Impacto do uso sistêmico de estatinas e de bisfosfonatos nos tecidos periodontais: revisão narrativa / Impact of the systemic use of statins and bisphosphonates in the periodontal tissues: narrative review

Introdução: A literatura tem apontado uma possível relação entre diversas condições sistêmicas e as doenças periodontais. Dentro das doenças sistêmicas que podem gerar o uso crônico de medicamentos, com potencial associação com as doenças periodontais, destacam-se a hipercolesterolemia e o uso de estatinas; e as doenças do metabolismo ósseo e o uso de bisfosfonatos. Objetivo: Dessa maneira, o presente estudo objetivou revisar a literatura sobre o efeito das estatinas e dos bisfosfonatos nos parâmetros clínicos e radiográficos periodontais de indivíduos adultos. Resultados: Apenas estudos observacionais em humanos foram incluídos. Um estudo mostrou que, em pacientes que apresentam doença periodontal e usam estatina, houve 37% menos bolsas periodontais (profundidade de sondagem ≥4mm) quando comparadas aos que não utilizam a medicação, além de apresentarem menor índice de carga inflamatória e menor perda de inserção clínica. Em relação aos bisfosfonatos em indivíduos com doenças que envolvem o metabolismo ósseo, sugere-se que a utilização do fármaco tem obtido resultados positivos nos parâmetros periodontais, como menores sinais clínicos de inflamação gengival, menor profundidade de sondagem, menor perda de inserção clínica e maior nível de osso alveolar, quando comparados aos que nunca realizam essa terapia. Conclusão: Dessa forma, as estatinas e os bisfosfonatos apresentam efeitos promissores, em pacientes sob tratamento para suas respectivas condições sistêmicas, na melhoria dos parâmetros periodontais, porém é importante salientar que são necessários mais estudos sobre o assunto para melhor entender os reais efeitos a longo prazo do uso desses fármacos.(AU)

Introduction: The literature showed a possible relationship between several systemic conditions and periodontal diseases. Within the systemic diseases that can generate the chronic use of these drugs, potentially related with periodontal diseases, it may be cited the hypercholesterolemia and the use of statins; and bone metabolism diseases and the use of bisphosphonates. Objective: In this sense, the present study aimed to review the literature about the effect of statins and bisphosphonates in the periodontal parameters of adults individuals. Results: Only observational studies in humans were included. A study showed that, in patients with periodontal disease and users of statins, there 37% fewer periodontal pockets (probing depth ≥4mm) when compared to those who do not use the medication, as well as having a lower rate of inflammatory burden and less loss of clinical insertion. Regarding the bisphosphonates in individuals diagnosed with diseases involving bone metabolism, it was suggested that the use of the drug has obtained positive results in periodontal parameters, such as a greater absence of plaque, less clinical signs of gingival inflammation, less probing depth, lower level of clinical insertion and higher level of alveolar bone when compared to those who never undergo this therapy. Conclusion: Thus, statins and bisphosphonates have promising effects in patients under treatment for their respective systemic condition in improving periodontal parameters, but it is important to emphasize that further studies on the subject are needed to better understand the long-term effects of the use of these drugs.(AU)

Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial / 中华心血管病杂志

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Effect of "Natural Polypill", Xuezhikang on Serum Cholesterol Metabolism Markers in Early Menopausal Women with Hypercholesterolemia / 中国结合医学杂志

OBJECTIVE@#To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia, and preliminarily explore its lipid-lowering mechanism.@*METHODS@#A total of 90 early menopausal women with hypercholesterolemia were enrolled from December, 2014 to May, 2016 from Beijing Anzhen Hospital, Capital Medical University, who were randomly allocated to receive Xuezhikang (1200 mg/d, orally) or atorvastatin (10 mg/d, orally) according to a random number table. Serum levels of some related biomarkers, including cholesterol synthesis markers (squalene, dihydrocholesterol, dehydrocholesterol, and lathosterol), and absorption markers (campesterol, stigmasterol, and sitosterol) as well as safety indices were obtained at baseline and after 8 weeks of the intervention.@*RESULTS@#Eight weeks after treatment, both Xuezhikang and atorvastatin significantly reduced the levels of total cholesterol, triglycerides, low density cholesterol compared to baseline (all P<0.01). Xuezhikang significantly reduced the levels of squalene, dehydrocholesterol and lathosterol compared to baseline (all P<0.01), but atorvastatin only significantly reduced the level of squalene (P<0.01), compared to baseline. All cholesterol absorption markers showed no significant differences before and after treatment (P>0.05), however, a more obvious downward trend was shown in the Xuezhikang group. In addition, all the safety indices showed no significant differences between the two groups. Although the creatinekinase level in the Xuezhikang group was significantly higher, it remained within the safe range.@*CONCLUSIONS@#Xuezhikang may have more comprehensive effects on the markers of cholesterol synthesis and metabolism in early menopausal women with hypercholesterolemia through ergosterol and flavonoids in its "natural polypill."

