PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of 46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available

Patterns and predictors of statin prescription in patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>The benefit of statins for prevention of cardiovascular events in type 2 diabetes is established, but a gap exists between guideline recommendations and clinical practice. The aim of the study was to identify patient-related factors predicting statin prescription.</p> <p>Methods</p> <p>We assessed the quality of care in 51,640 patients with type 2 diabetes in a German diabetes registry. Patients were stratified according to primary and secondary prevention. Five-year risk for cardiovascular events was calculated in primary prevention patients. A multivariate adjusted logistic regression model was constructed to determine which parameters influenced statin prescription.</p> <p>Results</p> <p>34% had established atherosclerotic disease and 25.5% received a statin. Prescription was significantly higher in the secondary compared to the primary prevention group (38.1% [95% CI 37.4–38.9%] vs. 18.5% [95% CI 18.0–19.0%], respectively). In primary prevention the odds for statin prescription increased with estimated cardiovascular risk (OR 1.17 per 5% increase in 5-year risk, 95% CI 1.11–1.22). Positive predictors for statin prescription were secondary prevention, hypertension, former smoking, baseline LDL-cholesterol, and microalbuminuria. The odds of receiving a statin had an inverted U-shaped relation with age (nadir, 66 years), age at first diagnosis of diabetes (nadir, 56 years), and body mass index (nadir, 32 kg/m²). The model predicted prescription in 70% of the patients correctly.</p> <p>Conclusion</p> <p>The majority of patients with type 2 diabetes are not receiving statins. The predominant factors determining statin prescription are the patient's prevention status and, in primary prevention, estimated cardiovascular risk. The results suggest that although physicians are aware of the general concept of cardiovascular risk, they fail to consistently implement guidelines.</p

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial

Aims The predominance of small dense low-density lipoproteins (sdLDLs) has been associated with increased cardiovascular risk. The effect of ezetimibe on LDL subfraction distribution has not been fully elucidated. This study assessed by gradient gel electrophoresis the effects of ezetimibe alone, simvastatin alone, and their combination on sdLDL subfraction distribution. Methods and results A single-centre, randomized, parallel three-group open-label study was performed in 72 healthy men with a baseline LDL-cholesterol (LDL-C) concentration of 111 ± 30 mg/dL (2.9 ± 0.8 mmol/L). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24), or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. Generalized estimating equations were used to assess the influence of drug therapy on LDL subfraction distribution, controlling for within-subject patterns (clustering). We adjusted for age, body mass index, and baseline concentrations of LDL-C and triglycerides. Ezetimibe alone changed LDL subfraction distribution towards a more atherogenic profile by significantly increasing sdLDL subfractions (LDL-IVA +14.2%, P = 0.0216 and LDL-IVB +16.7%, P = 0.039; fully adjusted Wald χ2 test). In contrast, simvastatin alone significantly decreased the LDL-IVB subfraction (−16.7%, P = 0.002). This effect was offset when simvastatin was combined with ezetimibe (LDL-IVB +14.3%, P = 0.44). All three treatments decreased the large, more buoyant LDL-I subfraction, the effects of ezetimibe being the most pronounced (ezetimibe -13.9%, P < 0.0001; combination therapy −7.3%, P = 0.0743; simvastatin −4.6%, P < 0.0001). Conclusion In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT0031799

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Context and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993

Association between the Interleukin-6 Promoter Polymorphism −174G/C and Serum Lipoprotein(a) Concentrations in Humans

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism 2174G/C is associated with baseline serum Lp(a) concentrations. Methodology/Principal Findings: We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations $60 mg/dl (n = 510), and the ones with Lp(a),60 mg/ dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95 % CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95 % CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations. Conclusions/Significance: The IL-6 single nucleotide polymorphism 2174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to b

Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial

Importance: Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P &lt; .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P &lt; .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety

L’influence des relations familiales et sociales sur la consommation de médicaments psychotropes chez les personnes âgées

