Patients Receiving Statin Therapy Research Articles

Lower and higher-potency statins on glycemic control in type 2 diabetes: A retrospective cohort study

AimsEvidences showed a link between statins and new-onset diabetes and large clinical trials in type 2 diabetes (T2DM) suggested a mild glycemic progression in statin treated. Since this effect has not yet elucidated in real world, we investigated the effects of different statins on glycemia in T2DM clinic outpatients. MethodsIn a retrospective cohort study, we recorded at 6 and 12months modifications of fasting glucose (FPG), HbA1c, diabetes intensification therapy and target rate for HbA1c in 421 T2DM non-users and new statin users. Statins were categorized with low or high potency. ResultsCompared to statin users, no statin group showed a significant HbA1c reduction from 52.8±14.0mmol/mol to 48.2±8.5 (p=0.003) at 6months and 48.6±8.8 (p=0.007) at 12months. This trend without statins was also observed in FPG starting from 7.1±2.0mmol/l to 6.7±1.6 (p=0.12) at 6months and 6.6±1.5 (p=0.032) at 12months. Statins determined a significant diabetes treatment intensification: 48.7% vs 27.4% (p=0.002) with hazard ratio 2.4 [95% CI 1.14–5.2], p=0.022. HbA1c target was significantly lower in statin users 62.0% vs 75.4%, p=0.042. Only lower-potency statins showed a significant reduction of HbA1c from 52.0±11.1mmol/mol to 50.7±9.0 (p=0.017) and 50.7±9.5 (p=0.038) at 6 and 12months, respectively. The same effect for these statins was registered in FPG from 7.5±2.2mmol/l to 7.0±1.6 (p=0.021) at 6months and 7.2±1.5 (p=0.026) at 12months. ConclusionsIn patients receiving statin therapy a greater intensification diabetes therapy is need. This impact seems to be less pronounced by statins with lower potency.

Effect of ETC-1002 on Serum Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients Receiving Statin Therapy

ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia. This phase 2b, multicenter, double-blind trial (NCT02072161) randomized 134 hypercholesterolemic patients (LDL-C, 115 to 220mg/dl) on stable background statin therapy to 12weeks of add-on treatment with ETC-1002 120mg, ETC-1002 180mg, or placebo. The primary efficacy end point was the percent change in calculated LDL-C from baseline to week 12. For LDL-C, the least-squares mean percent change ± standard error from baseline to week 12 was significantly greater with ETC-1002 120mg (-17 ± 4%, p= 0.0055) and ETC-1002 180 mg (-24 ± 4%, p <0.0001) than placebo (-4 ± 4%). ETC-1002 also dose dependently reduced apolipoprotein B by 15% to 17%, non-high-density lipoprotein cholesterol by 14% to 17%, total cholesterol by 13% to 15%, and LDL particle number by 17% to 21%. All these reductions in ETC-1002-treated cohorts were significantly greater than those with placebo. Rates of adverse events (AEs), muscle-related AEs, and discontinuations for AEs with ETC-1002 were similar to placebo. In conclusion, ETC-1002 120mg or 180mg added to stable statin therapy significantly reduced LDL-C compared to placebo and has a similar tolerability profile.

Switching statin-treated patients from fenofibrate to the prescription omega-3 therapy icosapent ethyl: a retrospective case series.

IntroductionPatients receiving statin therapy for dyslipidaemia often require treatment with an additional agent to control triglyceride levels. Options for add-on therapy include fibrates and omega-3 fatty acids. This case series describes the effects of switching add-on therapy from fenofibrate to icosapent ethyl (the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on patient lipid profiles.MethodsThis was a retrospective analysis of patient records from a private medical practice in western New York. Statin-treated patients with dyslipidaemia who had been treated with fenofibrate and later switched to icosapent ethyl were selected for analysis. Lipid profiles before and after the switch to icosapent ethyl were compared.ResultsThe records of five patients were analysed. All patients had hypertension and were overweight, male, and at high cardiovascular risk. After the switch to icosapent ethyl (treatment duration 3.9–5.8 months), triglyceride levels decreased in four patients, and low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and total cholesterol levels decreased in all patients. High-density lipoprotein levels increased in four patients. Icosapent ethyl was well tolerated.ConclusionsSwitching from fenofibrate to icosapent ethyl as add-on to a statin therapy due to clinical need may provide an option for patients to maintain or improve lipid parameters.