Perfil de Prescrição de Estatinas e de Níveis Lipêmicos em Ambulatórios de Hospital Terciário Público / Statins Prescriptions and Lipid Levels in a Tertiary Public Hospital

Resumo Fundamento: O surgimento de nova classe de medicamentos com elevada capacidade de reduzir o LDL-colesterol (LDL-c) renovou o interesse na caracterização da hipercolesterolemia familiar (HF). Pouco se conhece do perfil lipídico de pacientes em atendimento terciário em nosso meio para caracterizar a real ocorrência de HF, que começa a ser suspeitada com níveis de LDL-c acima de 190mg/dL. Objetivos: O estudo avaliou o perfil lipídico (colesterol total [CT] e LDL-c) de pacientes de hospital público terciário. Métodos: Estudo retrospectivo de avaliação de prescrições de estatinas e resultados dos lipídios. O nível de significância foi estabelecido em 5%. Resultados: Em 1 ano, 9.594 indivíduos receberam prescrição ambulatorial de estatinas, 51,5% do gênero feminino, idade média de 63,7±12,9 anos (18 a 100 anos). Trinta e duas especialidades prescreveram estatinas, sendo a cardiologia responsável por 43%. Cerca de 15% das prescrições não tinham dosagem recente de CT, e 1.746 (18,0%) não apresentavam resultado recente de LDL-c. A ocorrência de LDL-c > 130mg/dL e < 190mg/dL ocorreu em 1.643 (17,1%) casos, e 228 (2,4%) apresentaram LDL-c ≥ 190mg/dL dentre os que utilizavam estatinas nas diversas doses. Apenas duas estatinas foram utilizadas: sinvastatina e atorvastatina, e a primeira foi prescrita em 77,6% das receitas. Conclusão: Nesta coorte transversal de hospital terciário, foi possível verificar que a prescrição de estatinas é disseminada, mas que a obtenção de metas adequadas de CT e LDL-c não é atingida em grande percentual, e que há, possivelmente, significativo contingente de portadores de HF que necessitariam ser investigados por suas implicações prognósticas.

Abstract Background: The development of a new class of medications that are highly capable of reducing LDL-cholesterol renewed the interest in the characterization of familial hypercholesterolemia patients. Nevertheless, little is known about the lipid profile of patients in tertiary healthcare centers in Brazil in order to better estimate the real occurrence of familial hypercholesterolemia, with initial suspect of LDL-cholesterol levels above 190 mg/d/L. Objectives: This study evaluated the lipid profile (total cholesterol and LDL-cholesterol) in ambulatory patients from a general tertiary public hospital. Methods: Retrospective study comparing prescriptions of statins and lipid profile results. The significance level was established in 5%. Results: In one year, 9,594 individuals received statin prescriptions, of whom 51.5% were females and the mean age was 63.7±12.9 years-old (18 to 100 years-old). Thirty-two medical specialties prescribed statins. Cardiology was responsible for 43% of the total. Nearly 15% of those patients with a prescription did not have a recent total cholesterol result and 1,746 (18%) did not have a recent LDL-cholesterol measurement. The occurrence of the latter between 130 and 190 mg/dL was present in 1,643 (17.1%) individuals, and 228 (2.4%) patients had an LDL-cholesterol ≥190mg/dL among those using statins at distinct doses. Only two statins were used: simvastatin and atorvastatin. The first was prescribed in 77.6% of the prescriptions. Conclusion: In this cross-sectional cohort at a tertiary general hospital, statins have been widely prescribed but with little success in achieving recognized levels of control. There is probably a significant number of FH individuals in this cohort that need to be properly diagnosed in order to receive adequate treatment due to its prognostic implications.

