Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Plaque stabilizing effects of apolipoprotein A-IV.

BACKGROUND AND AIMS: Apolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo. METHODS: Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD. RESULTS: In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity. CONCLUSIONS: ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.

Clinical guidelines on hyperlipidaemia: recent developments, future challenges and the need for an Australian review.

Large reductions in cardiovascular disease (CVD) mortality have been achieved over the last 50 years in developed countries. The health policies that have contributed so much to this success have largely been coordinated by means of expert guidelines for the management of the classic modifiable risk factors such as blood pressure, diabetes and blood lipids. National and international guidelines for lipid management have demonstrated a high degree of consistency between numerous sets of recommendations. It has been argued that some important components of the consensus that has been established over the past decade have been challenged by the latest guidelines of the American Heart Association - American College of Cardiologists (AHA-ACC). Clinicians can be reassured that continued reliance on extensive scientific evidence has reaffirmed the importance of lipid metabolism as a modifiable risk factor for atherosclerotic cardiovascular disease. On the other hand, the recent AHA-ACC guidelines suggest changes in the strategies by which metabolic risk factors may be modified. This small number of important changes should not be sensationalised because these differences usefully reflect the need for guidelines to evolve to accommodate different contexts and changing perspectives as well as emerging issues and new information for which clinical trial evidence is incomplete. This article will consider the recent policies and responses of national and supranational organisations on topics including components of CVD risk assessment, sources of CVD risk information and re-appraisal of lipid-lowering interventions. Timely review of Australian lipid management guidelines will require consideration of these issues because they are creating a new context within which new guidelines must evolve.

Visceral, subcutaneous abdominal adiposity and liver fat content distribution in normal glucose tolerance, impaired fasting glucose and/or impaired glucose tolerance.

OBJECTIVES: To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). DESIGN: Multicenter, international observational study: cross-sectional analysis. SUBJECTS: Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. RESULTS: Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15-1.74), women: OR 1.62 (1.29-2.04)), iIGT (men: OR 1.59 (1.15-2.01), women: OR 1.30 (0.96-1.76)), IFG+IGT (men: OR 1.64 (1.27-2.13), women: OR 1.83 (1.36-2.48)) and nT2D (men: OR 1.80 (1.35-2.42), women: OR 1.73 (1.25-2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12-1.90), women: OR 1.81 (1.41-2.35)), IFG+IGT (men: OR 1.42 (1.14-1.77), women: OR 1.74 (1.35-2.26)) and nT2D (men: OR 1.77 (1.40-2.27), women: OR 2.38 (1.81-3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45-0.88)). CONCLUSIONS: Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.

Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: results from INSPIRE ME IAA.

AIM: Visceral adipose tissue (VAT) and liver fat (LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's (ADA) diabetes management goals. METHODS: We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes (noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications (T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin (T2Dmeds-ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin (T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. RESULTS: Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol (HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. CONCLUSION: Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF.

Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: results from VOYAGER.

BACKGROUND AND AIMS: Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl(-1) (∼2.5 mmol l(-1)), and 80 (∼2.0 mmol l(-1)) or 70 mg dl(-1) (∼1.8 mmol l(-1)) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients. METHODS AND RESULTS: The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl(-1) for LDL-C. It was also more effective than atorvastatin at raising high-density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results. CONCLUSIONS: This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident.

Ability of traditional lipid ratios and apolipoprotein ratios to predict cardiovascular risk in people with type 2 diabetes.

