Early intensive statin treatment for six months improves long-term clinical outcomes in patients with acute coronary syndrome (Extended-ESTABLISH trial): A follow-up study

Background

The ESTABLISH trial found using volumetric intravascular ultrasound that atorvastatin therapy started early and continued for 6 months significantly reduced plaque volume in patients with acute coronary syndrome (ACS). However, the benefits of early statin administration on long-term outcomes remain unclear. We therefore examined whether the early initiation of statin in patients with ACS improves long-term prognosis.

Methods and results

The Extended-ESTABLISH trial included 180 patients with ACS who underwent emergency percutaneous coronary intervention (PCI). These patients were randomized here to groups given either early intensive lipid-lowering therapy (n = 90; atorvastatin 20 mg/day) or standard care (control, n = 90) within 48 h of events. Baseline characteristics between the two groups did not significantly differ at the time of ACS onset. Six months after PCI, all patients were treated with statins to achieve an LDL-C value of <100 mg/dL. We compared the first occurrence of major adverse cardiac and cerebrovascular events (MACCE). Prognostic data were fully documented during the entire follow-up period (mean, 1538 ± 707 days). Cumulative event-free survival was significantly higher in the atorvastatin, than in the control group (p = 0.041; log-rank test). Furthermore, by adjusting for validated prognosticators, early statin administration was identified as a good predictor of MACCE (HR 0.46, 95%CI 0.23–0.86; p = 0.015).

Conclusions

In-hospital initiation of statin therapy immediately after ACS conferred long-term benefits and 6 months of intensive lipid-lowering therapy improved long-term clinical outcomes after PCI in patients with ACS.     

Accuracy of Statin Assignment Using the 2013 AHA/ACC Cholesterol Guideline Versus the 2001 NCEP ATP III Guideline : Correlation With Atherosclerotic Plaque Imaging

Background

Accurate assignment of statin therapy is a major public health issue.

Objectives

The American Heart Association and the American College of Cardiology released a new guideline on the assessment of cardiovascular risk (GACR) to replace the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III recommendations. The aim of this study was to determine which method more accurately assigns statins to patients with features of coronary imaging known to have predictive value for cardiovascular events and whether more patients would be assigned to statins under the new method.

Methods

The burden of coronary atherosclerosis on computed tomography angiography was measured in several ways on the basis of a 16-segment model. Whether to assign a given patient to statin therapy was compared between the NCEP and GACR guidelines.

Results

A total of 3,076 subjects were studied (65.3% men, mean age 55.4 ± 10.3 years, mean age of women 58.9 ± 10.3 years). The probability of prescribing statins rose sharply with increasing plaque burden under the GACR compared with the NCEP guideline. Under the NCEP guideline, 59% of patients with ≥50% stenosis of the left main coronary artery and 40% of patients with ≥50% stenosis of other branches would not have been treated. The comparable results for the GACR were 19% and 10%. The use of low-density lipoprotein targets seriously degraded the accuracy of the NCEP guideline for statin assignment. The proportion of patients assigned to statin therapy was 15% higher under the GACR.

Conclusions

The new American Heart Association/American College of Cardiology guideline matches statin assignment to total plaque burden better than the older guidelines, with only a modest increase in the number of patients who were assigned statins.     

Effectiveness of combined therapy with angiotensin-converting enzyme inhibitors and statins in reducing mortality in diabetic patients with critical limb ischemia: An observational study

Aims

To investigate the effect of combined treatment with angiotensin-converting enzyme inhibitors (ACE) and statins on mortality in diabetic patients with critical limb ischemia (CLI).

Methods

Prospective observational study of 553 consecutive diabetic patients admitted because of CLI followed for a mean of 2.2 years. All patients underwent peripheral revascularization and antithrombotic therapy was prescribed or continued and therapy with statin and ACE was recorded. Mortality from any cause was assessed and Kaplan–Meier analyses were performed to compare the relationship between survival and recorded variables.

Results

One hundred thirty-nine patients did not have therapy with statin or an ACE, 78 had therapy with statin without ACE, 164 had therapy with ACE without statin and 172 patients had therapy with both statin and ACE. One hundred thirty-six patients died, 45/139 with neither statin nor ACE, 40/164 with ACE only, 26/78 with statin only, and 25/172 with both statin and ACE. Multivariate analysis confirmed the independent role of age, history of stroke, renal insufficiency and dialysis. Combined treatment with ACE and statin appeared to have a protective role.