Percepção Inadequada do Risco Cardiovascular e Baixo Conhecimento sobre Hipercolesterolemia Familiar em Indivíduos com Hipercolesterolemia Grave / Cardiovascular Risk Misperception and Low Awareness of Familial Hypercholesterolemia in Individuals with Severe Hypercholesterolemia

Resumo Fundamento Indivíduos com hipercolesterolemia grave apresentam alto risco de desenvolver doença cardiovascular aterosclerótica (DCVA). Muitos deles apresentam hipercolesterolemia familiar (HF). Objetivos Avaliar, a partir da perspectiva dos pacientes, o nível de conhecimento sobre a hipercolesterolemia grave, especialmente em relação a HF, DCVA, percepção de risco, desempenho do rastreamento em cascata e tratamento de indivíduos participantes de um programa de avaliação periódica de saúde. Métodos De um banco de dados de 70.000 brasileiros avaliados entre 2006 e 2016, 1.987 (2,8%) atenderam aos critérios de inclusão (idade ≥ 18 anos e LDL-C ≥ 190 mg/dL ou ≥ 160 mg/dL se sem uso de estatinas ou em terapia com estatinas, respectivamente). Desses, 200 foram aleatoriamente convidados a preencher um questionário extenso. A HF foi diagnosticada em caso de suspeita pelo médico responsável. Resultados Embora 97% da amostra (48±9 anos; 16% do sexo feminino; 95% com ensino superior; 88% em prevenção primária; LDL-C 209±47 mg/dL) tenha apresentado hipercolesterolemia grave, apenas 18% e 29,5% se consideravam de alto risco para desenvolver DCVA e relataram saber sua meta recomendada de LDL-C, respectivamente. Em relação à possibilidade de o colesterol alto ser uma doença hereditária, 58% relataram conhecimento sobre o fato; 24,5% (n = 49) já tinham ouvido falar em HF; e apenas 14% (n = 20) foram previamente identificados com suspeita de HF (idade ao diagnóstico de HF: 35±12 anos; 79% e 31% foram diagnosticados com > 30 e > 40 anos, respectivamente). Apenas 2,5% foram submetidos a testes genéticos; 17%, à rastreamento em cascata; e 17% não faziam uso de tratamento farmacológico. Conclusões Identificou-se uma importante lacuna na percepção de risco, no controle do colesterol e em aspectos relacionados à HF em indivíduos com hipercolesterolemia grave. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)

Abstract Background Individuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH). Objectives To assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program. Methods From a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician. Results Although 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment. Conclusions An important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)

Phytosterol supplementation in the treatment of dyslipidemia in children and adolescents: a systematic review / Suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes: uma revisão sistemática

ABSTRACT Objective: To carry out a systematic review on the effects of phytosterol supplementation on the treatment of dyslipidemia in children and adolescents. Data sources: Review in the SciELO, Lilacs, Bireme, PubMed and Web of Science databases, with no time limit. Descriptors: phytosterols or plant sterols and dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, in English and Portuguese. The articles included were published in Portuguese, English or Spanish and evaluated the effect of phytosterol supplementation in pediatric patients with dyslipidemia. Documents that involved adults or animals, review papers, case studies and abstracts were excluded. Two authors performed independent extraction of articles. Of 113 abstracts, 19 were read in full and 12 were used in this manuscript. Data synthesis: Phytosterol supplementation to reduce cholesterol levels has been shown to be effective in reducing LDL-cholesterol levels by approximately 10%, with reductions above 10% in LDL-cholesterol levels observed after 8 to 12 weeks of intervention. Studies have not shown significant changes in HDL-cholesterol and triglyceride levels. Based on the absence of adverse effects, its use seems to be safe and of good tolerance in children and adolescents. Conclusions: Phytosterol supplementation seems to be of great therapeutic aid for the treatment of hypercholesterolemia in children and adolescents. Further studies assessing the long-term effect of phytosterol supplementation are necessary.