AIMS/HYPOTHESIS: The apolipoprotein B (ApoB):apolipoprotein A (ApoA)-I ratio may be a better indicator of cardiovascular disease (CVD) risk in people with type 2 diabetes than traditional lipid risk markers (LDL-cholesterol, HDL-cholesterol and triacylglycerol), but whether the ApoB:ApoA-I ratio should be used to indicate lipid-lowering therapy is still debated. METHODS: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomised 9,795 patients with type 2 diabetes to fenofibrate (200 mg daily) or placebo and followed them up for a median of 5 years. We compared ApoB, ApoA-I, ApoAII and the ApoB:ApoA-I ratio with traditional lipid variables as predictors of CVD risk. We estimated the HR of the effect of 1 SD difference in baseline concentrations of lipids, apolipoproteins and respective ratios on the risk of CVD events and also used receiver operating characteristic curve analysis. RESULTS: In the placebo group, the variables best predicting CVD events were non-HDL-cholesterol:HDL-cholesterol, total cholesterol:HDL-cholesterol (HR 1.21, p < 0.001 for both), ApoB:ApoA-I (HR 1.20, p < 0.001), LDL-cholesterol:HDL-cholesterol (HR 1.17, p < 0.001), HDL-cholesterol (HR 0.84, p < 0.001) and ApoA-I (HR 0.85, p < 0.001). In the fenofibrate group, the first four predictors were very similar (but ApoB:ApoA-I was fourth), followed by non-HDL-cholesterol and ApoB. Lipid ratios and ApoB:ApoA-I performed better than any single lipid or apolipoprotein in predicting CVD risk. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes in the FIELD study, traditional lipid ratios were as strong as the ApoB:ApoA-I ratio in predicting CVD risk. The data provide little evidence for replacement of traditional lipids and their ratios with measures of ApoB, ApoA-I and their ratio.

Role of 3beta-hydroxysteroid-delta 24 reductase in mediating antiinflammatory effects of high-density lipoproteins in endothelial cells.

OBJECTIVE: The purpose of this study was to investigate the ability of high-density lipoproteins (HDLs) to upregulate genes with the potential to protect against inflammation in endothelial cells. METHODS AND RESULTS: Human coronary artery endothelial cells (HCAECs) were exposed to reconstituted HDLs (rHDLs) for 16 hours before being activated with tumor necrosis factor-alpha (TNF-alpha) for 5 hours. rHDLs decreased vascular cell adhesion molecule-1 (VCAM-1) promoter activity by 75% (P<0.05), via the nuclear factor-kappa B (NF-kappaB) binding site. rHDLs suppressed the canonical NF-kappaB pathway and decreased many NF-kappaB target genes. Suppression of NF-kappaB and VCAM-1 expression by rHDLs or native HDLs was dependent on an increase in 3beta-hydroxysteroid-Delta 24 reductase (DHCR24) levels (P<0.05). The effect of HDLs on DHCR24 is dependent on SR-BI but not ABCAI or ABCGI. Silencing DHCR24 expression increased NF-kappaB (1.2-fold, P<0.05), VCAM-1 (30-fold, P<0.05), and NF-kappaB p50 (4-fold, P<0.05) and p65 subunits (150-fold, P<0.05). TNF-alpha activation of siDHCR24-treated cells increased expression of VCAM-1 (550-fold, P<0.001) and NF-kappaB (9-fold, P<0.001) that could no longer be suppressed by rHDLs. CONCLUSIONS: Results suggest that antiinflammatory effects of rHDLs are mediated partly through an upregulation of DHCR24. These findings raise the possibility of considering DHCR24 as a target for therapeutic modulation.

Effects of cross-link breakers, glycation inhibitors and insulin sensitisers on HDL function and the non-enzymatic glycation of apolipoprotein A-I.