Conclusions

In patients with diabetes and CLI mortality after two years is high. Life expectancy was better in patients receiving combined therapy with ACE and statin but not with therapy with only a statin or an ACE.     

Insulin treatment affects leukocyte telomere length in patients with type 2 diabetes: 6-year longitudinal study

Objective

Many studies demonstrated a close relationship between type 2 diabetes mellitus (T2DM) and leukocyte telomere length (LTL). However, how the LTL changes in T2DM and what are the potential causal factors in it, particularly in patients during a long period treatment, have not been studied. Here we performed a longitudinal observation of LTL in trained T2DM patients during a 6-year follow-up and evaluated the possible risk factors that were associated with LTL alteration.

Dose-related effect of statins in venous thrombosis risk reduction

Background

Atherosclerosis and venous thromboembolism share similar pathophysiology based on common inflammatory mediators. The dose-related effect of statin therapy in venous thromboembolism remains controversial. This study investigated whether the use of antiplatelet therapy and statins decrease the occurrence of venous thromboembolism in patients with atherosclerosis.

Methods

We conducted a retrospective cohort study reviewing 1795 consecutive patients with atherosclerosis admitted to a teaching hospital between 2005 and 2010. Patients who had been treated with anticoagulation therapy were excluded. Patients who either used statins for <2 months or never used them were allocated to the nonuser group.

Results

The final analysis included 1100 patients. The overall incidence of venous thromboembolism was 9.7%. Among statin users, 6.3% (54/861) developed venous thromboembolism, compared with 22.2% (53/239) in the nonuser group (hazard ratio [HR] 0.24; P <.001). After controlling for confounding factors, statin use was still associated with a lower risk of developing venous thromboembolism (HR 0.29; P <.001). High-dose statin use (average 50.9 mg/day) (HR 0.25; P <.001) lowered the risk of venous thromboembolism compared with standard-dose statins (average 22.2 mg/day) (HR 0.38; P <.001). Dual antiplatelet therapy with aspirin and clopidogrel decreased occurrence of venous thromboembolism (HR 0.19; P <.001). Interestingly, combined statins and antiplatelet therapy further reduced the occurrence of venous thromboembolism (HR 0.16; P <.001).

Conclusions

The use of statins and antiplatelet therapy is associated with a significant reduction in the occurrence of venous thromboembolism with a dose-related response of statins.     

Efficacy and Plasma Drug Concentrations With Nondaily Dosing of Rosuvastatin

Background

Nondaily statin dosing is an alternative for patients unable to tolerate daily dosing. The higher potency and longer half-life of rosuvastatin lends itself to this regimen. The basis of this improved tolerability is not understood, but might be related to lower plasma drug concentrations. We examined the efficacy of nondaily rosuvastatin in previously statin-intolerant patients and determined plasma drug concentrations at various dose regimens.

Methods

A retrospective analysis at a specialty lipid clinic identified 58 patients eligible for evaluation after therapy with nondaily rosuvastatin. Plasma rosuvastatin levels were measured by liquid chromatography-mass spectrometry in 12 patients taking 10 mg nondaily rosuvastatin and in 11 and 12 age- and sex-matched patients taking 10 mg and 5 mg rosuvastatin daily, respectively. Whole body cholesterol synthesis was estimated from serum lathosterol measured by liquid chromatography-mass spectrometry.

Results

In patients with a previous history of statin intolerance, nondaily rosuvastatin (average of 29.4 mg per week) lowered low-density lipoprotein cholesterol by 34.4 ± 21.3% (P < 0.001). Serum lathosterol levels were significantly higher in patients on nondaily regimens, as expected. However, mean plasma rosuvastatin levels of patients taking 10 mg nondaily did not significantly differ from those taking 10 mg daily.

Conclusions

In statin intolerant patients, nondaily rosuvastatin resulted in clinically relevant reductions in low-density lipoprotein cholesterol levels, with improved compliance. Whole body cholesterol synthesis was higher in patients taking nondaily rosuvastatin, but no differences in plasma drug concentrations were observed, suggesting that the improved tolerability was independent of plasma rosuvastatin levels.     

