Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Insulin sensitivity estimates and their longitudinal association with coronary artery disease in type 1 diabetes. Does it matter?

BACKGROUND: Insulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes. METHODS: The baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status. RESULTS: In 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status. CONCLUSIONS: In type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.

The diabetes management experiences questionnaire: Psychometric validation among adults with type 1 diabetes.

AIMS: To examine the psychometric properties of the Diabetes Management Experiences Questionnaire (DME-Q). Adapted from the validated Glucose Monitoring Experiences Questionnaire, the DME-Q captures satisfaction with diabetes management irrespective of treatment modalities. METHODS: The DME-Q was completed by adults with type 1 diabetes as part of a randomized controlled trial comparing hybrid closed loop (HCL) to standard therapy. Most psychometric properties were examined with pre-randomization data (n = 149); responsiveness was examined using baseline and 26-week follow-up data (n = 120). RESULTS: Pre-randomization, participants' mean age was 44 ± 12 years, 52% were women. HbA1c was 61 ± 11 mmol/mol (7.8 ± 1.0%), diabetes duration was 24 ± 12 years and 47% used an insulin pump prior to the trial. A forced three-factor analysis revealed three expected domains, that is, 'Convenience', 'Effectiveness' and 'Intrusiveness', and a forced one-factor solution was also satisfactory. Internal consistency reliability was strong for the three subscales ( α range = 0.74-0.84) and 'Total satisfaction' ( α = 0.85). Convergent validity was demonstrated with moderate correlations between DME-Q 'Total satisfaction' and diabetes distress (PAID: rs = -0.57) and treatment satisfaction (DTSQ; rs = 0.58). Divergent validity was demonstrated with a weak correlation with prospective/retrospective memory (PRMQ: rs = -0.16 and - 0.13 respectively). Responsiveness was demonstrated, as participants randomized to HCL had higher 'Effectiveness' and 'Total satisfaction' scores than those randomized to standard therapy. CONCLUSIONS: The 22-item DME-Q is a brief, acceptable, reliable measure with satisfactory structural and construct validity, which is responsive to intervention. The DME-Q is likely to be useful for evaluation of new pharmaceutical agents and technologies in research and clinical settings.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Review and comparison of retinal vessel calibre and geometry software and their application to diabetes, cardiovascular disease, and dementia.

Developments in retinal imaging technologies have enabled the quantitative evaluation of the retinal vasculature. Changes in retinal calibre and/or geometry have been reported in systemic vascular diseases, including diabetes mellitus (DM), cardiovascular disease (CVD), and more recently in neurodegenerative diseases, such as dementia. Several retinal vessel analysis softwares exist, some being disease-specific, others for a broader context. In the research setting, retinal vasculature analysis using semi-automated software has identified associations between retinal vessel calibre and geometry and the presence of or risk of DM and its chronic complications, and of CVD and dementia, including in the general population. In this article, we review and compare the most widely used semi-automated retinal vessel analysis softwares and their associations with ocular imaging findings in common systemic diseases, including DM and its chronic complications, CVD, and dementia. We also provide original data comparing retinal calibre grading in people with Type 1 DM using two softwares, with good concordance.

No relationship between socioeconomic status, education level and development and progression of diabetic retinopathy in type 2 diabetes: a FIELD trial substudy.

In 6002 Australian adults with type 2 diabetes and a median 5-year follow-up in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, baseline socioeconomic status (SES) and self-reported education level were not related to development of on-trial sight-threatening diabetic retinopathy. Similarly, in a retinal photography substudy (n = 549), two-step diabetic retinopathy progression was not related to SES or education.

Lipids, hyperreflective crystalline deposits and diabetic retinopathy: potential systemic and retinal-specific effect of lipid-lowering therapies.