RESUMO Objetivo: Realizar uma revisão sistemática sobre os efeitos da suplementação de fitoesteróis no tratamento da dislipidemia em crianças e adolescentes. Fontes de dados: Revisão nos bancos SciELO, Lilacs, Bireme, Pubmed e Web of Science, sem limite de tempo. Descritores: phytosterols or plant sterols, dyslipidemias, hypercholesterolemia, cholesterol, children, adolescent, nas línguas inglesa e portuguesa. Os artigos incluídos foram publicados nos idiomas português, inglês ou espanhol e avaliaram o efeito da suplementação de fitoesteróis em pacientes pediátricos com dislipidemia. Estudos que envolviam adultos ou animais, trabalhos de revisão, estudos de caso e resumos foram excluídos. A extração independente de artigos foi realizada por dois autores. Do total de 113 resumos, 19 foram lidos na íntegra, e 12 utilizados neste manuscrito. Síntese de dados: A suplementação de fitoesteróis para a redução dos níveis de colesterol mostrou-se eficiente, de forma a promover a redução de aproximadamente 10% dos níveis de LDL-colesterol, sendo observadas reduções acima de 10% em 8 a 12 semanas de intervenção. Os estudos não mostraram alterações significantes nos níveis de HDL-colesterol e triglicérides. Com base na ausência de efeitos adversos, seu uso parece ser seguro e de boa tolerância em crianças e adolescentes. Conclusões: A suplementação com fitoesteróis parece ser de grande auxílio terapêutico para o tratamento da hipercolesterolemia em crianças e adolescentes. São necessários mais estudos que avaliem o efeito em longo prazo da suplementação de fitoesteróis.

Factors influencing achievement of low-density lipoprotein cholesterol goals in mexico: the international cholesterol management practice study

ABSTRACT Background The International Cholesterol Management Practice Study is a multinational collaborative effort to describe the effectiveness of the lipid-lowering therapy (LLT) as well as the main barriers to achieve the low-density lipoprotein cholesterol (LDL-C) goals Objective The objective of the study was to investigate factors associated with the achievement of LDL-C goals in Mexico using real-life data Methods This was a cross-sectional observational study from 18 physicians across different health facilities in Mexico, who provided information about their practices between August 2015 and August 2016. We included patients treated for ≥3 months with any LLT in whom LDL-C measurement on stable LLT was available for the previous 12 months Results We included 623 patients with a mean age of 59.3 ± 12.7 years; 55.6% were women. The mean LDL-C value on LLT was 141.8 ± 56.1 mg/dL. At enrollment, 97.4% of patients were receiving statin therapy (11.3% on high-intensity treatment). Only 24.8% of the very-high cardiovascular (CV) risk patients versus 26.4% of the high risk and 52.4% of the moderate risk patients achieved their LDL-C goals. Independent factors associated with non-achievement of LDL-C goal were statin intolerance, overweight and obesity, abdominal obesity, female sex, high CV risk, use of public health-care service, metabolic syndrome, type 2 diabetes, and hypertriglyceridemia. Higher-level of education was associated with a lower risk of not achieving LDL-C goals Conclusions Achievement of LDL-C goals is suboptimal in Mexico, especially in patients with the highest CV risk. The main barriers to achieve the goal are easily detectable. Implementation of LLT should be adapted to the patient’s needs and profile.

Elegibilidad para la indicación de inhibidores de PCSK9 según las recomendaciones de diferentes sociedades científicas / Eligibility for the indication of PCSK9 inhibitors according to the recommendations of different scientific societies

