Ezetimibe therapy: mechanism of action and clinical update.

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios

Dyslipidemia treatment of patients with diabetes mellitus in a US managed care plan: a retrospective database analysis

<p>Abstract</p> <p>Background</p> <p>To evaluate real-world pharmacologic treatment of mixed dyslipidemia in patients with diabetes mellitus (DM).</p> <p>Methods</p> <p>All commercial health plan members in a large US managed care database with complete lipid panel results (HDL-C, LDL-C, TG) between 1/1/2006 and 12/31/2006 were identified (N = 529,236). DM patients (N = 53,679) with mixed dyslipidemia were defined as having any 2 suboptimal lipid parameters (N = 28,728). Lipid treatment status 6 months pre- and post-index date was determined using pharmacy claims for any lipid therapy.</p> <p>Results</p> <p>Post-index, 41.1% of DM patients with 2 abnormal lipid parameters and 45.1% with 3 abnormal lipid parameters did not receive lipid-modifying treatment. Post-index treatment rates were 57.4%, 63.6%, and 66.4% for patients with LDL-C, HDL-C, and TG in the most severe quartiles, respectively. Statin monotherapy was the primary lipid-modifying regimen prescribed (54.8% and 47.8% of patients with any 2 and all 3 lipids not at goal, respectively). Less than 30% of treated patients received combination therapy.</p> <p>Conclusion</p> <p>Over 40% of DM patients with mixed dyslipidemia received no lipid-modifying therapy during the follow-up period. Those who were treated were primarily prescribed statin monotherapy. This study suggests that DM patients are not being treated to ADA-suggested targets.</p

Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Leczenie dużymi dawkami statyn: korzyści i bezpieczeństwo intensywnej terapii hipolipemizującej

Cholesterol frakcji LDL (LDL-C) jest biomarkerem miażdżycy. Zmniejszenie stężenia LDL-C wiąże się ze zmniejszeniem ryzyka niepożądanych punktów końcowych o etiologii sercowo-naczyniowej. W ostatnich badaniach wykazano korzyści z obniżenia stężenia LDL-C poniżej 100 mg/dl, a nawet poniżej 70 mg/dl. Na ich podstawie dokonano aktualizacji zaleceń, sugerując niższe docelowe stężenia LDL-C u niektórych pacjentów należących do grupy wysokiego ryzyka. U pacjentów bez potwierdzonej choroby wieńcowej lub ekwiwalentu choroby wieńcowej z co najmniej 2 czynnikami ryzyka, należy obliczyć 10-letnie ryzyko według skali Framingham w celu ustalenia docelowej wartości LDL-C. Wydaje się, że optymalne stężenie LDL-C u wszystkich pacjentów z chorobą sercowo-naczyniową wynosi poniżej 70 mg/dl. U pacjentów bez choroby sercowo-naczyniowej celowe jest zmniejszenie stężenia LDL-C o co najmniej 50% w stosunku do stężenia wyjściowego. Stężenie LDL-C poniżej 70 mg/dl można osiągnąć w bezpieczny sposób u większości pacjentów z chorobą sercowo-naczyniową, o ile stosuje się wysoce skuteczne leki hipolipemizujące. W ciągu ponad 20 lat stosowania statyn przez miliony pacjentów udowodniono, że taka terapia jest bezpieczna i dobrze tolerowana. Lekarze powinni wybrać lek, który pozwoli osiągnąć odpowiednie stężenie LDL-C, na podstawie danych dotyczących klinicznych punktów końcowych, wybrać odpowiednio dużą dawkę początkową oraz modyfikować dawkę tak, aby osiągnąć docelowe stężenie

Dietary food patterns and glucose/insulin homeostasis: a cross-sectional study involving 24,182 adult Americans

AIM: To investigate the association of major dietary patterns with glucose and insulin homeostasis parameters in a large American sample. The association between dietary patterns (DP) derived via principal components analysis (PCA), with glucose/insulin homeostasis parameters was assessed. The likelihood of insulin resistance (IR) across the DPs quarters was also explored. METHOD: The United States National Health and Nutrition Examination Survey (NHANES) participants during 2005-2012 were included if they underwent measurement of dietary intake as well as glucose and insulin homeostasis parameters. Analysis of covariance (ANCOVA) and adjusted logistic and linear regression models were employed to account for the complex survey design and sample weights. RESULTS: A total of 24,182 participants were included; 48.9% (n = 11,815) were men. Applying PCA revealed three DP (56.8% of variance): the first was comprised mainly of saturated fat (SFA), total fat, mono-unsaturated fatty acids (MUFA) and carbohydrate (CHO); the second is highly enriched with vitamins, trace elements and dietary fiber; and the third was composed of polyunsaturated fatty acids (PUFA), cholesterol and protein. Among the total population, after adjustment for age, sex, race, C-reactive protein, smoking, and physical activity, glucose homeostasis factors, visceral adiposity index and lipid accumulation product improved across the quarters of the first and third DP; and a reverse pattern with the second DP. The same trend was observed for the non-diabetic subjects. Moreover, subjects with higher adherence to the first and third DP had higher likelihood for developing IR, whereas there was a lower likelihood for the second DP. CONCLUSION: This study shows that the DP heavily loaded with CHO, SFA, PUFA, protein, total fat and MUFA as well as high-cholesterol-load foods is associated with impaired glucose tolerance; in contrast, the healthy pattern which is high in vitamins, minerals and fiber may have favourable effects on insulin sensitivity and glucose tolerance