Association of plasma soluble E-selectin and adiponectin with carotid plaque in patients with systemic lupus erythematosus

Background

Systemic lupus erythematosus (SLE) is associated with premature atherosclerosis but the mechanisms underlying this association are not understood. The role of endothelial dysfunction is hypothesized.

Methods

In predominantly non-Caucasian patients with SLE (N = 119) and controls (N = 71), carotid ultrasonography was performed and circulating endothelial cells (CECs), soluble endothelial protein C receptor and gene polymorphism at A6936G, soluble E-selectin (sE-selectin), and adiponectin were assessed.

Results

Carotid plaque was more prevalent among patients than controls (43% vs 17%, p = 0.0002). Mean CCA IMT was greater in patients compared to controls (0.59 ± 0.19 mm vs 0.54 ± 0.11 mm, p = 0.03). Among SLE patients, plaque was not associated with smoking, body-mass index, LDL, triglycerides, homocysteine, C-reactive protein, anti-ds DNA antibody, C3, C4, SLE activity, or medications. Age and levels of soluble E-selectin and adiponectin were significantly higher in the SLE patients with plaque compared to those without plaque in univariate and multivariate analyses. sE-selectin and adiponectin were found to serve as independent predictors of carotid plaque and that elevations were persistent over more than one visit. Unexpectedly, these biomarkers were present despite clinical quiescence.

Conclusion

Premature atherosclerosis is a consistent feature of SLE and extends across ethnicities. Higher levels of adiponectin may represent a physiological attempt to limit further endothelial damage already reflected by the elevation in sE-selectin and the observed increase in plaque represents overwhelming of this reparative process by atherogenic stimuli.     

Decreased circulating lipoprotein-associated phospholipase A2 levels are associated with coronary plaque regression in patients with acute coronary syndrome

Objective

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory enzyme, of which increases are associated with cardiovascular events. However, the relationship between circulating Lp-PLA2 levels and coronary plaque volume has not been clarified in patients with acute coronary syndrome (ACS).

Methods

We studied 40 patients with ACS (age, 61.4 ± 8.0 years; male, 87.5%; statin use, 45.0%) who had undergone successful percutaneous coronary intervention (PCI). Plaque volume (PV) in non-culprit sites of PCI lesions was precisely determined using grayscale intravascular ultrasound (IVUS) at onset and at six months later. We then analyzed associations among PV, lipid profiles and Lp-PLA2 levels.

Results

Circulating Lp-PLA2 levels and PV significantly decreased between baseline and six months of follow-up (458.6 ± 166.7 IU/L vs. 378.4 ± 158.5 IU/L, p < 0.001 and 82.2 ± 34.8 mm³ vs. 77.3 ± 33.1 mm³, p < 0.001, respectively). The % change in PV positively and significantly correlated with % change in LDL-C and in the LDL-C/HDL-C ratio (r = 0.444, p = 0.004 and r = 0.462, p = 0.003, respectively). Furthermore, % changes in Lp-PLA2 and in PV correlated even more closely (r = 0.496, p = 0.001). The absolute change in PV also significantly correlated with the change in Lp-PLA2 levels (r = 0.404, p = 0.009).

Conclusions

Circulating Lp-PLA2 levels are associated with changes in coronary plaque determined by IVUS in patients with ACS.     

Mechanisms of statin-induced myalgia assessed by physiogenomic associations

Objective

We investigated genetic variants predictive of muscular side effects in patients treated with statins. We utilized a physiogenomic approach to prototype a multi-gene panel correlated with statin-induced myalgia.

Background

Statin-induced myalgia occurs in ∼10% of lipid clinic outpatients. Its clinical manifestation may depend in part upon gene variation from patient to patient.

Methods

We genotyped 793 patients (377 with myalgia and 416 without) undergoing statin therapy at four U.S. outpatient clinic sites to evaluate 31 candidate genes from the literature for their association with statin-induced common myalgia.

Results

Three previously hypothesized candidate genes were validated: COQ2 (rs4693570) encoding para-hydroxybenzoate-polyprenyltransferase, which participates in the biosynthesis of coenzyme Q10 (p < 0.000041); ATP2B1 (rs17381194) which encodes a calcium transporting ATPase involved in calcium homeostasis (p < 0.00079); and DMPK (rs672348) which encodes a protein kinase implicated in myotonic dystrophy (p < 0.0016).