The metabolically active retina obtains essential lipids by endogenous biosynthesis and from the systemic circulation. Clinical studies provide limited and sometimes conflicting evidence as to the relationships between circulating lipid levels and the development and progression of diabetic retinopathy in people with diabetes. Cardiovascular-system-focused clinical trials that also evaluated some retinal outcomes demonstrate the potential protective power of lipid-lowering therapies in diabetic retinopathy and some trials with ocular primary endpoints are in progress. Although triacylglycerol-lowering therapies with fibrates afforded some protection against diabetic retinopathy, the effect was independent of changes in traditional blood lipid classes. While systemic LDL-cholesterol lowering with statins did not afford protection against diabetic retinopathy in most clinical trials, and none of the trials focused on retinopathy as the main outcome, data from very large database studies suggest the possible effectiveness of statins. Potential challenges in these studies are discussed, including lipid-independent effects of fibrates and statins, modified lipoproteins and retinal-specific effects of lipid-lowering drugs. Dysregulation of retinal-specific cholesterol metabolism leading to retinal cholesterol accumulation and potential formation of cholesterol crystals are also addressed.

Relative leucocyte telomere length is associated with incident end-stage kidney disease and rapid decline of kidney function in type 2 diabetes: analysis from the Hong Kong Diabetes Register.

AIMS/HYPOTHESIS: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. METHODS: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. RESULTS: In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p < 0.001) than the non-progressors (n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p = 0.024). CONCLUSIONS/INTERPRETATION: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.

BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life. METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction. RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (ß=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels. CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Skin autofluorescence is associated with progression of kidney disease in type 2 diabetes: A prospective cohort study from the Hong Kong diabetes biobank.

BACKGROUND AND AIMS: Skin autofluorescence (SAF) can non-invasively assess the accumulation of tissue AGEs. We investigated the association between SAF and kidney dysfunction in participants with T2D. METHODS: Of 4030 participants consecutively measured SAF at baseline, 3725 participants free of end-stage kidney disease (ESKD) were included in the analyses. The association of SAF with incident ESKD or ≥30% reduction in estimated glomerular filtration rate (eGFR) was examined with Cox regression, linear mixed-effects model for the association with annual eGFR decline, and mediation analyses for the mediating roles of renal markers. RESULTS: During a median (IQR) 1.8 (1.1-3.1) years of follow-up, 411 participants developed the outcome. SAF was associated with progression of kidney disease (hazard ratio 1.15 per SD, 95% confidence interval [CI] [1.04, 1.28]) and annual decline in eGFR (ß -0.39 per SD, 95% CI [-0.71, -0.07]) after adjustment for risk factors, including baseline eGFR and urinary albumin-creatinine ratio (UACR). Decreased eGFR (12.9%) and increased UACR (25.8%) accounted for 38.7% of the effect of SAF on renal outcome. CONCLUSIONS: SAF is independently associated with progression of kidney disease. More than half of its effect is independent of renal markers. SAF is of potential to be a prognostic marker for kidney dysfunction.

Multifocal pupillographic objective perimetry for assessment of early diabetic retinopathy and generalised diabetes-related tissue injury in persons with type 1 diabetes.

BACKGROUND: To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). METHODS: Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. RESULTS: The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. CONCLUSIONS/INTERPRETATION: In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

Fenofibrate, which reduces risk of sight-threatening diabetic retinopathy in type 2 diabetes, is associated with early narrowing of retinal venules: a FIELD trial substudy.

Retinal vessel calibre metrics were evaluated at baseline and 2 years in a FIELD substudy (n = 208). Central retinal venule calibre was significantly reduced by fenofibrate and unchanged by placebo. Arteriole metrics did not change. Larger studies relating retinal vessel calibre to future diabetes complications and response to therapy are merited.

Insulin antibodies are prevalent in adults with type 1 diabetes referred for islet cell transplantation and are modified by islet transplantation and immunosuppression: an Australian experience.

We have analysed insulin antibodies in 149 adults with type 1 diabetes and 2859 people without diabetes. We have determined that insulin antibody levels are higher in adults with, versus without, diabetes and that the levels are falling, and more patients are becoming antibody-negative post islet cell transplantation.

Epidemiology of Type 1 Diabetes.

PURPOSE OF REVIEW: Epidemiological research on type 1 diabetes (T1D) has traditionally focussed on the paediatric age group, but recent data in adults has confirmed it to be a disease of all ages with a wide clinical spectrum. We review the epidemiology and clinical features of T1D across the lifespan. RECENT FINDINGS: While the peak incidence of T1D is still in early adolescence, T1D is now diagnosed more commonly in adulthood than childhood due to increasing recognition of adult-onset T1D and the length of the adult lifespan. It still follows the known geographic variations in incidence, being highest in Northern Europe and lowest in Asia. The onset of T1D in adulthood is usually less acute than in childhood and confers a lower, although still substantial, risk of complications and early mortality. Interventions to delay T1D onset are emerging and screening for those at risk at birth is increasingly available. Type 1 diabetes can develop at any age and may not present with ketosis or an immediate insulin requirement in adults. Macro- and microvascular complications are the greatest cause of excess morbidity and mortality in this population.