La reducción del colesterol-LDL (C-LDL) es un objetivo primordial en prevención cardiovascular. Estudios recientes demostraron beneficio clínico al administrar inhibidores de la proprotein convertase subtilisin/kexin-9 (iPCSK9) a pacientes que no habían logrado la meta de C-LDL con estatinas de alta intensidad y ezetimibe, sin embargo el uso de estos fármacos está limitado por su costo. El American College of Cardiology, la Sociedad Argentina de Cardiología y la European Society of Cardiology recomiendan una meta de C-LDL menor a 70 mg/dl en prevención secundaria, determinando umbrales de C-LDL de 70, 100 o 140 mg/dl respectivamente, para iniciar el tratamiento con iPCSK9. Con el objetivo de evaluar el esquema hipolipemiante prescripto en internados por síndrome coronario agudo o revascularización coronaria y analizar la proporción de elegibles para ser tratados con iPCSK9 en un escenario real y simulado, realizamos un estudio que incluyó 351 pacientes con enfermedad coronaria, tomados de una base de datos electrónica de un hospital universitario. El 48.4% recibió estatinas de elevada intensidad, 11.4% ezetimibe y 54.7% no logró la meta de C-LDL menor a 70 mg/dl. Utilizando un modelo de simulación en el que todos serían medicados con estatinas de elevada intensidad y ezetimibe, la elegibilidad para prescribir iPCSK9 fue de 31.1%, 12.8% y 9.1% según los umbrales de C-LDL determinados por las tres sociedades científicas. Nuestro estudio demostró una brecha entre las recomendaciones de los consensos para reducir el colesterol y la práctica habitual que debería ser minimizada para optimizar la relación costo/efectividad en prevención secundaria.

LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.

PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice / Inibidores de PCSK9: Importância Clínica, Mecanismos Moleculares, e Segurança na Prática Clínica

Abstract Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.

Resumo A doença arterial coronariana (DAC) é uma das principais causas de mortalidade. Níveis circulantes elevados de lipoproteína de baixa densidade (LDL) no sangue estão associados com mortalidade cardiovascular, seja por um papel etiológico ou por sua associação com a progressão da DAC em si. Estudos clínicos randomizados mostram que, quando os níveis de LDL são reduzidos, o risco cardiovascular também é reduzido, o que reforça tal associação. O primeiro ensaio importante envolvendo um agente hipolipemiante da família da estatina, o estudo Scandinavian Simvastatin Survival Study (4S), foi publicado em 1994 e encontrou uma redução significativa na mortalidade de pacientes com risco cardiovascular elevado. Contudo, mesmo em estudos subsequentes com diferentes estatinas, observou-se um risco residual persistente, o qual aparentemente não mudou ao longo dos anos. Especula-se que esse risco se deve à intolerância às estatinas. Nesse cenário, existe um potencial para novos agentes hipolipemiantes que levem a uma verdadeira revolução no tratamento das dislipidemias. A descoberta recente dos inibidores de PCSK9 (PCSK9i), uma classe de anticorpos monoclonais, é extremamente promissora. A inibição da PCSK9 é capaz de promover uma redução média nos níveis de LDL de até 60%, com potencial para repercussões clínicas muito significativas, já que para cada redução de 38 mg/dL, parece haver uma redução de 22% no risco cardiovascular. Esta revisão aborda uma breve história dos PCSK9i, os principais ensaios envolvendo esses medicamentos, desfechos cardiovasculares, e aspectos relacionados a sua eficácia e segurança. Finalmente, os mecanismos moleculares e possíveis efeitos pleiotrópicos dos PCSK9i são também discutidos.

Tratamento atual da hipercolesterolemia e novas perspectivas / Current dyslipidemia treatments and new perspectives

Novos fármacos para o tratamento da hipercolesterolemia foram desenvolvidos, que poderão ser incorporadas nas diretrizes, resultantes de estudos clínicos robustos que demonstraram redução de desfechos cardiovasculares adicionais aos resultados obtidos com a otimização terapêutica disponível com as estatinas. O objetivo deste artigo é atualizar o conhecimento para o tratamento das dislipidemias baseado nas melhores evidências e as novas opções terapêuticas para reduzir o risco de eventos cardiovasculares em pacientes com dislipidemia refratária à otimização do tratamento atual.

New drugs for dyslipidemia treatment have been developed in solid clinical studies, which demonstrated an additional reduction of cardiovascular outcomes compared to therapeutic treatment with statins, and might be incorporated in new treatment guidelines. The aim of this article is to update the knowledge for the treatment of dyslipidemias based on the best evidences and the new therapeutic options incorporated to reduce the risk of cardiovascular events in patients with dyslipidemia refractory to treatment optimization.

Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases / Fitosteróis no Tratamento da Hipercolesterolemia e Prevenção de Doenças Cardiovasculares

Abstract Phytosterols are bioactive compounds found in foods of plant origin, which can be divided into plant sterols and plant stanols. Clinical studies consistently indicate that the intake of phytosterols (2 g/day) is associated with a significant reduction (8-10%) in levels of low-density lipoprotein cholesterol (LDL-cholesterol). Thus, several guidelines recommend the intake of 2 g/day of plant sterols and/or stanols in order to reduce LDL-cholesterol levels. As the typical western diet contains only about 300 mg/day of phytosterols, foods enriched with phytosterols are usually used to achieve the recommended intake. Although phytosterols decrease LDL-cholesterol levels, there is no evidence that they reduce the risk of cardiovascular diseases; on the contrary, some studies suggest an increased risk of atherosclerosis with increasing serum levels of phytosterols. This review aims to address the evidence available in the literature on the relationship between phytosterols and risk of cardiovascular disease.

Resumo Os fitosteróis são compostos bioativos encontrados em alimentos de origem vegetal e que podem ser divididos em esteróis vegetais e estanóis vegetais. Estudos clínicos indicam de forma consistente que a ingestão de fitosteróis (2 g/dia) está associada a uma redução significativa (8-10%) de níveis de colesterol da lipoproteína de baixa densidade (LDL-C). Desta forma, diversas diretrizes recomendam a ingestão de 2 g/dia de esteróis e/ou estanóis vegetais com o objetivo de reduzir os níveis de LDL-C. Como uma dieta ocidental típica contém apenas cerca de 300 mg/dia de fitosteróis, normalmente são utilizados alimentos enriquecidos com fitosteróis para alcançar a ingestão recomendada. Apesar dos fitosteróis reduzirem os níveis de LDL-C, não há evidências de que reduzam o risco de doenças cardiovasculares. Pelo contrário, alguns estudos sugerem que a elevação na concentração sérica de fitosteróis possa estar associada com aumento no risco de aterosclerose. Esta revisão tem como objetivo abordar as evidências disponíveis na literatura sobre a relação entre fitosteróis e risco de doenças cardiovasculares.

Fosfatasa alcalina ósea sérica elevada no mediada por metástasis en un paciente con cáncer renal / Elevated bone alkaline phosphatase not mediated by metastasis in a patient with renal cancer

Presentamos un paciente de 63 años con cáncer renal y aumento de fosfatasa alcalina sérica de tipo óseo de acuerdo con su reactividad con anticuerpos monoclonales específicos. Se descartaron las causas conocidas de aumento de la isoenzima, incluyendo metástasis óseas. Los niveles enzimáticos cayeron abruptamente con la remoción del tumor, por lo que consideramos a este último como su origen. Diversas isoenzimas de fosfatasa alcalina pueden ser producidas y secretadas por tumores como manifestación paraneoplásica. El conocimiento de esto puede, en ocasiones, orientarnos hacia la presencia de una neoplasia oculta. Además, los cambios en los niveles séricos de esas isoenzimas pueden ser indicadores de respuesta al tratamiento o de recidiva tumoral. (AU)

A 63-year old man was seen in the outpatient clinic because of renal cancer and elevation in bone alkaline phosphatase measured by monoclonal antibodies assay. Known causes of bone isoenzyme augmentation, including bone metastases, were ruled out. The tumoral origin of the isoenzyme was diagnosed because after removal of the tumor the enzymatic levels fell sharply. Several alkaline phosphatase isoenzymes can be produced and secreted by tumors as a paraneoplasic manifestation and their elevation could be a manifestation of an occult neoplasia. Furthermore the monitoring of their blood levels can be useful means of treatment response and a tool to monitoring recurrence if a sharp decrease after removal of the tumor is observed. (AU)

Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management / Estratificação de Risco Cardiovascular e Elegibilidade para Estatina com Base na Diretriz Brasileira vs. Norte-Americana para Manejo do Colesterol