Effect of n-3 Polyunsaturated Fatty Acids on Regression of Coronary Atherosclerosis in Statin Treated Patients Undergoing Percutaneous Coronary Intervention.

Background and ObjectivesStatins remain the mainstay of secondary coronary artery disease (CAD) prevention, but n-3 polyunsaturated fatty acids (ω-3 PUFA) display biological effects that may also reduce the risk of atherosclerosis and CAD. However, data on the possible antiatherosclerotic benefits of adding ω-3 PUFA to statin therapy are limited. This study aimed to investigate the potential additive effects of ω-3 PUFA on regression of atherosclerosis in CAD patients receiving statin therapy and stent implantation.Subjects and MethodsSeventy-four CAD patients undergoing percutaneous coronary intervention (PCI) with stent implantation were enrolled, prescribed statins, and randomly assigned to two groups: n-3 group (ω-3 PUFA 3 g/day, n=38) or placebo group (placebo, n=36). All patients completed the study follow-up consisting of an intravascular ultrasound at baseline and at 12 months.ResultsThere was no difference in the baseline characteristics and distribution of other medications. No significant differences were observed in primary endpoints, including changes in atheroma volume index (−12.65% vs. −8.51%, p=0.768) and percent atheroma volume (−4.36% vs. −9.98%, p=0.526), and in secondary endpoints including a change in neointimal volume index (7.84 vs. 4.94 mm3/mm, p=0.087).Conclusionω-3 PUFA had no definite additional effect on the regression of coronary atherosclerosis when added to statin in CAD patients undergoing PCI.

Abstract 9805: Lack of Correlation Between HDL Level and Fecal Cholesterol in Multiple Mouse Models Suggests Importance of HDL Functionality in Atherosclerosis Attenuation

To circumvent the residual cardiovascular disease burden in patients receiving statin therapy, HDL-raising was suggested as a plausible approach. However, lack of benefits of CETP inhibitors, Torcetrapib and Dalcetrapib, despite substantial increase in HDL, and lack of efficacy of CER-001, an apoA-I mimetic, proved disappointing. Paradoxically, apoA-I Milano subjects with low HDL have reduced CVD risk. These findings shifted the focus from HDL level to HDL function. Promoting reverse cholesterol transport (RCT) is one of the main functions of HDL, which is measured in an in vivo assay as macrophage-derived fecal 3H-cholesterol. Non-radioisotopic method to quantitate fecal cholesterol (chol) as an RCT index was found to correlate with macrophage radioisotopic method in mice. Using this method, we carried out a number of studies in several mouse models, including C57Bl, apoA-I-Tg, LDLr KO, and ob/ob, using tool compounds, LXR and PPAR-α agonists, known to enhance RCT. Animals were treated with LXR and PPAR-α agonists alone or in combination, and lipid profile, HDL level, serum chol efflux, fecal chol, and, in appropriate animal models, aortic lipid contents were measured. In C57Bl mice, LXR agonist, T1317, raised HDL by 30%, while feno decreased HDL by 30%, but fecal chol showed a 2-fold increase in both cases. Interestingly, combination (comb) treatment with LXR and PPAR-α agonists did not change HDL, but fecal chol increased by 4.5-fold. HDL in apoA-I-Tg mice increased by 40%, 80%, and 80% in LXR, PPAR-α, and comb treated groups; respective fecal chol increases were 1.8, 1.8, and 5-fold, suggesting a lack of correlation between HDL level and fecal chol. LXR, PPAR-α, and comb-treated ob/ob mice showed 40%, 35%, and 40% rise in HDL, but 3-, 3-, and 20-fold increases in fecal chol, respectively. No correlations in HDL level and fecal chol contents were noticed in LDLr KO mice as well. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr KO and ob.ob/LDLr DKO mice was associated with increased fecal chol, but not HDL level. These data suggest: a) a lack of correlation between HDL level and fecal chol; b) synergistic effect of LXR and PPAR-α agonists on RCT; c) reduced lesion area associated with increased fecal chol; and d) RCT influenced by additional mechanisms.

