Acute kidney injury: prevention, detection, and management. Summary of updated NICE guidance for adults receiving iodine-based contrast media.

The National Institute for Health and Care Excellence (NICE) has recently updated the guideline for Acute kidney injury: prevention, detection and management (NG148), providing new recommendations on preventing acute kidney injury (AKI) in adults receiving intravenous iodine-based contrast media. The association between intravenous iodinated contrast media and AKI is controversial, particularly with widespread use of iso-osmolar agents. Associations between contrast media administration and AKI are largely based on observational studies, with inherent heterogeneity in patient populations, definitions applied, and timing of laboratory investigations. In an attempt to mitigate risk, kidney protection has typically been employed using intravenous volume expansion and/or oral acetylcysteine. Such interventions are in widespread use, despite lacking high-quality evidence of benefit. In the non-emergency setting, glomerular filtration rate (GFR) measurements should be obtained within the preceding 3 months before offering intravenous iodine-based contrast media. In the acute setting, adults should also have their risk of AKI assessed before offering intravenous iodine-based contrast media; however, this should not delay emergency imaging. Based on the evidence available from randomised controlled trials, the NICE committee recommends that oral hydration should be encouraged in adults at increased risk of AKI and that volume expansion with intravenous V fluids should only be considered for inpatients at particularly high risk.

Further options for treating lipids in people with diabetes: targeting LDL-cholesterol and beyond.

Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL-cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off-patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD.

Decomposition Algorithms for a Multi-Hard Problem.

Real-world optimization problems have been studied in the past, but the work resulted in approaches tailored to individual problems that could not be easily generalized. The reason for this limitation was the lack of appropriate models for the systematic study of salient aspects of real-world problems. The aim of this article is to study one of such aspects: multi-hardness. We propose a variety of decomposition-based algorithms for an abstract multi-hard problem and compare them against the most promising heuristics.

Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for Adult Refsum Disease.

BACKGROUND: Adult Refsum's Disease (ARD) is caused by defects in the pathway for alpha-oxidation of phytanic acid (PA). Treatment involves restricting the dietary intake of phytanic acid by reducing the intake of dairy-derived fat. The adequacy of micronutrient intake in patients with ARD is unknown. METHODS: Patients established on the Chelsea low-PA diet had general diet macronutrients, vitamins and trace elements assessed using 7-day-weighed intakes and serial 24-h recalls. Intakes were compared with biochemical assessments of nutritional status for haematinics (ferritin), trace elements (copper, zinc, iron, selenium), water- (vitamin B6 , B12 and folate) and fat-soluble vitamins (A, D, E and K). RESULTS: Eleven subjects (four women, seven men) were studied. Body mass index was 27 ± 5 kg/m(2) (range 19-38). All subjects had high sodium intakes (range 1873-4828 mg). Fat-soluble vitamin insufficiencies occurred in some individuals (vitamin A, n = 2; vitamin D, n = 6; vitamin E, n = 3; vitamin K, n = 10) but were not coincident. Vitamin B6 levels were normal or elevated (n = 6). Folate and 5-methyltetrahydrofolate concentrations were normal. Metabolic vitamin B12 insufficiency was suspected in four subjects based on elevated methylmalonic acid concentrations. Low copper and selenium intakes were noted in some subjects (n = 7, n = 2) but plasma levels were adequate. Iron, ferritin and zinc intakes and concentrations were normal. CONCLUSION: Subjects with ARD can be safely managed on the Chelsea low PA without routine micronutrient supplementation. Sodium intake should be monitored and reduced. Periodic nutritional screening may be necessary for fat-soluble vitamins, vitamin B12 , copper or selenium.

Familial Hypercholesterolaemia in the Era of Genetic Testing.

Familial hypercholesterolaemia (FH) is a relatively common autosomal dominant genetic condition leading to premature ischaemic vascular disease and mortality if left untreated. Currently, a universal consensus on the diagnostic criteria of FH does not exist but the diagnosis of FH largely relies on the evaluation of low density lipoprotein-cholesterol (LDL-C) levels, a careful documentation of family history, and the identification of clinical features. Diagnosis based purely on lipid levels remains common but there are several limitations to this method of diagnosis both practically and in the proportion of false-negatives and false-positives detected, resulting in substantial under-diagnosis of FH. In some countries, diagnostic algorithms are supplemented with genetic testing of the index case as well as genetic and lipid testing of relatives of the index case. Such "cascade" screening of families following identification of index cases appears to not only improve the rate of diagnosis but is also cost-effective. Currently, we observe a great variation in the excess mortality among patients with FH, which likely reflects a combination of additional genetic and environmental effects on risk overlaid on the risk associated with FH. Current accepted drug therapies for FH include statins and PSCK9 inhibitors. Further work is required to evaluate the cardiovascular disease risk in patients with genetically diagnosed FH and to determine whether a risk-based approach to the treatment of FH is appropriate.