Baseline extended zone retinal vascular calibres associate with sensory nerve abnormalities in adolescents with type 1 diabetes: A prospective longitudinal study.

OBJECTIVE: The relationship between retinal vascular calibres (RVCs) and diabetic neuropathy is unclear. We investigated associations between RVCs and sensory nerve abnormality in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a prospective longitudinal study of 889 adolescents with type 1 diabetes with baseline mean (±SD) age 14.1 ± 1.5 years and HbA1c IFCC 69.4 ± 14.1 mmol/mol (8.6 ± 1.3%), RVCs were assessed from baseline retinal photographs: 'central zone' calibres, summarized as central retinal arteriolar (CRAE) and venular equivalents (CRVE) and 'extended zone' calibres: mean width of arterioles (MWa) and venules (MWv). Sensory nerve abnormality was defined as at least one abnormal sensory quantitative testing from two thermal and two vibration threshold tests measured at foot every 1-2 years. Associations between baseline RVC and sensory nerve function were examined using generalized estimating equations and cumulative risk by Cox regression analyses. RESULTS: During a median study follow-up of 6.2 [IQR 3.7-10.4] years, sensory nerve abnormality was found in 27% of adolescents. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs. Q2-4: OR 1.35 (95% CI 1.02, 1.61) and MWv (Q1 vs. Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA1c , duration and blood pressure. Similarly, in Cox regression, the narrowest quartiles were associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8) and MWv 1.6 (1.4, 1.9). CONCLUSIONS: Narrower extended zone retinal calibres were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Uric acid predicts long-term cardiovascular risk in type 2 diabetes but does not mediate the benefits of fenofibrate: The FIELD study.

AIM: To explore the relationship between baseline uric acid (UA) levels and long-term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA-lowering effects. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week, active fenofibrate run-in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre-to-post run-in reductions in UA and long-term cardiovascular outcomes. RESULTS: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13-1.29, P < .001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run-in was also a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long-term risk (HR 0.86, 95% CI 0.76-0.97, P = .015). This effect was not modified by treatment allocation (Pinteraction = .77). CONCLUSIONS: UA is a strong independent predictor of long-term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate.

Point-of-care testing of HbA1c, renal function and lipids in remote or disadvantaged regions.

For optimal diabetes management HbA1c, lipid and renal function measurements are key. Suitable point-of-care systems can provide such data in remote areas, diabetes camps, disaster relief, small community hospitals and in community screening days in disadvantaged regions. Some systems are currently used in Australian rural, remote and indigenous health services.

Serum apolipoproteins and apolipoprotein-defined lipoprotein subclasses: a hypothesis-generating prospective study of cardiovascular events in T1D.

APOB, APOC3, and APOE and apolipoprotein-defined lipoprotein subclasses (ADLSs; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and CVD. Our main objective was to define associations of serum apolipoproteins and ADLSs with "any CVD" and "major atherosclerotic cardiovascular events" (MACEs) in a prospective study of T1D. Serum apolipoproteins and ADLSs (14 biomarkers in total) were measured in sera (obtained between 1997 and 2000) from a subset (n = 465) of the Epidemiology of Diabetes Interventions and Complications cohort. Prospective associations of "any CVD" (myocardial infarction, stroke, confirmed angina, silent myocardial infarction, revascularization, or congestive heart failure) and MACEs (fatal or nonfatal myocardial infarction or stroke), over 5,943 and 6,180 patient-years follow-up, respectively, were investigated using Cox proportional hazards models that were unadjusted and adjusted for risk factors. During 15 years of follow-up, 50 "any CVD" events and 24 MACEs occurred. Nominally significant positive univariate associations with "any CVD" were APOB, APOC3 and its subfractions [heparin precipitate, heparin-soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACEs were APOC3 and its subfractions and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjusting for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLSs with either "any CVD" or MACEs. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for any CVD and MACEs in adults with T1D.