Conclusions

The candidate genes COQ2, ATP2B1, and DMPK, representing pathways involved in myocellular energy transfer, calcium homeostasis, and myotonic dystonia, respectively, were validated as markers for the common myalgia observed in patients receiving statin therapy. The three genes integrated into a physiogenomic predictive system could be relevant to myalgia diagnosis and prognosis in clinical practice.     

Genetic and environmental determinants of total and high-molecular weight adiponectin in families with low HDL-cholesterol and early onset coronary heart disease

Objective

Plasma adiponectin and high-density lipoprotein cholesterol (HDL-C) exhibit a well-known positive metabolic correlation. Neither heritability nor genome-wide linkage analysis for the high-molecular weight (HMW) adiponectin is available. This work estimates the genetic and environmental determinants and the heritabilities of the adiponectins and lipid traits in Finnish families with early onset coronary heart disease (CHD) and low HDL-C.

Methods

Heritability and genome-wide univariate linkage analysis was performed for total and HMW adiponectin in extended families from Northern Finland with early onset CHD and low HDL-C using a variance components approach. The genetic and environmental correlations between the plasma adiponectins and various lipid traits were also studied and a bivariate analysis for HDL-C and the adiponectins carried out.

Results

In the partial correlation analysis (adjusted for sex, age, BMI and statin use) the adiponectins showed a stronger correlation with HDL-C (total 0.57, p = 0.001, HMW 0.51, p < 0.005) than with any other lipid trait in unrelated subjects. Our estimates detected strong heritability for total (0.53 ± 0.10), HMW (0.51 ± 0.10) and the HMW/total adiponectin ratio (0.68 ± 0.11). Univariate linkage analysis showed suggestive evidence of linkage on chromosome 11p15 for total adiponectin and on 3q13.2-q24 and 6p21 for the HMW adiponectin. The strongest environmental cross-correlation between the adiponectins and lipids was seen between HDL-C and total adiponectin (ρ_e = 0.64, p < 0.05), whereas the strongest genetic correlation was detected between low-density lipoprotein cholesterol and the HMW adiponectin (ρ_g = −0.48, p < 0.05).

Conclusion

No significant genetic correlations between HDL-C and the adiponectins were observed. Therefore, the metabolic association between HDL-C and adiponectin is most likely regulated by complex genetic pathways and environmental factors.     

Nonadherence to statin therapy: discontinuation after a single fill

Introduction

Adherence to statin medications is known to be suboptimal. What is less known is the rate of discontinuation immediately after therapy has been initiated. The primary objective of this study was to determine what proportion of nonadherence in the first year of statin therapy was due to discontinuation after a single fill.

Methods

We identified new statin users within low-risk (hypertension [HTN]), medium-risk (coronary heart disease [CHD]), and high-risk (heart failure [HF]) cohorts during a 9-year period. All data came from administrative health care databases.

Results

The cohorts included 9445 HTN, 1141 CHD, and 778 HF patients. At 1 year, the proportions of patients with less than 80% adherence to statin medications were 47.9% (HTN), 38.3% (CHD), and 50.0% (HF). Among all patients classified as nonadherent at 1 year, 18.0% of HTN, 16.3% of CHD, and 28.2% of HF patients had discontinued statin medications after only 1 dispensation. Within 3 months of starting statin therapy, 29.7%, 40.3%, and 47.5% of all nonadherent HTN, CHD, and HF patients, respectively, had discontinued the new statin medication. After regression analysis, the only independent covariate that was consistently associated with discontinuation after a single fill was receiving fewer medical follow-up visits.

Conclusions

Immediate discontinuation after a single fill contributes disproportionately to statin nonadherence. This suggests an important time to prevent nonadherence is within the first month of treatment initiation.     

Recurrence of angina pectoris after percutaneous coronary intervention is reduced by statins in Japanese patients

Background

Statins have been reported to reduce cardiovascular events in patients with coronary artery disease (CAD). Percutaneous coronary intervention (PCI) is commonly used to relieve ischemic symptoms in patients with CAD. However, there is little information on the effect of statins on cardiovascular events after PCI, even in the era of coronary stent implantation.