Improving the odds: ezetimibe and cardiovascular disease.

The beauty of science is that well-conducted experiments provide answers to questions which were posed in times of greater ignorance. Cardiovascular disease (CVD) is the leading cause of death worldwide and will be for some time. Cholesterol is a critical player which drives the underlying pathophysiological process of atherosclerosis. Statins are the first line treatment for lipids in CVD given their ability to low-density lipoprotein cholesterol (LDL-C) by up to 50%, and their proven benefits in both primary and secondary intervention . Despite the unprecedented efficacy of statins, additional treatments are sought to potentially reduce the residual risk that remains despite statin treatment such as that associated with reduced high-density lipoprotein cholesterol levels (HDL-C) or triglycerides . In the last 5 years, several trials have reported on their potential additional benefit beyond statin therapy. These include omega-3 fatty acids in patients with prediabetes or diabetes , fibrates in diabetes , nicotinic acid/niacin in cardiovascular disease and cholesterol ester transfer protein inhibitors in cardiovascular disease . Despite their promise, none of these treatments were able to demonstrate benefit beyond baseline statin therapy when compared with placebo . The idea that benefit beyond statin treatment may be an unachievable goal has dogged the medical community working on CVD prevention. The phrase, 'Statins for atherosclerosis - as good as it gets?' was coined in 2005 and has rung true up until now .

Vitamin K and other markers of micronutrient status in morbidly obese patients before bariatric surgery.

BACKGROUND: Micronutrient deficiencies occur in morbidly obese patients. The aim of this study was to assess vitamin deficiencies prior to bariatric surgery including vitamin K about which there is little data in this population. METHODS: A prospective assessment of 118 consecutive patients was performed. Clinical allied with haematological and biochemical variables were measured. Micronutrients measured included vitamins K1 , PIVKA-II (protein-induced in vitamin K absence factor II), vitamin D, vitamin B12 (holotranscobalamin), iron, transferrin and folate. RESULTS: Patients were aged 49 ± 11 [mean (SD, standard deviation)] years, body mass index (BMI) 50 ± 8 kg/m(2), 66% female and 78% Caucasian. Hypertension was present in 47% and type 2 diabetes in 32%. Vitamin D supplements had been prescribed in 8%. Micronutrient insufficiencies were found for vitamin K (40%), vitamin D (92%) and vitamin B12 (25%), and also iron (44%) and folate (18%). Normocalcaemic vitamin D insufficiency with secondary hyperparathyroidism was present in 18%. Iron and transferrin levels were associated with age, sex and estimated glomerular filtration rate. Vitamin K levels were associated with age, and inversely with BMI and diabetes mellitus; and PIVKA-II with smoking, triglycerides and liver function markers. Vitamin D levels were associated with statin use and prescription of supplements and inversely with BMI. Vitamin B12 levels were associated with ethnicity and HbA1c. CONCLUSION: Micronutrient status shows differing relationships with age, gender and BMI. Vitamin K insufficiency was present in 40% and not related to deficiencies in other vitamins or micronutrients. Vitamin D and vitamin K supplementation should be considered prebariatric surgery in patients with diabetes or severe insulin resistance.

Pro-protein convertase subtilisin/kexin 9 concentrations correlate with coronary artery disease atheroma burden in a Pakistani cohort with chronic chest pain.

OBJECTIVE: To determine the relationship between proprotein convertase subtilisin kexin 9 (PCSK9) levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective matched case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and PCSK-9 levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: In this population, PCSK-9 levels were weakly correlated (r = 0.23) with male gender (p = 0.06) and number of diabetes years (p = 0.09), and inversely with log10 of lipoprotein (a) concentration (p = 0.07) but not LDL-C. In multiple regression analysis, Gensini score was associated with age (p = 0.002), established angina (p = 0.001), duration of diabetes (p = 0.05), low HDL-C (p < 0.001), lipoprotein (a) (p = 0.01), creatinine (p < 0.001), C-Reactive Protein (p = 0.02) and PSCK-9 (p = 0.05) concentrations. PCSK9 added to the regression model. Neither total cholesterol nor LDL-C were significant risk factors in this study. CONCLUSIONS: Proprotein convertase subtilisin kexin 9 concentrations are correlated with atheroma burden in Indian Asian populations from the sub-continent, not taking statin therapy, independent of LDL-C or other CVD risk factors.

