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Aims/Hypothesis In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects. Materials and Methods In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post‐randomization to fenofibrate or placebo. Results The Hp phenotypes 1‐1, 2‐1, and 2‐2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P < 0.0001) and decreased (median 21%) after 6 weeks fenofibrate in all phenotypes (adjusted mean (95% CI): −0.27 (−0.32, −0.23) mg/mL in Hp 1‐1, −0.29 (−0.31, −0.27) mg/mL in Hp 2‐1 and −0.05 (−0.07, −0.02) mg/mL in Hp 2‐2 (P = 0.005 and P = 0.055 vs Hp 1‐1 and Hp 2‐1, respectively)). At 2 years post‐randomization the Hp levels in the placebo group had returned to baseline, whilst the fenofibrate‐group levels remained similar to the 6 week levels. Conclusions In type 2 diabetes, Hp levels differ by Hp phenotype and are decreased by fenofibrate in all phenotypes, but the effect is diminished in Hp 2‐2. Haptoglobin (Hp) levels differed by Hp phenotype in adults with type 2 diabetes. Fenofibrate decreased Hp levels in all Hp phenotypes. A higher baseline Hp level and a smaller fenofibrate‐related decrease in Hp levels in Hp 2‐2 phenotype subjects might be indicative of a lower protective efficacy.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04–0.16, all p  < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p  ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p  < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% ( p  < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.

It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A ), the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period ( = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only ( = 0.01). Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.

Optimal care for familial hypercholesterolaemia (FH) requires patient-centred management, multidisciplinary teamwork, involvement of primary care practitioners, patient networks, support groups and high-quality clinical registries, implemented through models of care adapted to FH. Models of care — evidence-based and context-specific frameworks that aim to deliver the highest quality of care for patients and their families — allow the application of precision and multidisciplinary medicine to FH care and can serve as paradigms for the prevention of premature atherosclerotic cardiovascular disease in all at-risk patients and families worldwide. The exponential growth in the number of publications on diverse aspects of FH has provided new knowledge for developing essential elements of existing models of care. These elements include clinical diagnostic criteria and genetic testing; risk restratification strategies; LDL-cholesterol treatment targets; management protocols for children; care of women in pregnancy; use of pharmacotherapies, including ezetimibe and PCSK9 inhibitors; use of lipoprotein apheresis for severe FH; and addressing barriers to care. However, substantial gaps remain that need to be addressed by a broad research agenda, implementation strategies and global collaboration and advocacy, aimed at improving the uptake, cost-effectiveness and routine implementation of evidence-based standards. In this Review, we summarize the dramatic increase in knowledge that informs adaptive models of care, with an emphasis on articles published since 2014.Familial hypercholesterolaemia is a genetic disorder that impairs the hepatic clearance of LDL, leading to premature atherosclerotic cardiovascular disease. In this Review, Watts and colleagues summarize the latest advances that can inform the development and implementation of new models of care for familial hypercholesterolaemia.

Background and objective: Familial hypercholesterolaemia (FH) can be effectively detected and managed in primary care, but the health economic evidence for this is scarce. The aim of this study was to examine management pathways and cost implications of FH screening and management in Australian general practice. Methods: Cost-effectiveness outcomes were projected using a life table model. Data was used from 133 patients in 15 Australian general practice clinics from an earlier screening and management study. Costing and mortality data were sourced from governmental sources and published literature. Results: Most patients had a regular general practice consultation at baseline (82%), though the proportion seen under a chronic disease management item at follow-up increased to 23%. The median cost of management was $275 per annum in the first year of management. Managing patients with statins up to the age of 60 years yielded an increase of 248,954 life-years at a cost of $759 million, representing a cost per life-year gained of $3047. Discussion: Screening and management of FH in general practice has the potential for substantial health benefits while requiring relatively modest investments from the health system.

Background and objective: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices. Methods: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH. Overall, 63 interviews were conducted with general practice staff at 15 practices taking part in a National Health and Medical Research Council partnership grant study (GNT1142883). Results: Data were analysed thematically and coded into themes - knowledge/awareness/recall, management, use of guidelines/referrals, and contacting family members. Most general practitioners treated the high cholesterol component as their primary focus. Guidelines and referrals were rarely used. Discussion: This research reflected a lack of knowledge, awareness and use of guidelines similar to that shown in other published studies. Improved primary care infrastructure, knowledge and awareness of FH need to be addressed.