Achievement of combined goals of low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol with three different statins: Results from VOYAGER

AbstractBackgroundGuidelines suggest that the combination of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) is the most clinically relevant goal for lipid-lowering treatments.MethodsData from VOYAGER, an individual patient data meta-analysis including 32,258 patients from 37 clinical trials, was used to determine the percentage of patients reaching combined goals of LDL-C and non-HDL-C following treatment with simvastatin, atorvastatin, or rosuvastatin. Paired comparisons were made between each dose of rosuvastatin and the same or higher doses of simvastatin and atorvastatin.ResultsEach dose of rosuvastatin brought significantly more patients to the combined goal of LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL than the same or double dose of atorvastatin; atorvastatin 80 mg was significantly superior to rosuvastatin 10 mg (all p < 0.001). Each dose of rosuvastatin helped significantly more patients reach the combined goal than any dose of simvastatin (all p < 0.001), except for rosuvastatin 10 mg versus simvastatin 80 mg (non-significant). Also, each dose of rosuvastatin helped significantly more patients to reach the combined goal of LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL than the same or double dose of atorvastatin (all p < 0.001). Every dose of rosuvastatin was significantly superior to all doses of simvastatin (all p ≤ 0.020), except for rosuvastatin 10 mg versus simvastatin 40 mg and 80 mg (non-significant).ConclusionsPhysicians' choice of statin and dose is important in helping patients achieve the combined LDL-C and non-HDL-C goals recommended in established guidelines

Altilix\uae Supplement Containing Chlorogenic Acid and Luteolin Improved Hepatic and Cardiometabolic Parameters in Subjects with Metabolic Syndrome: A 6 Month Randomized, Double-Blind, Placebo-Controlled Study

The objective was to evaluate the eects of 6 months of supplementation with Altilix\uae, containing chlorogenic acid and its derivatives, and luteolin and its derivatives, on cardiovascular risk and hepatic markers in subjects with metabolic syndrome (MetS). A randomized, double-blind, placebo-controlled study was performed in 100 subjects with MetS with a follow-up period of 6 months; 50 subjects were randomized to Altilix\uae (26 men and 24 women, mean age 63 8 years) and the other 50 to placebo (28 men and 22 women, mean age 63 11 years). Anthropometric, cardiometabolic, and hepatic parameters were assessed at baseline and at the end of follow-up. Carotid intima-media thickness and endothelial function were assessed by doppler ultrasound and by flow-mediated dilation of the brachial artery, respectively. The presence and degree of non-alcoholic fatty liver disease (NAFLD) was assessed by the fatty liver index (FLI), and subjects were divided into three subgroups: (1) without NAFLD; (2) with borderline NAFLD; and (3) with NAFLD. After 6 months of Altilix\uae supplementation, we found a significant improvement vs. placebo in most of the evaluated parameters, including body weight (2.40% (95% CI 3.79, 1.01); p &lt; 0.001), waist circumference (2.76% (95% CI 4.55, 0.96); p = 0.003), HbA1c (0.95% (95% CI 1.22, 0.67); p &lt; 0.001), plasma lipids, FLI (21.83% (95% CI 27.39, 16.27); p &lt; 0.001), hepatic transaminases, flow-mediated dilation (10.56% (95% CI 5.00, 16.12); p &lt; 0.001), and carotid intima-media thickness (39.48% (95% CI 47.98, 30.97); p &lt; 0.001). Further, the improvement in cardiometabolic variables was independent of the degree of hepatic steatosis. Altilix\uae supplementation improved hepatic and cardio-metabolic parameters in MetS subjects. Altilix\uae supplementation was a beneficial approach in the management of hepatic and cardiometabolic alterations in MetS subjects

Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia

Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low‐density lipoprotein cholesterol (LDL‐C) when added to statin therapy in patients who need additional LDL‐C reduction. Methods and Results: We conducted a systematic review and network meta‐analysis of randomized trials of lipid‐lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid‐lowering therapies that enrolled patients requiring further LDL‐C reduction while on maximally tolerated medium‐ or high‐intensity statin, of which 15 could be relevant for inclusion in LDL‐C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL‐C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (−74.1%; 95% credible interval −79.81% to −68.58%), alirocumab 75 mg (−20.03%; 95% credible interval −27.32% to −12.96%), and alirocumab 150 mg (−13.63%; 95% credible interval −22.43% to −5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe. Conclusions: PCSK9 inhibitors added to medium‐ to high‐intensity statin therapy significantly reduce LDL‐C in patients requiring further LDL‐C reduction. The network meta‐analysis showed a significant treatment difference in LDL‐C reduction for evolocumab versus alirocumab