Angiographic coronary artery disease and high-sensitivity troponin-T in a native Pakistani cohort presenting with chronic chest pain.

OBJECTIVE: To determine the relationship between troponin-T levels and atheroma burden in Pakistanis presenting to an ambulatory centre with chest pain. METHODS: A prospective case-control study of 400 patients selected for presence/absence of angiographic disease referred between 2001 and 2003. A comprehensive cardiovascular disease (CVD) risk factor profile was assessed including demographics, environmental and biochemical risk factors including insulin resistance and troponin-T levels. Coronary atheroma burden was quantified by Gensini score. RESULTS: Clinically significant elevated troponin-T levels (> 30 pmol/l) were found in 40 patients (10%) with equal numbers in groups selected with or without angiographic disease. Troponin-T elevation (> 13 pmol/l) was present in 59 vs. 47 patients (30% vs. 24%; p = 0.04). Troponin-T levels did not correlate with any measured demographical, environmental, drug therapy or biochemical risk factor. No difference was found in concentrations of lipids, apolipoproteins, insulin resistance, C-reactive protein or sialic acid in cohorts stratified by troponin-T concentrations. In univariate analysis comparing patients with high (> 30 pmol/l) and low troponin-T levels (< 13 pmol/l) higher plasma total protein (91 g/l vs. 85 g/l; p = 0.01), increased immunoglobulin levels (41 g/l vs. 36 g/l; p = 0.02) and prevalence of hyperparathyroidism (40% vs. 21%; p = 0.04) were associated with higher troponin-T concentrations. CONCLUSIONS: This study shows that measurement of troponin-T is not an alternative to imaging in an Indian asian population, but that it does identify a separate potentially high-risk population that would not be identified by the use of imaging alone which is potentially at higher risk of CVD events.

Screening for chronic comorbid diseases in people with HIV: the need for a strategic approach.

Among people living with HIV, the proportion of deaths attributed to chronic noninfectious comorbid diseases has increased over the past 15 years. This is partly a result of increased longevity in the era of highly active antiretroviral therapy (HAART), and also because HIV infection is related, causally or otherwise, to several chronic conditions. These comorbidities include conditions that are strongly associated with modifiable risk factors, such as cardiovascular disease (CVD), diabetes, and renal and bone diseases, and increasingly management guidelines for HIV recommend risk evaluation for these conditions. The uptake of these screening approaches is often limited by the resources required for their application, and hence the management of risk reduction in most HIV-infected populations falls below a reasonable standard. The situation is compounded by the fact that few risk calculators have been adjusted for specific use in HIV infection. There is substantial overlap of risk factors for the four common comorbid diseases listed above that are especially relevant in HIV infection, and this offers an opportunity to develop a simple screening approach that encompasses the key risk factors for lifestyle-related chronic disease in people with HIV infection. This would identify those patients who require more in-depth investigation, and facilitate a stepwise approach to targeted management. Such a tool could improve communication between patient and clinician. A significant proportion of people with HIV are sufficiently engaged with their care to participate in health promotion and take the lead in using patient-centric screening measures. Health-based social networking offers a mechanism for dissemination of such a tool and is able to embed educational messages and support within the process.

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB-IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments. OBJECTIVES: To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. METHODS: Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature. RESULTS: The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting. CONCLUSION: Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.

Subnanometer atomic force microscopy of peptide-mineral interactions links clustering and competition to acceleration and catastrophe.

In vitro observations have revealed major effects on the structure, growth, and composition of biomineral phases, including stabilization of amorphous precursors, acceleration and inhibition of kinetics, and alteration of impurity signatures. However, deciphering the mechanistic sources of these effects has been problematic due to a lack of tools to resolve molecular structures on mineral surfaces during growth. Here we report atomic force microscopy investigations using a system designed to maximize resolution while minimizing contact force. By imaging the growth of calcium-oxalate monohydrate under the influence of aspartic-rich peptides at single-molecule resolution, we reveal how the unique interactions of polypeptides with mineral surfaces lead to acceleration, inhibition, and switching of growth between two distinct states. Interaction with the positively charged face of calcium-oxalate monohydrate leads to formation of a peptide film, but the slow adsorption kinetics and gradual relaxation to a well-bound state result in time-dependent effects. These include a positive feedback between peptide adsorption and step inhibition described by a mathematical catastrophe that results in growth hysteresis, characterized by rapid switching from fast to near-zero growth rates for very small reductions in supersaturation. Interactions with the negatively charged face result in formation of peptide clusters that impede step advancement. The result is a competition between accelerated solute attachment and inhibition due to blocking of the steps by the clusters. The findings have implications for control of pathological mineralization and suggest artificial strategies for directing crystallization.