Background and objective: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting. Methods: Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study. Results: Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing. Discussion: Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

ObjectiveFamilial hypercholesterolaemia (FH) is characterised by elevated low-density lipoprotein (LDL)-cholesterol and increased risk of cardiovascular disease. However, FH remains substantially underdiagnosed and undertreated. We employed a two-stage pragmatic approach to identify and manage patients with FH in primary healthcare.MethodsMedical records for 232 139 patients who attended 15 general practices at least once in the previous 2 years across five Australian States were first screened for potential risk of FH using an electronic tool (TARB-Ex) and confirmed by general practitioner (GP) clinical assessment based on phenotypic Dutch Lipid Clinic Network Criteria (DLCNC) score. Follow-up GP consultation and management was provided for patients with phenotypic FH.ResultsA total of 1843 patients were identified by TARB-Ex as at potential risk of FH (DLCNC score ≥5). After GP medical record review, 900 of these patients (49%) were confirmed with DLCNC score ≥5 and classified as high-risk of FH. From 556 patients subsequently clinically assessed by GPs, 147 (26%) were diagnosed with phenotypic FH (DLCNC score >6). Follow-up GP consultation and management for 77 patients resulted in a significant reduction in LDL-cholesterol (−16%, p<0.01). A higher proportion of these patients attained the treatment target of 50% reduction in LDL-cholesterol (74% vs 62%, p<0.001) and absolute levels of LDL-cholesterol goals compared with baseline (26% vs 12%, p<0.05).ConclusionsA pragmatic approach integrating electronic medical record tools and clinical GP follow-up consultation is a feasible method to identify and better manage patients with FH in the primary healthcare setting.Trial registration number12616000630415.

Aims/hypothesis Circulating fibroblast growth factor 21 (FGF21) levels are often elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. This study investigated the relationship of plasma FGF21 levels with cardiovascular events in patients with type 2 diabetes. Methods Plasma FGF21 levels were measured by ELISA at baseline in 9,697 individuals with type 2 diabetes participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. We assessed the association of FGF21 levels with the incidence of different cardiovascular outcomes over 5 years. The primary outcome was total cardiovascular disease (CVD) events and the secondary outcomes were the four individual components: coronary heart disease events, total stroke, CVD mortality and coronary and carotid revascularisation. The tertiary outcome was hospitalisation for angina pectoris. Results Higher baseline FGF21 levels were associated with higher risks of all cardiovascular outcome events after adjusting for the study treatment allocation (all p  < 0.01). The associations remained significant for total CVD events and for coronary and carotid revascularisation after further adjusting for confounding factors, with the HR (95% CI) being 1.28 (1.10, 1.50) and 1.26 (1.01, 1.56), respectively, for the highest tertile compared with the lowest tertile (overall effect p  = 0.002 and 0.007, respectively). The addition of FGF21 levels to a model including established CVD risk factors predicting total CVD events led to a non-significant increase in the C-statistic but there was a significant improvement in integrated discrimination and net reclassification. Conclusions/interpretation Higher baseline plasma FGF21 levels were associated with higher risk of cardiovascular events in patients with type 2 diabetes. Trial registration: ISRCTN64783481

Dyslipidemia is common in Obstructive Sleep Apnea (OSA). Postprandial lipidemia (PPL) is a strong marker of cardiovascular risk. Evidence that OSA treatment improves PPL is lacking. To investigate the effect of continuous positive airway pressure (CPAP) treatment on postprandial lipidemia (PPL) in patients with obstructive sleep apnea (OSA) in the upper moderate or severe range. In this randomized, placebo-controlled crossover trial, we compared the effects of 2 months each of therapeutic and placebo CPAP on PPL. PPL was determined from the area under the 24-hour triglyceride concentration curve (TAG-AUC(24)) using seven blood samples drawn across both the wake and sleep periods. Secondary outcomes were the difference in other 24-hour lipid profiles. Thirty-eight eligible patients were randomly assigned to a treatment order and 29 patients completed the trial. CPAP reduced PPL compared with placebo with a mean TAG-AUC(24) difference of -357 mmol/L/d (95% confidence interval [CI], -687.3 to -26.8; P = 0.035). During both the CPAP and placebo studies, TAG levels peaked during both wakefulness (2:00 p.m.) and sleep (3:00 a.m.). Both peaks were lower during CPAP than placebo: 2:00 p.m., -0.49 mmol/L (95% CI, -0.74 to -0.24; P < 0.0005) and 3:00 a.m., -0.40 mmol/L (95% CI, -0.65 to -0.15; P = 0.002). Moreover, mean 24-hour total cholesterol was -0.19 mmol/L lower on CPAP (95% CI, -0.27 to -0.11; P < 0.00001). This randomized trial demonstrated that treatment of severe OSA with CPAP improves postprandial TAG and total cholesterol levels. These effects may reduce the risk for cardiovascular events. The results imply that the association between OSA and cardiovascular disease may, in part, be caused by direct effects on dyslipidemia. Clinical trial registered with the Australian and New Zealand Clinical Trials Registry at www.anzctr.org.au (ACTRN 12605000066684).