, carotid artery stenosis, and aortic valve calcification may be also present, substantiating the need for prompt intervention. Statins constitute the mainstay of treatment both in adults and children >8 years old. In cases of statin intolerance or not achieving the LDL-C target despite maximally tolerated statin dose, ezetimibe and/or proprotein convertase subtilisin-kexin type 9 inhibitors may be used. The advent of recently approved medications, such as inclisiran and bempedoic acid, either as monotherapy or as add-on therapy to statins, has further enhanced the therapeutic armamentarium that can be used in FH patients. The purpose of this narrative review is to provide practical considerations regarding the diagnostic and therapeutic approach to FH patients.

Case Series of Genetically Confirmed Index Cases of Familial Hypercholesterolemia in Primary Care.

BACKGROUND In Malaysia, the prevalence of genetically confirmed heterozygous familial hypercholesterolemia (FH) was reported as 1 in 427. Despite this, FH remains largely underdiagnosed and undertreated in primary care. CASE REPORT In this case series, we report 3 FH cases detected in primary care due to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein-B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. The mutations in case 1 (frameshift c.660del pathogenic variant in LDLR gene) and case 2 (missense c.10579C>T pathogenic variant in APOB gene) were confirmed as pathogenic, while the mutation in case 3 (missense c.277C>T mutation in PCSK9 gene) may have been benign. In case 1, the patient had the highest LDL-c level, 8.6 mmol/L, and prominent tendon xanthomas. In case 2, the patient had an LDL-c level of 5.7 mmol/L and premature corneal arcus. In case 3, the patient had an LDL-c level of 5.4 mmol/L but had neither of the classical physical findings. Genetic counseling and diagnosis were delivered by primary care physicians. These index cases were initially managed in primary care with statins and therapeutic lifestyle modifications. They were referred to the lipid specialists for up-titration of lipid lowering medications. First-degree relatives were identified and referred for cascade testing. CONCLUSIONS This case series highlights different phenotypical expressions in patients with 3 different FH genetic mutations. Primary care physicians should play a pivotal role in the detection of FH index cases, genetic testing, management, and cascade screening of family members, in partnership with lipid specialists.

A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.

Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not cause abnormal lipid accumulation, and share a chemical structure that is distinct from any known cholesterol lowering drug.

Management and clinical outcomes of patients with homozygous familial hypercholesteremia in Saudi Arabia.

We report the incidence, patient characteristic with clinical outcomes in patients with homozygous familial hypercholesterolemia (HoFH) in Saudi Arabia. This is a retrospective and prospective, single center study which included 37 patients 14 years and older enrolled and followed up between 2018-2021 for three years. 46% were females, 78% were offspring of consanguineous marriage. LDLR mutation was in 78% and LDL-C/LDLRAP in 3% of patients. Mean LDL-C at the first presentation was 14.2±3.7 mmol/L, average Dutch lipid score was 20.9±6.24. LDL apheresis was performed on 70% of patients. Most patients were on ezetimibe (92%), high-dose statins ( 84%) and  PCSK9 inhibitors (32%). 48.6% had aortic stenosis, out of which 30% had severe aortic stenosis. Ten underwent aortic valve surgery (5 mechanical valve, 3 Ross procedure, 1 aortic valve repair, 1 bioprosthetic valve) and one had transcatheter aortic valve implantation (TAVI). Coronary artery bypass surgery (CABG) was performed on 32% and percutaneous intervention (PCI) on 11% of patients. HoFH patients have complex diseases with high morbidity and mortality, and benefit from a highly specialized multidisciplinary clinic to address their clinical needs. Although there are several therapeutic agents on the horizon, early diagnosis, and treatment of HoFH remain critical to optimize patient outcomes.

Qualitative and Quantitative Effects of PCSK9 Inhibitors in familial Hypercholesterolemia: a Synthetic Review.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused most commonly by mutations in the gene coding for LDL receptors. This results in increased circulating cholesterol, and clinical consequences of premature stroke, myocardial infarction, etc. FH remains underdiagnosed and thus undertreated, leading to a high health care burden. A newer group of agents, the PCSK9 inhibitors, effectively reduces plasma cholesterol, especially when combined with other lipid lowering agents. The purpose of this narrative review is to synthesize all existing qualitative and quantitative data on the utility of PCSK9 inhibitors in familial hypercholesterolemia, in order to clarify standards of care and identify areas needing further research. Through PubMed/MEDLINE keyword searching, we identified 12 existing randomized controlled trials comparing PCSK9 inhibitor to placebo in FH patients, and pooled their outcomes across a total 2533 patients. We also reviewed quantitative effect on ASCVD outcomes and cost/benefit ratios. In FH patients, PCSK9 inhibitors caused a mean LDL reduction of -49.1%, compared to -3.5% with placebo (weighted average was calculated to account for different study sizes). These findings are comparable to trial results in the non-FH ASCVD population. However, there are no data on PCSK9 inhibitors' effect on hard cardiovascular outcomes in FH. Furthermore, in order for PCSK9 inhibitors to qualify as high-value care, price must be significantly reduced or LDL goals increased. PCSK9 inhibitors are potent reducers of LDL in FH patients. However, dedicated randomized trials are needed to assess whether this translates into statistically significant ASCVD prevention long-term.

Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

BACKGROUND: VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. METHODS: Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). RESULTS: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. CONCLUSIONS: VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials.

BACKGROUND: Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) -61.3 - -47.2; p<0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI -57.9 - -47.8; p<0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.

Proprotein convertase subtilisin/kexin type 9 inhibition after acute coronary syndrome or prior myocardial infarction.

PURPOSE OF REVIEW: Lowering low-density lipoprotein cholesterol (LDL-C) with statins or ezetimibe reduces major adverse cardiovascular events (MACE) in patients with coronary heart disease. Additional treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may lower LDL-C to levels not achievable with conventional lipid-lowering agents. This review summarizes findings from two large, placebo-controlled trials that evaluated the cardiovascular efficacy of monoclonal antibodies directed against PCSK9, added to background statin therapy, in patients with established atherosclerotic cardiovascular disease (ASCVD) or recent acute coronary syndrome (ACS) and persistent elevation of atherogenic lipoproteins despite statin treatment. RECENT FINDINGS: The FOURIER trial with evolocumab and the ODYSSEY OUTCOMES trial with alirocumab demonstrated 15% overall reductions in MACE compared to placebo, associated with average achieved LDL-C levels as low as 30-40 mg/dl. Alirocumab treatment was associated with fewer deaths after ACS. Subgroups with large absolute treatment benefit included those with baseline LDL-C ≥100 mg/dl, diabetes, polyvascular or peripheral artery disease, prior coronary bypass surgery, statin intolerance, or elevated lipoprotein(a) levels. No safety concerns arose with use of PCSK9 monoclonal antibodies, even in patients who achieved LDL-C levels below 20 mg/dl. SUMMARY: In selected patients with established ASCVD or recent ACS, PCSK9 inhibitors can play an important role in reducing the risk of MACE, and may also reduce the risk of death after ACS.

Cellular and Molecular Aspects of Managing Familial Hypercholesterolemia: Recent and Emerging Therapeutic Approaches.

Familial hypercholesterolemia (FH) as a high-frequency genetic disorder is diagnosed based on family and/or patient's history of coronary heart disease (CHD) or some other atherosclerotic diseases, LDL-C levels, and/or clinical signs such as tendinous xanthoma, arcus cornealis before age 45 years as well as a functional mutation in the LDLR, apoB or PCSK9 gene. Its clinical features are detectable since early childhood. Early diagnosis and timely treatment increase life expectancy in most patients with FH. Current FH therapies decrease the level of lowdensity lipoprotein up to ≥50% from baseline with diet, pharmacotherapeutic treatment, lipid apheresis, and liver transplantation. The cornerstone of medical therapy is the use of more potent statins in higher doses, to which often ezetimibe has to be added, but some FH patients do not achieve the target LDL-C with this therapy Therefore, besides these and the most recent but already established therapeutic approaches including PCSK9 inhibitors, inclisiran, and bempedoic acid, new therapies are on the horizon such as gene therapy, CRISPR/Cas9 strategy, etc. This paper focuses on cellular and molecular potential strategies for the treatment of FH.

Latest clinical evidence about the effect of PCSK9 monoclonal antibodies in patients with familial hypercholesterolaemia: an updated meta-analysis.

INTRODUCTION: Familial hypercholesterolaemia (FH) is the most common autosomal genetic disease of cholesterol metabolism disorder. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody (mAb) is a new target lipid-regulating drug related to cholesterol metabolism that has been developed in recent years. The reported rate of reduction varies widely, and comprehensive assessments of efficacy and safety are lacking. Therefore, we conducted this study to investigate the clinical effect of PCSK9 mAbs in patients with familial hypercholesterolaemia to provide a theoretical reference for clinical practice. MATERIAL AND METHODS: We analysed the clinical data of patients, including the percentage change in LDL-C and the incidence rates of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), from selected articles. Weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated to compare the endpoints. RESULTS: The results showed that, compared with placebo, the PCSK9 mAb reduced the percentage change in LDL-C in FH patients (WMD = -45.52, 95% CI: -49.70 to -41.34, I2 = 99.6%). In addition, there was no significant difference between the experimental and placebo groups in the incidence of TEAEs (RR = 1.03, 95% CI: 0.97 to 1.10, I2 = 19.1%) and SAEs (RR = 1.02, 95% CI: 0.72 to 1.44, I2 = 0.0%). CONCLUSIONS: Overall, PSCK9 mAbs are an effective and safe method of LDL-C reduction in patients with FH.

Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate-citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug-drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients With Diabetes.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia. METHODS: Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones. FINDINGS: Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis. IMPLICATIONS: PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. METHODS AND RESULTS: We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. CONCLUSIONS: After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

BACKGROUND: The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. METHODS: Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. FINDINGS: Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3-58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5-56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32-6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20-5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). INTERPRETATION: Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. FUNDING: Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.