New directions in cardiovascular risk assessment: the role of secondary risk stratification markers.

Cardiovascular disease (CVD) risk screening is performed by multivariate methods relying on calculators derived from the Framingham study, other epidemiological studies or primary care records. However, it only identifies 70% of individuals at risk for CVD events and there has been interest in adding other risk factors to improve its predictive capacity. The addition of a family history of premature CVD is well established and there is evidence for adding lipoprotein (a) in some populations and possibly C-reactive protein may be suitable for general use in CVD risk assessment. Most new biochemical and imaging markers have been assessed in the context of improving risk classification in intermediate-risk groups rather than in the general population. There is evidence that N-terminal pro-B-type natriuretic peptide and coronary artery calcium score add significantly to risk prediction. The data for carotid intima-media thickness, ankle-brachial index are less strong and high sensitivity troponins look promising, but have had only limited data to date. Large scale meta-analyses ideally of pooled primary patient data will be required to determine the best additional markers to add to conventional risk prediction and in what groups to apply them.

New lipid-lowering drugs: an update.

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. Statins form the basis of care but are not able to treat all aspects of dyslipidaemia. Many novel therapeutic compounds are being developed. These include additional therapeutics for low-density lipoprotein cholesterol, for example, thyroid mimetics (thyroid receptor beta-agonists), antisense oligonucleotides or microsomal transfer protein inhibitors (MTPI); triglycerides, for example, novel peroxosimal proliferator activating receptors agonists, MTPIs, diacylglycerol acyl transferase-1 inhibitors and high-density lipoprotein cholesterol (HDL-C), for example, mimetic peptides; HDL delipidation strategies and cholesterol ester transfer protein inhibitors and modulators of inflammation, for example, phospholipase inhibitors. Gene therapy for specific rare disorders, for example, lipoprotein lipase deficiency using alipogene tiparvovec is also in clinical trials. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis.

Gender-based cardiometabolic risk evaluation in minority and non-minority men grading the evidence of non-traditional determinants of cardiovascular risk.

Evaluation of cardiometabolic risk has become vital in primary prevention of adverse vascular events (coronary artery disease, heart attack, stroke or congestive heart failure), particularly in younger middle-aged men (40-60 years old). To discern the prevalence of events in these men, clinicians often stratify cardiovascular risk and treat according to traditional Framingham risk criteria. Yet it is evident that the traditional Framingham risk assigned to intermediate- and low-risk men will miss several of these individuals deemed at high 'cardiometabolic risk', also known as residual cardiovascular risk. This review will elaborate the definition of cardiometabolic risk and apply the use of surrogate markers for cardiovascular risk stratification in men in addition to the traditional Framingham-based markers. It will utilise both gender non-specific and gender-specific determinants of cardiometabolic risk. Lastly, it will examine minority men's health and racial differences in these determinants of cardiovascular risk. This analysis includes an electronic literature search utilising PubMed, EMBASE and MEDLINE databases to clarify the level of evidence for the stepwise utility of novel biomarkers for cardiometabolic risk in the male patient. This manuscript generates discussion of the utility of markers of cardiometabolic risk stratification. The following questions are summarised: (i) Are there non-traditional tests that might define this risk better than traditional markers? (ii) Will treatment based on this risk assessment augment present risk stratification and lower cardiovascular risk? (iii) What is known regarding racial differences surrounding cardiometabolic risk assessment? Traditional risk factors including Framingham Risk Score underestimate the overall 10 year and lifetime risk for the intermediate-risk younger middle-aged men<60 years of age. This fact is especially true in the minority population. We have graded the evidence of non-gender specific and gender-specific markers of cardiometabolic risk, thereby, allowing greater clarification of risk in this population. The pragmatic use of these novel markers of cardiometabolic risk may help stratify those individuals at greater lifetime risk than that noted by the Framingham Risk Score.

Fibroblast growth factor-23 is associated with C-reactive protein, serum phosphate and bone mineral density in chronic kidney disease.

