The association between carotid disease, arterial stiffness and diabetic retinopathy in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIM: To determine whether macrovascular disease assessed by carotid ultrasonography and arterial stiffness by pulse wave velocity are independently associated with diabetic retinopathy in type 2 diabetes. METHODS: A random subgroup of surviving participants with type 2 diabetes from the Fremantle Diabetes Study Phase II were invited to take part in this sub-study in 2018-2019. In addition to standardized questionnaires, a physical examination and fasting biochemical tests, each underwent dilated colour fundus photography, carotid arterial ultrasonography with measurement of the intima-media thickness (IMT) and quantification of the degree of stenosis, and pulse wave analysis calculation of the carotid-femoral pulse wave velocity (cfPWV). The cross-sectional association between arterial disease parameters and diabetic retinopathy was assessed using generalized estimating equation models which enabled both eyes to be included in the analysis. RESULTS: Some 270 participants [mean ± sd age 72 ± 9 years, 153 (57%) men and median (IQR) diabetes duration 15 (11-22) years] were included in analysis. Of 524 assessable eyes, 82 (16%) had diabetic retinopathy. In multivariable analysis, significant independent associates of diabetic retinopathy were age at diabetes diagnosis (inversely), HbA1c , insulin treatment and urinary albumin to creatinine ratio (all P ≤ 0.022), as well as cfPWV [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.03, 1.23 per 1 m/s increase; P = 0.008] and common carotid artery (CCA) IMT ≥1 mm (OR 2.95, 95% CI 1.21, 7.23; P = 0.018). CONCLUSIONS: The association between diabetic retinopathy and CCA IMT suggests that carotid disease may share cardiovascular risk factors with diabetic retinopathy. The association between diabetic retinopathy and cfPWV may reflect the consequences of altered intravascular haemodynamics.

Risk factors and outcomes of anxiety symptom trajectories in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIM: To identify determinants and outcomes of 4-year trajectories of anxiety symptoms in a community-based cohort with type 2 diabetes. METHODS: Some 1091 participants in the Fremantle Diabetes Study-Phase II with type 2 diabetes completed the Generalized Anxiety Disorder Scale at baseline and biennially for 4 years, in addition to psychological, biomedical and self-management measures. Latent growth mixture modelling identified trajectories of anxiety symptom severity, and regression models determined predictors of trajectory membership and associated outcomes. RESULTS: Two distinct groups of participants were identified: those with continuously low-no anxiety symptoms (87%) and those with improving but consistently high anxiety symptoms (elevated anxiety; 13%). Higher HbA1c and BMI, macrovascular complications and a history of generalized anxiety and/or major depressive disorder increased the risk of elevated anxiety. Elevated anxiety did not predict change in health-related outcomes over time. Elevated anxiety and depression symptoms were highly comorbid and those with both displayed the most persistent anxiety symptoms. CONCLUSIONS: A subgroup of individuals with type 2 diabetes are at risk of persistently elevated anxiety symptoms. Routine monitoring of the severity of psychological symptoms over time in this population should facilitate earlier and more intensive mood management.

Clinical risk factors for depressive syndrome in Type 2 diabetes: the Fremantle Diabetes Study.

AIMS: To identify early clinical predictors of depressive syndrome in people with Type 2 diabetes. METHODS: Depressive syndrome was assessed in 325 individuals with Type 2 diabetes 15 years after a baseline assessment, which included information on antidepressant use and depressive symptoms obtained using a quality-of-life scale. Follow-up current and lifetime depressive syndrome were assessed using the nine-item Patient Health Questionnaire and the Brief Lifetime Depression Scale and taking account of antidepressant use. Analyses were conducted inclusive and exclusive of antidepressant use where Patient Health Questionnaire criteria were not met. RESULTS: At baseline, the participants were aged 57.2±9.3 years and the median (interquartile range) diabetes duration was 2.2 (0.6-6.0) years. After a mean of 14.7±1.1 years' follow-up, 81 participants (24.9%) had depressive syndrome (14.8% defined by the Patient Health Questionnaire, 10.2% defined by antidepressants) and 31.4% reported lifetime depression, and in 10.2% of participants this preceded diabetes onset. With logistic regression (inclusive of antidepressants), follow-up depressive syndrome was negatively associated with education level [odds ratio 0.39 (95% CI 0.20-0.75)] and antidepressant use [odds ratio 0.11 (95% CI 0.03-0.36)] and was positively associated with depression history before diabetes onset [odds ratio 2.79 (95% CI 1.24-6.27)]. In the model exclusive of antidepressants, depressive syndrome was positively associated with baseline depressive symptoms [odds ratio 2.57 (95% CI 1.32-5.03)] and antidepressant use [odds ratio 3.54 (95% CI 1.20-10.42)] and was negatively associated with education level [odds ratio 0.39 (95% CI 0.19-0.81)]. CONCLUSIONS: Risk factors for depressive syndrome can be identified early after the onset of Type 2 diabetes. The early presence of depressive symptoms or its treatment and/or history of depression are likely indicators of vulnerability. Early risk stratification for late depressive syndrome is feasible in people with Type 2 diabetes and could assist with depression treatment or prevention.