Abstract 12446: Frequency and Practice Level Variation in Statin Use Among Patients With Diabetes: Insights From the NCDR® PINNACLE Registry

Background: Statins reduce major adverse cardiovascular events and mortality among patients with diabetes and routine use is endorsed by clinical practice guidelines. However, national trends and practice level variation in statin use are not known. Methods: From the American College of Cardiology’s Practice Innovation and Clinical Excellence (PINNACLE) registry, we identified 256,701 patients with diabetes 40-75 years of age from 187 practices with at least 30 diabetic patients between May 1, 2008 and September 31, 2014. Among patients without contraindication to statin therapy, we calculated the percentage of patients receiving statin therapy at each practice. We then examined variation in statin use across practices using multivariable hierarchical regression to determine median rate ratio (MRR), which quantifies the likelihood that 2 randomly chosen practices would differ in treating an identical patient. Results: Overall, 141,900 (55%) diabetic patients were on statins. Those prescribed statins were more likely to be men, of white race, have coexisting dyslipidemia or hypertension, be on non-statin lipid lowering medications and have lower LDL-C levels (91 vs. 103 mg/dL, P&lt;0.001 for all). The median practice level use of statin was 57% (IQR, 48-63%), which remained similar throughout the study period. The adjusted MRR for statin use was 1.62 (95% CI: 1.57-1.67), indicating 62% differences in likelihood of statin treatment between 2 identical patients at 2 random practices (Figure). Conclusion: In a national outpatient registry, just over half of patients with diabetes 40-75 years old were treated with statins, with wide variation across cardiology practices. These results suggest that quality improvement initiatives are needed to support guideline recommended use of statins among patients with diabetes.

Effect of Statin Therapy on Fibrous Cap Thickness in Coronary Plaques Using Optical Coherence Tomography: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to evaluate the effect of statin therapy on coronary fibrous cap thickness (FCT) as assessed by optical coherence tomography (OCT) and the relationship between FCT and traditional coronary risk factors. Increasing evidence has shown that statin therapy results in a marked increase in coronary FCT. However, the relationship between this increase in FCT and the lipid profile has not been clearly elucidated. A literature search of PubMed, Embase, the Cochrane Library, and Web of Science up to March 17, 2015 was performed. Studies providing data on FCT using OCT at baseline and follow-up in patients receiving statin therapy were included. Weighted mean difference (WMD) with a random-effects model was used. Six OCT studies were included. The FCT in coronary plaques was significantly increased after statin therapy (WMD: 58.79 μm, 95% CI 33.82-83.76 μm, P < 0.001). When compared with the placebo group, the increase in FCT was also greater in the statin group (WMD: 72.28 μm, 95% CI 44.97-99.58 μm, P < 0.001). Meta regression analysis demonstrated no significant correlations between the increase in FTC and the changes in total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels during follow-up. Similarly, there were no significant correlations between the increase in FCT and age, male gender, hypertension, diabetes, and smoking. Statin therapy induced a significant increase in coronary FCT evaluated by OCT. This increase in FCT was independent of traditional coronary risk factors including the lipid profile.

Combining citrulline with atorvastatin preserves glucose homeostasis in a murine model of diet-induced obesity.

NO is a crucial regulator of energy and lipid metabolism, whose homeostasis is compromised during obesity. Combination of citrulline and atorvastatin potentiated NO production in vitro. Here we have assessed the effects of this combination in mice with diet-induced obesity (DIO). C57BL/6J male mice were given a standard diet (control) or a high fat-high sucrose diet (DIO) for 8 weeks. DIO mice were then treated with DIO alone, DIO with citrulline, DIO with atorvastatin or DIO with citrulline and atorvastatin (DIOcit-stat) for 3 weeks. Thereafter, body composition, glucose tolerance, insulin sensitivity and liver fat metabolism were measured. DIOcit-stat mice showed lower body weight, fat mass and epididymal fat depots compared with other DIO groups. Unlike other DIO groups, glucose tolerance and insulin sensitivity of DIOcit-stat, along with blood glucose and insulin concentrations in response to feeding, were restored to control values. Refeeding-induced changes in liver lipogenic activity were also reduced in DIOcit-stat mice compared with those of DIO animals. This was associated with decreased gene expression of the transcription factor SREBP-1, liver X receptor α, ChREBP and of target lipogenic enzymes in the liver of DIOcit-stat mice compared with those of other DIO groups. The citrulline-atorvastatin combination prevented fat mass accumulation and maintained glucose homeostasis in DIO mice. Furthermore, it potentiated inhibition of hepatic de novo lipogenesis activity. This combination has potential for preservation of glucose homeostasis in patients receiving statin therapy.

The Effect of Statin Therapy on Coronary Plaque Composition Using Virtual Histology Intravascular Ultrasound: A Meta-Analysis.