Abstract Background: The best way to select individuals for lipid-lowering treatment in the population is controversial. Objective: In healthy individuals in primary prevention: to assess the relationship between cardiovascular risk categorized according to the V Brazilian Guideline on Dyslipidemia and the risk calculated by the pooled cohort equations (PCE); to compare the proportion of individuals eligible for statins, according to different criteria. Methods: In individuals aged 40-75 years consecutively submitted to routine health assessment at one single center, four criteria of eligibility for statin were defined: BR-1, BR-2 (LDL-c above or at least 30 mg/dL above the goal recommended by the Brazilian Guideline, respectively), USA-1 and USA-2 (10-year risk estimated by the PCE ≥ 5.0% or ≥ 7.5%, respectively). Results: The final sample consisted of 13,947 individuals (48 ± 6 years, 71% men). Most individuals at intermediate or high risk based on the V Brazilian Guideline had a low risk calculated by the PCE, and more than 70% of those who were considered at high risk had this categorization because of the presence of aggravating factors. Among women, 24%, 17%, 4% and 2% were eligible for statin use according to the BR-1, BR-2, USA-1 and USA-2 criteria, respectively (p < 0.01). The respective figures for men were 75%, 58%, 31% and 17% (p < 0.01). Eighty-five percent of women and 60% of men who were eligible for statin based on the BR-1 criterion would not be candidates for statin based on the USA-1 criterion. Conclusions: As compared to the North American Guideline, the V Brazilian Guideline considers a substantially higher proportion of the population as eligible for statin use in primary prevention. This results from discrepancies between the risk stratified by the Brazilian Guideline and that calculated by the PCE, particularly because of the risk reclassification based on aggravating factors.

Resumo Fundamento: Existe controvérsia sobre a melhor forma de selecionar indivíduos para tratamento hipolipemiante na população. Objetivos: Em indivíduos saudáveis em prevenção primária: avaliar a relação entre o risco cardiovascular segundo a V Diretriz Brasileira de Dislipidemias e o risco calculado pelas pooled cohort equations (PCE); comparar a proporção de indivíduos elegíveis para estatinas, de acordo com diferentes critérios. Métodos: Em indivíduos de 40 a 75 anos submetidos consecutivamente a avaliação rotineira de saúde em um único centro, quatro critérios de elegibilidade para estatina foram definidos: BR-1, BR-2 (LDL-c acima ou pelo menos 30 mg/dL acima da meta preconizada pela diretriz brasileira, respectivamente), EUA-1 e EUA-2 (risco estimado pelas PCE em 10 anos ≥ 5,0% ou ≥ 7,5%, respectivamente). Resultados: Foram estudados 13.947 indivíduos (48 ± 6 anos, 71% homens). A maioria dos indivíduos de risco intermediário ou alto pela V Diretriz apresentou risco calculado pelas PCE baixo e mais de 70% daqueles considerados de alto risco o foram devido à presença de fator agravante. Foram elegíveis para estatina 24%, 17%, 4% e 2% das mulheres pelos critérios BR-1, BR-2, EUA-1 e EUA-2, respectivamente (p < 0,01). Os respectivos valores para os homens foram 75%, 58%, 31% e 17% (p < 0,01). Oitenta e cinco por cento das mulheres e 60% dos homens elegíveis para estatina pelo critério BR-1 não seriam candidatos pelo critério EUA-1. Conclusões: Comparada à diretriz norte-americana, a V Diretriz Brasileira considera uma proporção substancialmente maior da população como elegível para estatina em prevenção primária. Isso se relaciona com discrepâncias entre o risco estratificado pela diretriz brasileira e o calculado pelas PCE, particularmente devido à reclassificação de risco baseada em fatores agravantes.

Dislipidemias: ¿qué hay de nuevo? / Dyslipidemia: what's new?

En los últimos años han surgido algunas investigaciones y guías de práctica clínica relacionadas con el diagnóstico y tratamiento de las dislipidemias, que aportaron nuevos conocimientos (y controversias) sobre dicha problemática. En este resumen se describen, en primer lugar, las características de las "nuevas guías" norteamericanas para el manejo del colesterol publicadas a fines de 2013 y se comparan con las recomendaciones tradicionales. En segundo lugar, se analizan los últimos estudios que evaluaron el impacto cardiovascular de otros fármacos hipolipemiantes (ezetimibe y ácido nicotínico) en pacientes en prevención secundaria tratados con estatinas. Finalmente, se mencionan las nuevas drogas hipolipemiantes desarrolladas en los últimos años, como el lomitapide, el mipomersen y los inhibidores de la PCSK9, y se comentan el mecanismo de acción, su eficacia, sus efectos colaterales y los escenarios clínicos en donde podrían utilizarse. (AU)