Methods

A total of 1019 patients with acute or chronic CAD and modest total cholesterol levels (180–240 mg/dl) were enrolled and randomly assigned to treatment with or without statins. We evaluated the effect of any available statin on the incidence of cardiovascular events after PCI. The primary endpoint was a composite of cardiovascular death, nonfatal acute myocardial infarction (MI), recurrent angina pectoris requiring emergency rehospitalization (rAP), heart failure, and stroke.

Results

Indications for PCI were stable angina in 54%, ST-elevation MI in 41% and non-ST-elevation MI/unstable angina pectoris in 5%. After 2 years of statin treatment, low-density lipoprotein cholesterol (LDL-C) decreased from 133 to 96 mg/dl. Stents were implanted in 84% of all cases. The primary endpoint event rate was 9.5% in the statin group and 14.7% in the non-statin group (p = 0.0292). Of all primary endpoint events, only rAP was significantly suppressed by statins (p = 0.0027). In rAP patients, coronary angiography revealed that statins suppressed restenosis but not new lesions.

Conclusions

For Japanese CAD patients treated with PCI and stent implantation, statin therapy reduced the incidence of recurrent cardiovascular events, particularly rAP. Discretionary statin treatment to achieve LDL-C levels <100 mg/dl effectively reduced restenosis causing rAP.     

Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells

Human endothelial progenitor cells (EPCs) can differentiate into cardiomyogenic cells in vitro. We tested the effects of statin therapy on the differentiation rate of EPCs from patients with coronary artery disease (CAD), who may benefit from autologous cell therapy.EPCs from 3 age-matched groups were tested: No CAD (n = 13), CAD patients with (n = 10) or without (n = 16) statin therapy. From 4 CAD patients, EPCs were tested before and after 4 weeks of therapy with 20 mg atorvastatin. After 6 days of co-culture with rat neonatal cardiomyocytes, EPC differentiation was quantified by immunostaining for -sarcomeric actinin flow cytometry analysis. After 6 days of co-culture, the percentage of -sarcomeric actinin–positive EPCs was significantly (p = 0.014) higher in EPCs from adults without CAD (8.07% ± 1.48% of EPCs) compared to EPCs from CAD patients without statin (3.56% ± 0.72%). Importantly, patients with statin therapy revealed significantly higher numbers of -sarcomeric actinin-positive EPCs (6.36% ± 0.69%, p = 0.01) compared to CAD patients without statin. In addition, statin therapy resulted in a significant (p = 0.017) increase of EPC differentiation in all 4 CAD patients investigated before and 4 weeks after statin therapy. The survival of EPCs did not differ between the different groups suggesting that the regulation of EPC differentiation is not secondary to altered EPC survival. In vitro, EPC treatment with 0.1 µM atorvastatin did not affect EPC differentiation (116.15% ± 49.11% of control).EPCs from patients with CAD display impaired differentiation into cardiomyogenic cells. This defect can be improved by in vivo, statin therapy.     

Klinefelter's syndrome and bone mineral density: is osteoporosis a constant feature?

Objectives

Data on bone mineral density (BMD) in Klinefelter syndrome (KS) are scarce and contradictory. The aim of the present study was to investigate BMD in patients with KS and in healthy controls with special attention to gonadal status.

Material and methods

We investigated 26 patients with KS (30 ± 9 yr) who had never been treated with testosterone. Thirty-nine age-matched healthy males served as controls. We assessed BMD by performing dual energy X-ray absorptiometry and measured serum hormone levels, including total testosterone (T), free testosterone, estradiol (E2), leptin. The estrogen to androgen ratio (E2/T) was used as an indirect measure for aromatase activity.

Results

No difference was found in BMD at femoral neck (1.06 ± 0.16 vs 1.04 ± 0.14 g/cm²), or at lumbar spine (1.00 ± 0.09 vs 1.03 ± 0.11) between patients and controls. Two patients and one control were classified as osteoporotic (T-score ≤ −2.5). Compared with controls, patients had lower levels of T and free testosterone, similar E2 levels, and increased E2/T (P < 0.05). In KS patients, leptin was significantly higher and correlated positively with E2/T (r = 0.484, P = 0.02). E2/T correlated with femoral neck BMD (r = 0.566, p = 0.02), T and free T correlated with lumbar spine BMD (r = 0.433, P = 0.05 and r = 0.534, P = 0.05).