ObjectivePrevious studies have indicated that statin therapy may promote plaque regression. However, the impact of statin therapy on plaque composition has not been clearly elucidated. We performed a meta-analysis to investigate the effect of statin therapy on coronary plaque composition as assessed by virtual histology intravascular ultrasound (VH-IVUS).MethodsOnline databases were searched from inception to March 1, 2015. Studies providing VH-IVUS volumetric analyses of coronary plaque composition at baseline and follow-up in patients receiving statin therapy were included. Weighted mean difference (WMD) using a random-effects model was used.ResultsTen studies involving 682 patients were included. There was a substantial reduction in fibrous volume between baseline and follow-up (WMD: -2.37 mm3, 95% confidence interval (CI) -4.01 to -0.74 mm3, P=0.004), and a significant increase in dense calcium (DC) volume (WMD: 0.89 mm3, 95% CI 0.70 to 1.08 mm3, P<0.00001). No significant change was seen in fibro-fatty and necrotic core (NC) volumes. In stratified analyses, the fibrous volume was decreased significantly (WMD: -3.39 mm3, 95% CI -6.56 to -0.21 mm3, P=0.04) and the absolute DC volume (WMD: 0.99 mm3, 95% CI 0.23 to 1.76 mm3, P=0.01) was increased in the subgroup with ≥12 months follow-up, whereas no significant change was observed in the subgroup with < 12 months follow-up. Similarly, a substantial decrease in fibrous volume (WMD: -2.01 mm3, 95% CI -3.05 to -0.96 mm3, P< 0.0002) and an increase in DC volume (WMD: 0.90 mm3, 95% CI 0.70 to 1.10 mm3, P< 0.00001) were observed in the subgroup with high-intensive statin therapy, while the change in fibrous and DC volumes approached statistical significance (P=0.05 and P=0.05, respectively) in the subgroup with low-intensive statin therapy.ConclusionsStatin treatment, particularly of high-intensity and long-term duration, induced a marked modification in coronary plaque composition including a decrease in fibrous tissue and an increase in DC.

Statins can increase the risk of herpes zoster infection in Asia.

This study evaluated whether statin therapy increases the risk of herpes zoster (HZ) infection in Asia. This retrospective cohort study used the Longitudinal Health Insurance Database (LHID2000). From the LHID2000, patients aged 20years were divided into two cohorts according to their statin use and were matched at a 1:1 ratio according to propensity scores, which were calculated using a logistic regression for estimating the probability of treatment assignment. The primary outcome was HZ infection. All patients were followed from the index date until the date of HZ infection, withdrawal from the insurance system, or the end of 2011. The study included 53,069 patients receiving statin therapy as a statin cohort and 53,069 patients without statin therapy as a nonstatin cohort. The mean follow-up durations for the statin cohort and nonstatin cohort were 4.89 [standard deviation (SD) = 2.86] years and 4.75 (SD = 2.90) years, respectively. The patients in the statin cohort had a 21% higher risk of contracting HZ infection than the patients in the nonstatin cohort [95% confidence interval (CI) = 1.13-1.29]. The incidence of HZ infection increased with the Charlson comorbidity index (CCI) score in both cohorts. A high mean defined daily dose of the six types of statins considered in this study was associated with a significantly increased risk of HZ infection. Statin therapy can increase HZ infection in Asia. More benefit-risk evaluations for statin use are necessary in Asia.

Puesta al día en estatinas. Nuevas recomendaciones

In November 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) released a new clinical practice guideline for the treatment of blood cholesterol in people at high risk for cardiovascular disease. The guideline identifies: 1) 4 major groups of patients for whom statins should be prescribed to reduce the chance of stroke and heart attacks, 2) elimination of routine assessments of LDL cholesterol levels in patients receiving statin therapy, because target levels are no longer emphasized, and 3) avoidance of non-statin LDL cholesterol-lowering agents in statin-tolerant patients.This update represents the first major guideline revision since the released of the Adult Treatment Panel III report in 2002, which has been a subject of controversy. The main concerns focused on problems with the risk calculation, ethics (conflicts of interest), and inferences (too many people offered treatment).The guideline also emphasizes the importance of adopting a heart-healthy lifestyle to control high blood cholesterol, and create an opportunity to advance patient-centered care and share decision making. The new guideline gives the clinicians the tool to engage in discussing with individual patients about the potential benefits and potential harms of statin use to prevent future cardiovascular events.

