Efficacy and Tolerability of a Fixed-Dose Combination of Rosuvastatin and Ezetimibe Compared with a Fixed-Dose Combination of Simvastatin and Ezetimibe in Brazilian Patients with Primary Hypercholesterolemia or Mixed Dyslipidemia: A Multicenter, Randomized Trial.

BACKGROUND: The addition of ezetimibe to statin therapy has been reported to result in increased efficacy for reduction of LDL-C levels and achievement of lipid targets, compared with monotherapy. OBJECTIVE: This study was designed to demonstrate the noninferiority of therapy with fixed-dose rosuvastatin plus ezetimibe formulations versus fixed dose simvastatin and ezetimibe formulations for reduction of LDL-C levels in Brazilian patients with hypercholesterolemia or mixed dyslipidemia. METHODS: Phase III, multicenter, randomized, parallel, open-label, noninferiority study that included male and female participants (aged 21-80 years) with hypercholesterolemia or mixed dyslipidemia. After a 1-week screening period with washout of lipid-lowering medications when needed, patients were treated with simvastatin 20 mg/d for 5 weeks. Participants with LDL-C levels ≥100 mg/dL after the initial treatment were submitted to a 1-week washout period, and then randomized 1:1 to receive either combined rosuvastatin 10 mg + ezetimibe 10 mg (R/E) or simvastatin 20 mg + ezetimibe 10 mg (S/E) for 4 weeks and, if they still did not achieve the stipulated target, doses were readjusted to rosuvastatin 20 mg + ezetimibe 10 mg or simvastatin 40 mg + ezetimibe 10 mg, respectively, for 4 weeks. RESULTS: One hundred twenty-nine participants were enrolled, including 66 in R/E and 63 in S/E. At the end of simvastatin 20 mg treatment period, mean LDL-C values were 124.79 mg/dL and 121.27 mg/dL for participants randomized to R/E and S/E arms, respectively. After 4 weeks of R/E 10 mg + 10 mg or S/E 20 mg + 10 mg combined treatments, adjusted mean LDL-C values were 74.21 mg/dL and 85.58 mg/dL, respectively (P = 0.0005), and after 9 weeks, with dose adjustment to R/E 20 mg + 10 mg in 6 patients and to S/E 40 mg +10 mg in 19 patients, LDL-C adjusted mean values were 75.29 mg/dL and 86.62 mg/dL, respectively (P = 0.0006). There was a statistically significant difference between the association R/E and S/E (P = 0.0013) in percentage change of LDL-C after 9 weeks of combined treatments. The adjusted mean difference was estimated at -10.32% (95% CI, -16.94% to -3.70%). The LDL-C <100 mg/dL target was achieved in a significantly greater proportion of participants at week 4 in the R/E compared with the S/E arm (84.8% vs 68.2%; P = .0257), and at week 9, the proportion was 81.2% versus 73.0%, respectively (P = 0.23). LDL-C <70 mg/dL was achieved at a significantly greater proportion in the R/E arm, both at week 4 (45.4% vs 15.9%; P = 0.003) and week 9 (40.9% vs 15.9%; P = 0.0017). A statistically significant difference at week 9 (P = 0.0106) was observed in fasting blood glucose in the R/E arm, but the overall incidence of adverse events was not significantly different between groups. CONCLUSIONS: Rosuvastatin and ezetimibe fixed dose combination in both 10 mg/10 mg and 20 mg/10 mg doses, respectively, provided significantly lower levels of LDL-C compared with simvastatin and ezetimibe in doses of 20 mg/10 mg and 40 mg/10 mg, respectively. The fixed-dose combinations were both effective and well tolerated in this Brazilian study population. ClinicalTrials.gov identifier: NCT01420549. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Insulin resistance can impair reduction on carotid intima-media thickness in obese adolescents.

BACKGROUND: The atherosclerotic process at the endothelial level begins in early ages and seems to be associated with obesity and its comorbidities as insulin resistance. OBJECTIVE: The aim of this study was to verify the influence of insulin resistance on inflammatory and subclinical markers of atherosclerosis in obese adolescents. METHODS: Sixty-six post-pubescent obese adolescents were divided in two groups according to homeostasis model assessment of insulin resistance (HOMA-IR) measurement: with insulin resistance (IR) n=39 and without insulin resistance (NIR) n=27, and submitted to an interdisciplinary intervention over the course of 1 year. Common carotid artery intima-media thickness (cIMT), visceral and subcutaneous adipose tissue was determined by ultrasound. Body composition, blood pressure, HOMA-IR, lipid profile and adipokines concentrations [leptin, adiponectin, and plasminogen activator inhibitor type (PAI-1)] were analyzed before and after the therapy. RESULTS: Both groups presented significant improvements in body composition, inflammatory state (reduction of leptin and PAI-1 concentration; increasing of plasma adiponectin) and reduction of cIMT. Only NIR group showed positive correlation between changes in visceral fat (∆Visceral) and changes in cIMT (∆ cIMT) (r = 0.42; p < 0.05). Simple linear regression analyze revealed ∆Visceral to be an independent predictor to reduction of cIMT in this group (R2 adjusted = 0.14, p = 0.04). The final values of cIMT remained significantly higher in IR group when compared to NIR group. CONCLUSION: The presence of insulin resistance can impair changes in cIMT leading to early development of atherosclerosis in obese adolescents submitted to an interdisciplinary intervention..