Conclusion

Osteoporosis is not a constant feature in young patients with KS, even without testosterone substitution. The aromatisation of T into E2, related to adiposity, may contribute to the achievement and maintenance of normal BMD in some KS patients.     

Improvement of arterial stiffness by the antioxidant and anti-inflammatory effects of short-term statin therapy in patients with hypercholesterolemia

The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 ± 9.0 years) with hypercholesterolemia (total cholesterol 220mg/dl). The patients were treated with cerivastatin (0.15mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 ± 157.1 to 1349.0 ± 223.9cm/s and from 1592.1 ± 164.8 to 1424.8 ± 245.2cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 ± 42.4 to 119.4 ± 33.5U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.     

Insulin resistance in Type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle

Summary To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a +45 mU· ·min^–1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-³H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxyterminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5±2.1 and 34.0±4.8 vs 57.9±3.1 mol·kg lean body mass^–1·min^–1; p<0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0±2.4 and 15.6±3.9 vs 36.9±2.2 mol·kg lean body mass^–1·min^–1; p<0.01). The levels of GLUT-4 mRNA expressed both per g of total RNA and per g DNA, were higher in the diabetic patients compared with the control subjects (116±25 vs 53±10 pg/g RNA and 177±35 vs 112±29 pg/g DNA; p<0.05, p<0.01, respectively). The GLUT-4 mRNA levels in the relatives were not significantly different from that observed in the control subjects (90±16 pg/g RNA and 117±23 pg/g DNA; p = NS). The GLUT-4 protein levels did not significantly differ between control subjects, diabetic patients and relatives (494±85, 567±133 and 323±80 cpm/100 g protein). No correlation was observed between the level of GLUT-4 mRNA andits protein. However, the level of GLUT-4 mRNA and the rate of total-body glucose disposal correlated positively in the control group and in the relatives (both p<0.05) but not in the diabetic subjects. A positive correlation between the level of GLUT-4 protein and total-body glucose disposal was also observed in the control subjects (r = 0.759; p<0.05) and in the relatives (r = 0.794; p<0.01) but not in the diabetic subjects. We conclude that insulin resistance in Type 2 diabetes is not related to a defect in the expression of the GLUT-4 gene in skeletal muscle. Nevertheless, the levels of GLUT-4 mRNA and GLUT-4 protein are related to the rate of total-body glucose disposal in subjects with normal fasting glucose concentrations.     

High-dose statin pretreatment for the prevention of contrast-induced nephropathy: a meta-analysis

Background

Contrast-induced nephropathy (CIN) is a rare but serious complication following contrast-based procedures. Statins have been postulated to prevent CIN via various mechanisms. However, the outcomes following statin administration to prevent CIN have been inconsistent.

Methods

A meta-analysis of published randomized clinical trials was performed to determine if short-term administration of high-dose statin is superior to conventional-dose statin or placebo among patients undergoing catheterization and interventional procedures in preventing CIN.

Results

Data were combined across 8 published clinical trials in which 1423 patients were identified. Pooled analyses showed that short-term high-dose statin treatment can decrease the occurrence of CIN (risk ratio 0.51, 95% confidence interval [CI], 0.34-0.77; P = 0.001) and 48-hour serum creatinine level (standardized mean difference [SMD] -0.07 mg/dL; 95% CI, -0.11 to -0.04 mg/dL; P < 0.00001). However, subgroup analysis showed that statin pretreatment cannot decrease the occurrence of CIN in patients with preexisting renal impairment (RR 0.90; 95% CI, 0.49-1.65; P = 0.73). No evidence of publication bias was detected.

Conclusions

This meta-analysis supports the effectiveness of short-term high-dose statin pretreatment for both decreasing the level of serum creatinine and reducing the rate of CIN in patients undergoing diagnostic and interventional procedures requiring contrast media. However, prospective clinical trials will be needed to draw a definitive conclusion in this area.     

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events : A Meta-Analysis of Statin Trials

Background

Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives

The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods

This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results

Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions

The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.