Atherogenic Ratios in Patients with Recurrent Acute Coronary Syndrome and Receiving Statin Therapy: Clinical Usefullness as Cardiovascular Predictors

Patients who have already suffered a vascular event require more and better control of cardiovascular risk factors. Different atherogenic indexes such as TC/HDLc, LDLc/HDLc, apoB/apoA-I, LDLc/apoB and non-HDLc/HDLc have been used to follow-up the patients because of their predictive capacity of the lipid profile. The aim of this study was to evaluate atherogenic ratios as a marker of the lipid residual risk in high-risk patients receiving statin therapy and to know the changes produced by previous lipid-lowering drugs treatment for a previous coronary event. The study including patients admitted to coronary care units of six Spanish tertiary hospitals for Acute Coronary Syndrome (ACS). A total of 633 ACS patients were included; of these, 478 (75.8%) had presented a myocardial infarction and 153 (24.2%) angina. A previous ACS had occurred in 43.1% of cases, and was the first episode in 56.9% of the studied patients. Among patients with known ischemic heart disease, 187 (52.2%) were receiving lipid-lowering drugs, mainly statins (182 patients, 50.7%). Of those with a first ACS, 59 (21.7%) were on lipid-lowering drugs: 55 (20.1%) statins and 4 (1.7%) fibrates. Patients with recurrent ACS had similar triglyceride and HDLc levels, but significantly lower total cholesterol and LDLc concentrations compared with those presenting the first ACS. Patients with recurrent ACS had significantly lower non-HDLc levels, TC/HDLc and LDLc/HDLc, but higher HDLc/TC and HDLc/LDLc ratios compared with first ACS patients. In patients taking statins the lipid residual vascular risk was related with the persistence of cardiovascular risk factors, and related with lipid profile with dyslipemia no-LDL dependent. So, we can conclude that the correction of lipid profile by statin is not per se sufficient to control cardiovascular risk.

Effects of Coenzyme Q10 on Statin-Induced Myopathy: A Meta-analysis of Randomized Controlled Trials

ObjectiveTo evaluate the efficacy of coenzyme Q10 (CoQ10) supplementation on statin-induced myopathy. Participants and MethodsWe searched the MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin-induced myalgia. Two independent reviewers extracted data on study characteristics, methods, and outcomes. ResultsWe included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (mean difference, 11.69 U/L [to convert to μkat/L, multiply by 0.0167]; 95% CI, –14.25 to 37.63 U/L; P=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, –0.53; 95% CI, –1.33 to 0.28; P=.20). No dose-effect association between changes in plasma CK activity (slope, –0.001; 95% CI, –0.004 to 0.001; P=.33) or in the indices of muscle pain (slope, 0.002; 95% CI, –0.005 to 0.010; P=.67) and administered doses of CoQ10 were observed. ConclusionThe results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis.

Frequency-Domain Optical Coherence Tomographic Analysis of Plaque Microstructures at Nonculprit Narrowings in Patients Receiving Potent Statin Therapy

Potent statin therapy has been demonstrated to reduce cardiovascular events. Although statins have been considered to stabilize atherosclerotic plaque, this effect has not been well characterized invivo. We investigated the relation between potent statin therapy and plaque microstructures imaged by frequency-domain optical coherence tomography. Two hundred ninety nonculprit lipid plaques in 275 patients with stable coronary artery disease receiving atorvastatin or rosuvastatin were analyzed. Patients were stratified into no statin, low-, and high-dose statin groups. Plaques in the high-dose statin group demonstrated a smaller lipid arc (p= 0.02) and a greater fibrous cap thickness (p= 0.01). In patients receiving statin therapy, high-dose statin therapy was associated with a greater fibrous cap thickness in patients with smaller (148.2 ± 30.5 vs 105.3 ± 41.1 μm, p= 0.004) but not larger lipid index (91.1 ± 32.6 vs 78.1 ± 43.3 μm, p= 0.21). In conclusion, potent statin therapy is associated with less vulnerable plaque features on frequency-domain optical coherence tomography imaging. This finding varies according to the size of plaque lipid content, being less effective in lipid-loaded plaques.