UNLABELLED: We investigated the association between fibroblast growth factor-23 (FGF-23) and (1) the biochemical parameters implicated in chronic kidney disorder (CKD)-bone and mineral disorder (CKD-MBD) and (2) bone mineral density (BMD) in patients with CKD 1-4. C-reactive protein (CRP) and serum phosphate correlated with FGF-23. A significant association was seen between FGF-23 and BMD at the hip. INTRODUCTION: Circulating FGF-23 is elevated in CKD, although the primary stimulus remains unclear. Moreover, it is still unknown whether increase in FGF-23 has a biological effect on bone metabolism. The aim of the study was to investigate the association of FGF-23 with (1) the biochemical parameters linked with CKD-bone and mineral disorder (CKD-MBD) and (2) bone mineral density in CKD. METHODS: We studied 145 patients (74 M, 71 F) aged (mean [SD]) 53 [14] years with CKD 1-4. Serum calcium, phosphate, parathyroid hormone, FGF-23, 25 (OH) vitamin D, 1, 25 (OH)(2) vitamin D, bone turnover markers, CRP were determined. BMD was measured at the lumbar spine, femoral neck (FN), forearm, and total hip (TH). Multivariate analysis was undertaken to explore the association between (1) the biochemical variables and FGF-23 and (2) FGF-23 and BMD. RESULTS: Elevations in FGF-23 occurred in CKD stage 3 compared to CKD stage 1/2, although no significant differences in serum phosphate were observed. Serum phosphate (p<0.001), CRP (p<0.001) and diabetes mellitus (p<0.05) were associated with FGF-23. BMD Z-score was significantly lower at the TH and FN in CKD 4 (p<0.05). A significant association was seen between BMI, FGF-23, bone specific alkaline phosphatase and BMD at the TH (p<0.05). CONCLUSIONS: The data suggest that FGF-23 may be associated with parameters implicated in the complications of CKD. Longitudinal studies are required for further clinical evaluation.

Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: implications for clinical management: the CREATE 1 study.

AIMS: The aim of this study is to determine the cardiovascular disease (CVD) risk profile of a large UK HIV cohort and how highly active antiretroviral therapy (HAART) affects this. METHODS: It is a cross-sectional study within a large inner city hospital and neighbouring district hospital. A total of 1021 HIV positive outpatients representative of the complete cohort and 990 who had no previous CVD were included in CVD risk analysis. We recorded demographics, HAART history and CVD risk factors. CVD and coronary heart disease (CHD) risks were calculated using the Framingham (1991) algorithm adjusted for family history. RESULTS: The non-CVD cohort (n = 990) was 74% men, 51% Caucasian and 73.1% were on HAART. Mean age was 41 +/- 9 years, systolic blood pressure 120 +/- 14 mmHg, total cholesterol 4.70 +/- 1.05 mmol/l, high-density lipoprotein-C 1.32 +/- 0.48 mmol/l and 37% smoked. Median CVD risk was 4 (0-56) % in men and 1.4 (0-37) % in women; CHD risks were 3.5 (0-36) % and 0.6 (0-16) %. CVD risk was > 20% in 6% of men and 1% of women and > 10% in 12% of men and 4% of women. CVD risk was higher in Caucasians than other ethnicities; the risk factor contributing most was raised cholesterol. For patients on their first HAART, increased CHD risk (26.2% vs. 6.5%; odds ratio 4.03, p < 0.001) was strongly related to the duration of therapy. CONCLUSIONS: Modifiable risk factors, especially cholesterol, and also duration of HAART, were key determinants of CVD risk. DISCUSSION: Regular CHD and/or CVD risk assessment should be performed on patients with HIV, especially during HAART therapy. The effect of different HAART regimens on CHD risk should be considered when selecting therapy.

Infliximab improves vascular stiffness in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor alpha (TNFalpha)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFalpha blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. METHODS: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. RESULTS: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA p = 0.50) and CAP (chi(2) = 4.13, p = 0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. CONCLUSIONS: Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFalpha-blocking therapy.

Interpreting clinical trials of diabetic dyslipidaemia: new insights.

Current treatment guidelines highlight the importance of aggressive lipid-modifying therapy in reducing cardiovascular risk in patients with type 2 diabetes. Statins are established as the cornerstone of dyslipidaemia management in diabetic patients, based on their efficacy in lowering levels of low-density lipoprotein cholesterol (LDL-C). However, statins fail to address the high residual cardiovascular risk in treated patients, some of which may be attributable to low HDL cholesterol (HDL-C) and elevated triglycerides and to a preponderance of small, dense LDL particles, indicating the need for further intervention. Fibrates are effective against all components of atherogenic dyslipidaemia associated with type 2 diabetes. Clinical studies, most notably the Fenofibrate Intervention and Event Lowering in Diabetes, indicate that fibrates, most likely in combination with a statin, have a secondary role in reducing cardiovascular risk in patients with type 2 diabetes, particularly in those without prior cardiovascular disease or patients with low HDL-C. Results are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes trial to fully evaluate the outcome benefits of this combination strategy.