Feasibility of a multi-modal exercise program on cognition in older adults with Type 2 diabetes - a pilot randomised controlled trial.

BACKGROUND: Type 2 Diabetes (T2D) is associated with increased risk of dementia. We aimed to determine the feasibility of a randomised controlled trial (RCT) examining the efficacy of exercise on cognition and brain structure in people with T2D. METHODS: A 6-month pilot parallel RCT of a progressive aerobic- and resistance-training program versus a gentle movement control group in people with T2D aged 50-75 years (n = 50) at the University of Tasmania, Australia. Assessors were blinded to group allocation. Brain volume (total, white matter, hippocampus), cortical thickness and white matter microstructure (fractional anisotrophy and mean diffusivity) were measured using magnetic resonance imaging, and cognition using a battery of neuropsychological tests. Study design was assessed by any changes (during the pilot or recommended) to the protocol, recruitment by numbers screened and time to enrol 50 participants; randomisation by similarity of characteristics in groups at baseline, adherence by exercise class attendance; safety by number and description of adverse events and retention by numbers withdrawn. RESULTS: The mean age of participants was 66.2 (SD 4.9) years and 48% were women. There were no changes to the design during the study. A total of 114 people were screened for eligibility, with 50 participants with T2D enrolled over 8 months. Forty-seven participants (94%) completed the study (23 of 24 controls; 24 of 26 in the intervention group). Baseline characteristics were reasonably balanced between groups. Exercise class attendance was 79% for the intervention and 75% for the control group. There were 6 serious adverse events assessed as not or unlikely to be due to the intervention. Effect sizes for each outcome variable are provided. CONCLUSION: This study supports the feasibility of a large scale RCT to test the benefits of multi-modal exercise to prevent cognitive decline in people with T2D. Design changes to the future trial are provided. TRIAL REGISTRATION: ANZCTR 12614000222640 ; Registered 3/3/2014; First participant enrolled 26/6/2014, study screening commenced 1/9/2014; Australian and New Zealand Clinical Trial Registry.

Depression symptoms are persistent in Type 2 diabetes: risk factors and outcomes of 5-year depression trajectories using latent class growth analysis.

AIMS: To describe the long-term trajectories of depression symptom severity in people with Type 2 diabetes, and to identify predictors and associates of these trajectories. METHODS: A community-dwelling cohort of 1201 individuals with Type 2 diabetes from the Fremantle Diabetes Study Phase II was followed for 5 years. The nine-item version of the Patient Health Questionnaire was administered annually to assess depression symptoms, and biomedical and psychosocial measures were assessed at baseline and biennially. Latent class growth analysis was used to identify classes of depression severity trajectories and associated outcomes, and logistic regression models were used to determine predictors of class membership. RESULTS: Three trajectories of depression symptoms were identified: continuously low depression symptoms (85.2%); gradually worsening symptoms that then began to improve (persistent depression - low-start; 7.3%); and gradually improving symptoms which later worsened (persistent depression - high-start; 7.5%). Younger age, being a woman, and a lifetime history of major depressive disorder, were associated with greater risk of persistent depression symptoms. Persistent depression was associated with consistently higher BMI over time, but not with changes in HbA1c or self-monitoring of blood glucose. CONCLUSIONS: A subset of individuals with Type 2 diabetes is at risk of depression symptoms that remain elevated over time. Younger, overweight individuals with a history of depression may benefit from early and intensive depression management and ongoing follow-up as part of routine Type 2 diabetes care.

A population-based study of the association between dysglycaemia and hearing loss in middle age.