Les psychotropes occupent le deuxième rang dans la consommation de médicaments chez les personnes âgées. L'objectif de cette étude est de vérifier un modèle explicatif de la consommation de psychotropes dans cette population. Notre principale hypothèse est que la qualité des relations qu'entretient une personne âgée avec autrui, et particulièrement avec ses enfants, a une influence directe sur son bien-être psychologique, lequel a une influence directe sur la non-consommation de psychotropes. Une enquête a été réalisée auprès d'un échantillon de 500 personnes âgées de 65 à 84 ans, vivant à domicile. Au cours des trois mois précédant l'entrevue, 31,8 % des répondants ont consommé des psychotropes. Les données empiriques n'ayant pas permis de vérifier le modèle théorique retenu, des analyses multivariées ont conduit à l'élaboration d'un modèle explicatif de la consommation qui met en évidence que le bien-être psychologique et la santé sont les meilleurs prédicteurs de cette consommation. Un bien-être psychologique élevé diminue la consommation alors qu'un mauvais état de santé l'augmente. Les relations sociales influencent directement le bien-être psychologique alors que les relations familiales ont un effet de moindre importance. Le modèle explicatif proposé explique 13 % du phénomène de la consommation de psychotropes chez les personnes âgées.Psychotropic drugs are the second most commonly used medication by Quebec's elderly. The objective of this study is to test a theoretical model of psychotropic drug use in the elderly. The principal hypothesis is that the quality of relationships the elderly person has with others, particularly with his or her children, has a direct influence on his or her psychological well-being, which, in turn, directly affects the consumption of psychotropic agents. A survey was conducted on a sample of 500 elderly people, aged 65-84 years, living at home. 31.8% of the respondents used psychotropic drugs during the three-month period preceding the interview. Path analysis led to the elaboration of a modified model for the consumption of psychotropic drugs by the elderly which indicates that the best predictors of consumption are both the psychological well-being and the state of health of the individual. More elevated is the psychological well-being, less is the consumption of psychotropic drugs, whereas poor health condition increases it. The quality of an individual's social relationships has a direct influence on his or her psychological well-being, whereas family relationships are of lesser importance. Our model accounts for 13% of the predictors of psychotropic consumption by the elderly

Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS)

Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagn

Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.[Purpose] Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated.[Methods] DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated.[Results] Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81–115) mg/dl and 32% (25–43%), respectively. Median LDL-C reductions of 24 (12–46) and 39 (27–91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7–25%) and 22% (15–32%), respectively, and ARRs of 4% (2–7%) and 6% (4–9%), respectively.[Conclusion] In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach.This study was funded by Amgen Europe (GmbH).Peer reviewe

Significant Quality of Life Improvement Observed in a Patient With FCS Associated With a Marked Reduction in Triglycerides

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severely high triglycerides (TGs). It is associated with a marked increase in risk of recurrent, potentially fatal acute pancreatitis (AP), and symptoms including abdominal pain, fatigue, and anxiety that may substantially reduce quality of life (QoL). A 46-year-old woman with FCS and severely high TGs initially presented with necrotizing pancreatitis with pseudocysts, having previously experienced recurrent AP. The patient reported constant abdominal pain and fatigue, which were evident in her demeanor. Initial management included maximum doses of omega-3 fatty acids and fibrates, plus an extremely restricted diet (reduced intake: calories, fats, simple sugars; no alcohol). Despite adherence to all management strategies, TGs remained at approximately 2800 mg/dL (31.6 mmol/L) and symptoms persisted. The patient was enrolled in COMPASS, a phase 3, placebo-controlled trial to evaluate the effect of an investigational drug, volanesorsen, on fasting TGs in patients with hypertriglyceridemia (fasting TGs >= 500 mg/dL [>= 5.7 mmol/L]). The woman, a confirmed FCS patient, continued into the open-label extension study, during which fasting TGs decreased to 146 mg/dL (1.7 mmol/L) following 4 months of treatment. The restrictive diet was maintained throughout treatment and no serious adverse events were reported. Along with sustained TG reduction, the patient experienced progressive, perceived improvements in observable QoL measures and a marked reduction in symptom severity and frequency. In a patient with FCS, reduction in TGs following volanesorsen therapy appeared to be associated with marked improvement in clinical symptoms and observed QoL. (C) Endocrine Society 2019