AIMS/HYPOTHESIS: Hyperglycaemia, a key feature of diabetes, is associated with non-enzymatic glycation of plasma proteins. We have shown previously that the reactive alpha-oxoaldehyde, methylglyoxal, non-enzymatically glycates apolipoprotein (Apo)A-I, the main apolipoprotein of HDL, and prevents it from activating lecithin:cholesterol acyltransferase (LCAT), the enzyme that generates almost all of the cholesteryl esters in plasma. This study investigates whether the glycation inhibitors aminoguanidine and pyridoxamine, the insulin sensitiser metformin and the cross-link breaker alagebrium can inhibit and/or reverse the methylglyoxal-mediated glycation of ApoA-I and whether these changes can preserve or restore the ability of ApoA-I to activate LCAT. METHODS: Inhibition of ApoA-I glycation was assessed by incubating aminoguanidine, pyridoxamine, metformin and alagebrium with mixtures of methylglyoxal and discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and ApoA-I, ([A-I]rHDL). Glycation was assessed as the modification of ApoA-I arginine, lysine and tryptophan residues, and by the extent of ApoA-I cross-linking. The reversal of ApoA-I glycation was investigated by pre-incubating discoidal (A-I)rHDL with methylglyoxal, then incubating the modified rHDL with aminoguanidine, pyridoxamine or alagebrium. RESULTS: Aminoguanidine, pyridoxamine, metformin and alagebrium all decreased the methylglyoxal-mediated glycation of the ApoA-I in discoidal rHDL and conserved the ability of the particles to act as substrates for LCAT. However, neither aminoguanidine, pyridoxamine nor alagebrium could reverse the glycation of ApoA-I or restore its ability to activate LCAT. CONCLUSIONS/INTERPRETATION: Glycation inhibitors, insulin sensitisers and cross-link breakers are important for preserving normal HDL function in diabetes.

Aggressive management of obesity in children and young adults: the known challenges and potential opportunities.

The world is confronted with an impending epidemic of premature cardiovascular disease (CVD) that is being fueled by an increase in the prevalence of central obesity.

The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase.

AIMS/HYPOTHESIS: Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. MATERIALS AND METHODS: Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I]rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. RESULTS: Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipid-associated apoA-I were time- and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. CONCLUSIONS/INTERPRETATION: It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes.

The rationale for using apoA-I as a clinical marker of cardiovascular risk.

An inverse relationship between the concentration of high-density lipoprotein (HDL) cholesterol and the risk of developing cardiovascular is well established. There are several documented functions of HDLs that may contribute to a protective role of these lipoproteins. These include the ability of HDLs to promote the efflux of cholesterol from macrophages and foam cells in the artery wall and to anti-inflammatory/antioxidant properties of these lipoproteins. The fact that the main apolipoprotein of HDLs, apoA-I, plays a prominent role in each of these functions adds support to the view that apoA-I should be measured as a component of the assessment of cardiovascular risk in humans.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Effect of inhibiting cholesteryl ester transfer protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma: in vivo studies in rabbits.

OBJECTIVE: Inhibitors of cholesteryl ester transfer protein (CETP) have been developed as potential anti-atherogenic agents. Theoretically, however, they may be pro-atherogenic by blocking one of the pathways for removing high-density lipoprotein (HDL) cholesteryl esters (CE) from plasma in the final step of reverse cholesterol transport. Here we describe how CETP inhibition in rabbits impacts on the kinetics of HDL CE transport in plasma. METHODS AND RESULTS: Administration of a CETP inhibitor reduced CETP activity by 80% to 90% and doubled the HDL cholesteryl ester concentration. Multi-compartmental analysis was used to determine HDL CE kinetics in CETP-inhibited and control rabbits after injection of tracer amounts of both native and reconstituted HDL labeled with 3H in the CE moiety. In control rabbits, HDL CE was removed from plasma by both a direct pathway and an indirect pathway after transfer of HDL CE to the very-low-density lipoprotein/low-density lipoprotein fraction. In CETP-inhibited rabbits there was an almost complete block in removal via the indirect pathway. This did not compromise the overall removal of HDL CE from plasma, which was not different in control and inhibited animals. CONCLUSIONS: Inhibiting CETP in rabbits does not compromise the removal of HDL CE from plasma.

Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.

BACKGROUND: Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS: We did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). FINDINGS: Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects. INTERPRETATION: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481].