AIMS: To investigate the independent associations between hearing loss and dysglycaemia in a sample of middle-aged adults, including separate analysis of those aged < 60 years. METHODS: The first 2023 participants in the cross-sectional Busselton Health Ageing Survey were assessed for hearing loss ≥ 26 dB (better ear) for four-frequency average (4FA) of pure-tone thresholds at 500, 1000, 2000 and 4000 Hz, and high-frequency average (HFA) of pure-tone thresholds at 4000 and 8000 Hz. RESULTS: Valid data from 1864 participants in the Busselton Health Ageing Survey [92.1%; mean ± sd age 56.2 ± 5.5 years, 46.0% men, 120 (7.0%) with diabetes, 274 (14.7%) with prediabetes] were analysed, of whom 103 (5.5%) had four-frequency average hearing loss and 561 (30.1%) had high-frequency average hearing loss. In multivariable analyses, glycaemic status was not independently associated with four-frequency or high-frequency average hearing loss. In the 1286 participants aged < 60 years, there was no relationship between dysglycaemia and high-frequency average hearing loss, but the prevalence of four-frequency average hearing loss increased from 2.3% (95% CI 1.5-3.4) in participants with normoglycaemia to 5.7% (95% CI 3.0-10.6) in those with prediabetes and 10.2% (4.2-21.5) in those with diabetes (trend P = 0.003). In multivariable analysis with normoglycaemia as reference, the odds ratios for four-frequency average hearing loss were 2.84 (95% CI 1.29-6.27) for prediabetes and 5.93 (95% CI 1.67-21.05) for diabetes (P ≤ 0.01) in the < 60 year age group. CONCLUSIONS: There was progressively increasing mid-range hearing loss with worsening glucose tolerance in younger individuals, suggesting dysglycaemia-associated early-onset presbycusis.

Lifetime depression and anxiety increase prevalent psychological symptoms and worsen glycemic control in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: To determine the contribution of lifetime major depressive disorder (L-MDD) and lifetime generalized anxiety disorder (L-GAD) to current psychological symptom severity, health behaviour and glycaemic control in type 2 diabetes. METHODS: 1285 community-dwelling people with type 2 diabetes (Fremantle Diabetes Study Phase-II; FDS2) completed the PHQ-9 and Brief Life-Time Depression Scale (BLDS) to assess current and past MDD. The Generalized Anxiety Disorder Scale (GADS) and the Generalized Anxiety Disorder Scale-Lifetime (GAD-LT), designed for FDS2, assessed current and past anxiety. Data were analysed using analysis of covariance and multiple mediation models, controlling for age, gender, marital status, and diabetes duration. RESULTS: L-MDD and L-GAD were independently associated with more severe current depression (both P<0.001) and anxiety (both P<0.001) symptoms. Mediation models revealed that, through increasing the severity of current depressive symptoms, L-MDD was associated with higher HbA1c and body mass index (BMI), greater likelihood of current smoking, and reduced self-monitoring of blood glucose (SMBG) (indirect regression path ab, all P<0.001). In combination, L-MDD+L-GAD additionally elevated the risk of higher HbA1c and worse diabetes management, by increasing the severity of current depressive symptoms (indirect regression path ab, all P<0.001). CONCLUSIONS: Lifetime depression and anxiety increase risk of more severe psychological symptoms, hyperglycaemia, and difficulties with health behaviour in type 2 diabetes. Early screening for these disorders at diabetes diagnosis may be warranted to maximize long-term health outcomes.

Dose-response relationship between statin therapy and glycaemia in community-based patients with type 2 diabetes: the Fremantle Diabetes Study.

Although statins may increase glycaemia in type 2 diabetes, available data are from single-dose intervention trials or studies with no adjustment for concomitant changes in blood glucose-lowering therapy. To provide real-life data covering common statin types and doses, glycated haemoglobin (HbA1c) data from patients in the Fremantle Diabetes Study phases I (FDS1) and II (FDS2) and data on stable diabetes treatment before and after statin initiation were analysed. Intensity of statin therapy was categorized as low, moderate or high based on within-group dose regimens with similar serum LDL cholesterol-lowering effects. In pooled analyses of 335 eligible patients in FDS1 and FDS2, there was no change in HbA1c in the low-intensity group (0.04% or 0.4 mmol/mol; n = 159; p = .40), but a mean 0.22% (2.4 mmol/mol) increase in the moderate-intensity group (n = 185; p = .022) and a larger mean increase of 1.05% (11.5 mmol/mol) increase in the high-intensity group (n = 11; p = .023). These real-life data suggest a dose-response relationship between statin treatment intensity and glycaemia that has potential clinical implications.