Effect of olmesartan on the levels of circulating endothelial progenitor cell after drug-eluting stent implantation in patients receiving statin therapy

BackgroundThe endothelial progenitor cell (EPC) plays an important role in repairing vascular injury. Statins and angiotensin II receptor blockers increase the level of circulating EPCs. However, it is unknown whether the angiotensin II receptor blocker olmesartan synergistically acts with statins to increase the levels of circulating EPCs. Moreover, the association between the levels of circulating EPCs and endothelial dysfunction after implantation of drug-eluting stents (DESs) has not been evaluated. MethodsNine patients with stable coronary artery disease underwent percutaneous coronary intervention (PCI) and received DES implantation. All patients received olmesartan in addition to statin therapy after PCI. The dose of olmesartan was based on the physician's discretion as per the patients’ blood pressure. The levels of circulating EPCs were analyzed at baseline, post-PCI, and 1, 2, 3, and 8 months after PCI. Coronary angiography and the acetylcholine provocation test were performed on all patients at 8 months. ResultsAlthough the angiotensin II level significantly changed, the levels of circulating EPCs did not change during 8 months of olmesartan treatment (3.1±0.6cells/ml, 2.5±0.8cells/ml, 2.0±0.6cells/ml, 2.9±0.9cells/ml, 3.0±0.4cells/ml, 3.4±0.8cells/ml, p=0.64). The patients were subsequently divided into two groups based on whether the level of circulating EPCs was less or greater than 4cells/ml at 8 months. There were no significant differences in the mean vessel diameter of each segment (proximal, proximal edge, distal edge, and distal) after the acetylcholine provocation test between the two groups. ConclusionsLow-to-moderate doses of olmesartan might not increase the level of circulating EPCs in patients receiving statin therapy. There might be no association between the levels of circulating EPCs and the degree of coronary vasospasm in the acetylcholine provocation test 8 months after DES implantation.

Statin Use and Risk of Delirium in the Critically Ill

Delirium is common in intensive care unit (ICU) patients and is a predictor of worse outcomes and neuroinflammation is a possible mechanism. The antiinflammatory actions of statins may reduce delirium. To determine whether critically ill patients receiving statin therapy had a reduced risk of delirium than those not on statins. A prospective cohort analysis of data from consecutive ICU patients admitted to a UK mixed medical and surgical critical care unit between August 2011 and February 2012; the Confusion Assessment Method for ICU was used to determine the days each patient was assessed as being free of delirium during ICU admission. Delirium-free days, daily administration of statins, and serum C-reactive protein (CRP) were recorded. Four hundred and seventy consecutive critical care patients were followed, of whom 151 patients received statins. Using random-effects multivariable logistic regression, statin administration the previous evening was associated with the patient being assessed as free of delirium (odds ratio, 2.28; confidence interval, 1.01-5.13; P < 0.05) and with lower CRP (β = -0.52; P < 0.01) the following day. When the association between statin and being assessed as free of delirium was controlled for CRP, the effect size became nonsignificant (odds ratio, 1.56; confidence interval, 0.64-3.79; P = 0.32). Ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients. An ongoing clinical trial, informed by this study, is investigating if statins are a potential therapy for delirium in the critically ill.

Examination of the FDA Warning for Statins and Cognitive Dysfunction

Background: The ACC/AHA released new guidelines in December of 2013 for treatment of high blood cholesterol to simplify identification and treatment of patients most likely to benefit from statins. These guidelines may result in more patients receiving statin therapy, and at younger ages. In 2012, the U.S. Food and Drug Administration (FDA) mandated warnings for all statin drugs for possible adverse effects on cognitive performance. Statins can be classified as having greater lipophilic or hydrophilic solubility properties with lipophilic statins more readily crossing the blood brain barrier, and possibly differentially inducing detrimental cognitive effects. Objective: We sought to analyze generalizability of the FDA statin class warning. Methods: De-identified publicly-available data were analyzed from the FDA Adverse Event Reporting System (AERS) in relation to reports of cognitive dysfunction (primary outcome), and by type of statin (lipophilic, hydrophilic) versus “control” drugs used in the general population. Results: Significantly higher proportional reporting ratios (PRRs) were observed for lipophilic statins, which more readily cross the blood-brain barrier, (range: 1.47-3.51) compared to hydrophilic statins (range: 0.69-1.64). However, fluvastatin, lovastatin, and pitavastatin (lipophilic) had relatively few adverse reports. The signal of higher risk of cognitive dysfunction was observed for the lipophilic statin atorvastatin (PRR = 2.59, 95% confidence interval: 2.44-2.75) followed by simvastatin (PRR = 2.22, 95% confidence interval: 2.04-2.31). Hydrophilic statins (rosuvastatin, pravastatin) showed essentially no evidence suggestive of heightened risk of cognitive dysfunction. Fluvastatin, lovastatin, and pitavastatin had relatively few adverse reports, and no evidence of a higher proportion of cognitive dysfunction reports compared to the control drugs in aggregate (PRR range: 0.22 to 1.48). Conclusions: Inconsistent with the FDA class warning, highly lipophilic statins with specific pharmacokinetic properties (atorvastatin, simvastatin) appear to confer a significantly greater risk of adverse cognitive effects compared to other lipophilic statins and those with hydrophilic solubility properties.