OBJECTIVE: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. RESEARCH DESIGN AND METHODS: FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. RESULTS: About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI > 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement (41%), high waist measurement (65%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). CONCLUSION: The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.

Comparison of rosuvastatin with atorvastatin, simvastatin and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholesterolaemic patients with or without the metabolic syndrome in the MERCURY I trial.

AIM: The metabolic syndrome (MS) increases the risk of coronary heart disease, yet few data are available on the effects of statin treatment in improving lipid measures in patients with the syndrome. This analysis compares the effects of statin therapy on plasma low-density lipoprotein cholesterol (LDL-C) goal achievement and lipid levels in hypercholesterolaemic patients with or without the MS. METHODS: The Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY I (MERCURY I) trial compared rosuvastatin 10 mg with atorvastatin 10 mg and 20 mg, simvastatin 20 mg and pravastatin 40 mg over 8 weeks in patients with coronary or other atherosclerotic diseases or diabetes who had fasting levels of LDL-C of >or=2.99 mmol/l and triglycerides of <4.52 mmol/l. Modified National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria for the MS were met by 1342 (43%) of 3140 patients. RESULTS: LDL-C goal achievement rates and reductions in LDL-C, total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) were similar in patients with and without the MS within statin treatment groups; triglycerides were reduced more and HDL-C tended to be increased more in patients with the MS, as expected. Treatment with rosuvastatin 10 mg was more effective in allowing patients with and without the MS to reach European and ATP III LDL-C goals, compared to atorvastatin 10 mg, simvastatin 20 mg and pravastatin 40 mg (p < 0.0001 for all comparisons); consistently produced greater reductions in LDL-C, total cholesterol and non-HDL-C, compared to these treatments; and produced similar or greater reductions in triglycerides and increases in HDL-C, compared to the other treatments. CONCLUSIONS: Statin therapy is effective in allowing LDL-C goal achievement and improving the lipid profile in hypercholesterolaemic high-risk patients with the MS. Rosuvastatin 10 mg presents significant advantages in goal achievement and lipid lowering over other statins at commonly used doses in patients both with and without the MS.

Investigation of pond velocities using dye and small drogues: a case study of the Nelson City waste stabilisation pond.

The city of Nelson, New Zealand, has a 27 hectare oxidation pond as its primary wastewater treatment facility. Recent changes in the configuration of the pond and installation of a mixer/aerator raised concerns that pond treatment rates and effluent quality may be affected by high internal pond velocities and short retention times. This paper presents the findings of an investigation into wastewater velocity and movement within the pond using qualitative dye dispersion and tracking of small-scale "holey-sock" drogues. Simultaneous deployment of drogues and dye allowed methods to be compared, since small-scale drogues have not commonly been used in wastewater ponds. Dye dispersion was assessed using low-level aerial photography from a tethered helium blimp to track short term movement and mixing, while a datalogger and fluorometer were used to measure pond retention time. Drogue movement was tracked in conjunction with the dye study from a small boat using hand-held GPS. The dye study found that: (i) the first portion of pond influent discharged from the pond after 37.5 hours, substantially quicker than the theoretical pond retention time of 27 days. However, the measured retention time was with a mixer in place and the theoretical time was without a mixer; (ii) the position of the paddle wheel mixer/aerator was not optimally placed for mixing the influent and a quiescent region existed adjacent to the influent point; and (iii) the low-level aerial photography was an effective method of evaluating larger pond systems. The "holey-sock" drogue studies showed that: (i) the drogues accurately followed the movement and velocity of dyed influent within the pond; (ii) wastewater velocity and movement was dominated by the paddle wheel mixer/aerator; and (iii) wind direction had a minor influence on wastewater velocity and movement in areas not directly affected by the paddle wheel mixer/aerator. The study demonstrated that the combined use of dye and drogues was a relatively low-cost and effective means of determining internal pond velocities and movement. Future studies using similar methods will be useful in helping validate computer-modelled movement and velocity.