Resistência insulínica pode prejudicar a redução da espessura mediointimal em adolescentes obesos / Insulin resistance can impair reduction on carotid intima-media thickness in obese adolescents

FUNDAMENTO: O processo aterosclerótico no nível endotelial começa em idade precoce e parece estar associado com a obesidade e suas comorbidades como a resistência insulínica. OBJETIVO: O objetivo deste estudo foi verificar a influência da resistência insulínica em marcadores inflamatórios e subclínicos de aterosclerose em adolescentes obesos. MÉTODOS: Sessenta e seis adolescentes obesos pós-púberes foram divididos em dois grupos de acordo com o índice de resistência insulínica estimado pelo Modelo de Avaliação da Homeostase (HOMA-RI): com resistência insulínica (RI) n = 39 e sem resistência insulínica (NRI) n = 27, e foram submetidos a uma intervenção interdisciplinar ao longo de um ano. A espessura mediointimal da artéria carótida comum (EMIC), e o tecido adiposo visceral e subcutâneo foram determinados por ultrassonografia. A composição corporal, pressão arterial, índice HOMA-RI, perfil lipídico e as concentrações de adipocinas [leptina, adiponectina, e inibidor do ativador do plasminogênio-1 (PAI-1)] foram analisados antes e após a terapia. RESULTADOS: Ambos os grupos apresentaram melhoras significativas na composição corporal, estado inflamatório (redução da concentração de leptina e PAI 1; aumento de adiponectina plasmática) e redução da EMIC. Apenas o grupo NRI mostrou correlação positiva entre as alterações na gordura visceral (∆Visceral) e mudanças na EMIC (∆ EMIC) (r = 0,42, p < 0,05). A análise por regressão linear simples revelou o ∆Visceral ser um preditor independente para a redução da EMIC nesse grupo (R2 ajustado = 0,14, p = 0,04). Os valores finais da EIMC permaneceram significativamente maiores no grupo RI, quando comparado com grupo NRI. CONCLUSÃO: A presença de resistência insulínica pode prejudicar mudanças na EMIC levando ao desenvolvimento precoce da aterosclerose em adolescentes obesos submetidos a uma intervenção interdisciplinar.

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Micropartículas e células progenitoras: novos marcadores da disfunção endotelial / Microparticles and progenitor cells: new markers of endothelial dysfunction

O endotélio vascular compreende uma população altamente dinâmica decélulas com papel na proteção vascular contra inflamação, resposta imune,trombose e doenças cardiovasculares, Células progenitoras endoteliais(CPE) compreendem um grupo celular extremamente raro de células nãohematopoiéticas que podem ser recrutadas da medula óssea por váriosestímulos, como citocinas, fármacos, estrógenos, eritropoietina, atividadefísica,e participam na manutenção da integridade endotelial. Aregeneraçãovascular após dano endotelial ocorre tanto pela proliferação de célulasendoteliais maduras, residentes na parede dos vasos (angiogênese), comopor migração e diferenciação de CPE da medula óssea para áreas deisquemia, com a formação de novos vasos sanguíneos (vasculogênese).As CPE podem ser identificadas por citometria de fluxo por meio daexpressão dos marcadores de superfície celular CD34, CD309 (KDR) eCD133. Micropartículas (MP) são pequenas vesículas liberadas por diferentestipos celulares após ativação ou apoptose, contendo material celularcomo proteínas, mRNA, lipoproteínas e debris. Têm papel relacionado àresposta imune adaptativa, sendo utilizados também como biomarcadoresde disfunção endotelial e de algumas afecções como diabetes, infarto, HIV,além de promoverem a transferência de material e comunicação entrecélulas. CPE associadas às MP podem ser consideradas biomarcadoresúteis da doença cardiovascular por estarem diretamente relacionadas àhomeostase endotelial. O recrutamento de CPE sugere um mecanismocompensatório de reparo vascular que contribui para a restauração daintegridade endotelial. Aumento de MP associa-se à disfunção endoteliale à progressão da aterosclerose. Assim, a relação MP/CPE pode indicar ograu de desequilíbrio entre dano endotelial e capacidade de reparo...

The vascular endothelium comprises a highly dinamic population of cellswith a role in vascular protection against inflammation, imune response,thrombosis and cardiovascular diseases. Endothelial progenitor cells(EPC) are an extremely rare population of non-hematopoietic cells thatcan be recruited from bone marrow by many stimuli, such as cytokines,drugs, estrogens, erithropoetin, physical activity and can participate inthe manteinance of endothelium integrity. Vascular repair after injury ofthe endothelium can occur by both proliferation of mature adjacent cells(angiogenesis), or by EPC migration and proliferation from bone marrowto ischemic areas, forming new vessels (vasculogenesis). EPC can beidentified by flow citometry by using surface markers CD34, CD309(KDR) and CDl33. Microparticles (MP) are small vesicles released bydiferent cell types after acti vation or apoptosis, and contain cell materialsuch as proteins, mRNA, lipoproteins and debris. Their role is related tothe adaptive immune responses, and are also potential biomarkers of endotelialdysfunction in diabetes, myocardial infarction and in HIV infection.Further, MP can promote transfer of cell material and cell communication.EPC and MP can be used as useful biomarkers in cardiovascular diseasefor being associated with endothelial homeostasis. EPC mobilization is acompensatory mechanisrn for vascular repair that contributes to restoreendothelial integrity. Conversely, increase in circulating MP is associatedwith endotelial dysfunction and atherosclerosis progression. Though, theassessment of the MPIEPC ratio can indicate the degree of disbalancebetween endothelial damage and repair...