Prevalence of persistent lipid abnormalities in statin‐treated patients: Belgian results of the Dyslipidaemia International Study ( DYSIS )

AimA substantial number of cardiovascular events are not prevented by statin therapy, which is still regarded as the first-line therapy for hyperlipidaemia. Insights into the prevalence of lipid abnormalities of statin-treated patients in Belgium are lacking and may shed light on an unmet medical need for optimal use of current lipid-lowering therapies. This study aims to assess the prevalence and types of persistent lipid abnormalities in patients receiving statin therapy in a real-life primary care setting in Belgium.MethodsThis cross-sectional cohort study was designed to estimate the prevalence of specific lipid abnormalities in statin-treated patients in Belgium. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides were recorded from the patients' medical record. Patient's total cardiovascular risk and corresponding lipid treatment goals were defined based on the recent European Society of Cardiology/European Atherosclerosis Society recommendations.ResultsOverall, 56.2% of the statin-treated patients were not at goal for LDL-C. Low HDL-C (< 40 mg dl−1 in men, < 45 mg dl−1 in women) and elevated triglycerides (> 150 mg dl−1) were seen in 16.3% and 29.0% of patients, respectively. Very high-risk patients were more likely to have LDL-C not at goal (71.4% of them), while 60.0% of high-risk patients and 34.1% of moderate-risk patients were not at goal for LDL-C. Use of ezetimibe (10 mg) was strongly associated with meeting LDL-C goals (OR 16.9, p < 0.0001).ConclusionIn Belgium, lipid abnormalities remained highly prevalent despite statin treatment, with more than half of all patients not reaching their LDL-C treatment goal. This finding clearly indicates that more aggressive lipid-lowering treatment is required in clinical daily practice to achieve the goals of the current guidelines.

Incremental Lowering of Low-Density Lipoprotein Cholesterol With Ezetimibe 20 mg vs 10 mg Daily in Patients Receiving Concomitant Statin Therapy

BackgroundEzetimibe is typically administered at a dose of 10 mg daily, with few reports of use at other doses. We compared plasma concentrations of low-density lipoprotein (LDL) cholesterol and other lipid variables in patients with dyslipidemia who were receiving ezetimibe 10 mg and then 20 mg daily. MethodsA retrospective chart review identified 27 patients who received ezetimibe 10 mg and then 20 mg daily at different times; 15 participants were receiving stable statin therapy and 12 were not receiving concomitant statins. Plasma concentrations of lipids, creatine kinase (CK), and aspartate transaminase (AST) were determined. Plasma concentrations of ezetimibe and ezetimibe glucuronide were measured in a second group of patients. ResultsPatients taking statins and ezetimibe 20 mg had further reductions in total and LDL cholesterol of 7.1% and 10.3%, respectively (both P < 0.05) than did those receiving the 10-mg dose. No difference between 20-mg and 10-mg dosing was seen among patients not receiving statins. Plasma concentrations of ezetimibe and its active metabolite were about 2-fold higher (P < 0.05) in patients taking ezetimibe 20 mg than in those receiving 10 mg daily. All patients tolerated ezetimibe 20 mg without side effects. ConclusionsEzetimibe 20 mg daily reduced total and LDL cholesterol further in patients receiving statin therapy compared with 10 mg daily. Prospective studies are required to show whether the higher plasma levels of ezetimibe and its active metabolite in patients taking the 20-mg dose have any detrimental effects. Increasing the ezetimibe dose to 20 mg daily might be an interesting potential approach for patients who fail to reach lipid targets on ezetimibe 10 mg daily along with maximally tolerated doses of statin.

AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy

Background— Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). Methods and Results— As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively ( P &lt;0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively ( P &lt;0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P &lt;0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. Conclusions— AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient’s atherogenic lipid profile. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01380730.