In recent years, some research and clinical practice guidelines related to the diagnosis and treatment of dyslipidemia, which provided new knowledge (and controversy) about this problem have emerged. In this review, the characteristics of the American "new guidelines" for cholesterol management published by the end of 2013 are described, and they are compared with the traditional recommendations. In addition, recent studies assessing the cardiovascular impact of other lipid-lowering drugs (ezetimibe and nicotinic acid) in patients in secondary prevention treated with statins are analyzed. Finally, new hypolipidemic drugs developed in recent years are mentioned (lomitapide, mipomersen and PCSK9 inhibitors), discussing the mechanism of action, efficacy, side effects and clinical settings where they could be used. (AU)

Importancia de la interpretación del colesterol total y de los triglicéridos para el diagnóstico de las dislipidemias / Importance of the interpretation of the total cholesterol and triglyceride content for the diagnosis of dyslipidemias

Objetivo: describir la importancia de la interpretación del colesterol total y de los triglicéridos para el diagnóstico de las dislipidemias. Métodos: se evaluaron 2 159 resultados de lipidogramas, realizados en el Laboratorio de Bioquímica, del Instituto de Angiología y Cirugía Vascular entre enero-2008-2009. Se utilizaron las recomendaciones de expertos y las referencias de los diagnosticadores para decidir la positividad o no del resultado. Resultados: se encontró que el colesterol fue positivo en el 32 por ciento de las órdenes según las recomendaciones y el 9,96 por ciento según la referencia. En el mismo orden los triglicéridos fueron positivos en el 43,14 por ciento y en el 38,96 por ciento, respectivamente. Estos hallazgos denotaron que al seguir los criterios de las referencias se deja de diagnosticar una hipercolesterolemia o una hipertrigliceridemia en el 68,88 y 9,68 por ciento respectivamente. Por las recomendacione de expertos se encontró que el orden de frecuencias de las dislipidemias fue: hipertrigliceridemia (42,42 por ciento), hipercolesterolemia (30,33 por ciento) e hiperlipemia combinada (27,25 por ciento). Al constatar la gravedad de las dos primeras se observó que la hipercolesterolemia era: leve (59,89 por ciento), moderada (31,59 por ciento) y grave (8,52 por ciento), mientras que la hipertrigliceridemia era moderada (51,67 por ciento) y grave (48,33 por ciento). Conclusiones: la interpretación correcta de los resultado del estudio lipídico es de gran importancia y representa un aporte social para el diagnóstico de una dislipidemia(AU)

Objective: to describe the importance of right interpretation of the total cholesterol and triglyceride content for the diagnosis of the dyslipidemias. Methods: evaluation of 2 159 results of study of lipid analyses made at the laboratory of biochemistry of the Institute of Angiology and Vascular Surgery from January 2008 to January 2009. The experts' recommendations and diagnosticians' references were used to decide whether the results were positive or not. Results: it was found that the cholesterol indexes were positive in 32 percent of the analyses according to the recommendations and in 9.96 percent according to the references. Similarly, triglycerides indexes were positive in 43.14 percent and 38.96 percent, respectively. These findings indicated that applying the criteria of the diagnosticians' references, hypercholesterolemia or hypertriglyceridemia was not duly diagnosed in 68.88 percent and 9.68 of analyses, respectively. According to the experts' recommendations, the order of frequency of dyslipidemias was hypertriglyceridaemia (42.42 percent), hypercholesterolemia (30.33 percent) and combined hyperlipidemia (27.25 percent). Considering the severity of the two first, it was observed that hypercholesterolemia was mild (59.89 percent), moderate (31.59 percent) and severe (8.52 percent) whereas hypertriglyceridemia was moderate (51.67 percent) and severe (48.33 percent). Conclusions: the correct interpretation of results of the lipid study is highly significant and represents a social contribution to diagnosis of dyslipidemia(AU)

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort / Papel do Dimorfismo Sexual na Eficácia e Segurança da Terapia com Sinvastatina ou Atorvastatina em uma Coorte no Sul do Brasil

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .

Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...