Metabolic memory and all-cause death in community-based patients with type 2 diabetes: the Fremantle Diabetes Study.

AIMS: To validate the findings, in a usual care setting, of glycaemic intervention trials, which have shown that tight control in patients with recently diagnosed type 2 diabetes protects against death during post-study monitoring, but that it may be deleterious in long-duration diabetes with vascular complications. METHODS: A subset of 531 patients with type 2 diabetes from the community-based observational Fremantle Diabetes Study Phase 1, who attended ≥5 annual reviews (mean follow-up 15.9 years), were categorized by baseline diabetes duration [<1 year (Group 1); 1 to <5 years (Group 2); and ≥5 years (Group 3)]. Glycated haemoglobin (HbA1c) trajectories over the first 5 years were determined [low, medium and high; equivalent to mean HbA1c ≤6.6% (<49 mmol/mol), 6.7-8.0% (50-64 mmol/mol) and ≥8.0% (>64 mmol/mol), respectively]. Kaplan-Meier analysis was used to assess survival by duration and HbA1c trajectory. Cox proportional hazards modelling identified predictors of all-cause death. RESULTS: There was greater mortality in patients with a medium versus those with a low trajectory in Group 1: hazard ratio (HR) 1.99 [95% confidence interval (CI) 1.003-3.94; p = 0.049], and in patients with a high versus a low trajectory in Group 2: HR 2.02 (95% CI 1.11-3.71; p = 0.022). In Group 3, both medium [HR 0.57 (95% CI 0.35-0.92; p = 0.022)] and high [HR 0.56 (95% CI 0.32-0.96); p = 0.035] trajectories were independently and inversely associated with death. CONCLUSIONS: In community-based patients with newly or recently diagnosed type 2 diabetes, poor glycaemic control was an adverse prognostic indicator. Tight control was independently associated with death in patients with diabetes duration ≥5 years. These data parallel intervention trial findings and support individualization of HbA1c targets.

A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children.

Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case-control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29-0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor α were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype.

Risk of suicide in Australian adults with diabetes: the Fremantle Diabetes Study.

Type 1 diabetes is associated with increased suicide risk. Data for older diabetic individuals are inconsistent. In longitudinal data from 1413 adults recruited to the Fremantle Diabetes Study from 1993-1996 and 5660 matched non-diabetic residents, followed to end-2012, the age and sex-adjusted sub-hazard ratio (95% confidence interval) for suicide in diabetic versus non-diabetic individuals was 1.16 (0.38-3.51). Older Australians with diabetes are not at increased suicide risk.

The metabolic syndrome and cancer: Is the metabolic syndrome useful for predicting cancer risk above and beyond its individual components?

AIMS: The metabolic syndrome (MetS) is a risk factor for cancer. However, it is not known if the MetS confers a greater cancer risk than the sum of its individual components, which components drive the association, or if the MetS predicts future cancer risk. MATERIALS AND METHODS: We linked 20,648 participants from the Australian and New Zealand Diabetes and Cancer Collaboration with complete data on the MetS to national cancer registries and used Cox proportional hazards models to estimate associations of the MetS, the number of positive MetS components, and each of the five MetS components separately with the risk for overall, colorectal, prostate and breast cancer. Hazard ratios (HR) and 95% confidence intervals (95%CI) are reported. We assessed predictive ability of the MetS using Harrell's c-statistic. RESULTS: The MetS was inversely associated with prostate cancer (HR 0.85; 95% CI 0.72-0.99). We found no evidence of an association between the MetS overall, colorectal and breast cancers. For those with five positive MetS components the HR was 1.12 (1.02-1.48) and 2.07 (1.26-3.39) for overall, and colorectal cancer, respectively, compared with those with zero positive MetS components. Greater waist circumference (WC) (1.38; 1.13-1.70) and elevated blood pressure (1.29; 1.01-1.64) were associated with colorectal cancer. Elevated WC and triglycerides were (inversely) associated with prostate cancer. MetS models were only poor to moderate discriminators for all cancer outcomes. CONCLUSIONS: We show that the MetS is (inversely) associated with prostate cancer, but is not associated with overall, colorectal or breast cancer. Although, persons with five positive components of the MetS are at a 1.2 and 2.1 increased risk for overall and colorectal cancer, respectively, and these associations appear to be driven, largely, by elevated WC and BP. We also demonstrate that the MetS is only a moderate discriminator of cancer risk.

Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria.

There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children.

Effect of coadministered fat on the tolerability, safety, and pharmacokinetic properties of dihydroartemisinin-piperaquine in Papua New Guinean children with uncomplicated malaria.

Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0-∞) for PQ (median, 41,906 versus 36,752 µg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 µg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTc tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms(0.5) in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms(0.5), P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded.

Self-awareness of foot health status in patients with Type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIMS: To determine self-awareness of diabetes-related foot problems and its associates in a community-based cohort of people with Type 2 diabetes. METHODS: A survey concerning diabetic foot problems was administered to 358 consecutive patients with Type 2 diabetes [mean ± SD age 67.4 ± 10.8 years, 56.1% males, median (interquartile range) diabetes duration 9.0 (3.9-16.8) years] attending for detailed clinical, biochemical and questionnaire assessment as part of the longitudinal observational Fremantle Diabetes Study Phase II. RESULTS: Compared with the 213 patients (59.5%) who considered their feet to be normal, the 145 (40.5%) who considered their feet to be abnormal were older, had longer diabetes duration and were more likely to have sensory neuropathic symptoms and self-reported poor circulation (P < 0.001). In those who considered their feet to be normal, 67.9% had peripheral sensory neuropathy (score >2/8 on the Michigan Neuropathy Screening Instrument clinical portion), 9.9% had an ankle-brachial index < 0.9, 6.1% had both peripheral sensory neuropathy and an ankle-brachial index < 0.90, and 86.9% had one or more features on inspection, such as deformity, dry skin, callus and fissures that could facilitate more serious complications, despite the majority having had at least one foot examination by a healthcare professional in the previous year. CONCLUSIONS: Self-assessment of diabetes-related foot problems by patients in the Fremantle Diabetes Study Phase II was unreliable. The present data suggest that self-perceived foot health should be assessed together with foot examination findings. Intensive education and monitoring may be necessary in those who consider their feet to be normal but who have neurovascular, structural and/or other precursors of serious foot pathology.

Dipeptidyl peptidase-4 inhibitors: pharmacokinetics, efficacy, tolerability and safety in renal impairment.

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.

Incidence and precipitants of hospitalization for pancreatitis in people with diabetes: the Fremantle Diabetes Study.

AIMS: To determine the relative risk of pancreatitis in diabetes, and to establish whether diabetes-related as well as recognized risk factors contribute. METHODS: We studied 1426 participants [mean (SD) age 62.1 (13.3) years, 49.6% male, 90.9% type 2 diabetes, median (interquartile range) diabetes duration 4.0 (1.0-10.0) years] from the community-based Fremantle Diabetes Study Phase I and 5663 matched residents without diabetes from the same geographical area. Pancreatitis hospitalizations between 1982 and 2010 were ascertained using validated data linkage. For Fremantle Diabetes Study Phase I participants, chart review provided data on the likely causes of pancreatitis. RESULTS: A total of 21 Fremantle Diabetes Study Phase I participants (1.5%) were hospitalized for pancreatitis before study entry vs 29 (0.5%) of contemporaneous residents without diabetes. During a mean (SD) of 12.1 (5.4) years of follow-up from entry, 22 (1.6%) Fremantle Diabetes Study Phase I participants were hospitalized for a first-ever episode of pancreatitis on 37 occasions (1.31/1000 person-years) compared with 58 (1.0%) residents without diabetes on 81 occasions during a mean (SD) 13.6 (4.8) years (0.75/1000 person-years). The age- and sex-adjusted hazard ratio (95% CI) for first-ever pancreatitis hospitalization in Fremantle Diabetes Study Phase I participants was 1.73 (1.06-2.83; P=0.029). Chart review of 17 of the 22 Fremantle Diabetes Study Phase I participants (77%) with incident pancreatitis and available case notes revealed that four (24%) presented without objective evidence of pancreatitis, seven (41%) presented with cholelithiasis, three (18%) with excessive alcohol consumption, two (12%) as a complication of elective endoscopic retrograde cholangiopancreatography, and one (6%) with hypertriglyceridaemia. CONCLUSION: Consistent with previously published data, the risk of pancreatitis was higher in community-dwelling Fremantle Diabetes Study Phase I participants but conventional precipitants accounted for confirmed cases. These data question whether diabetes-specific risk factors cause or contribute to pancreatitis.

Intensification of medication and glycaemic control among patients with type 2 diabetes - the ADVANCE trial.

AIMS: The aim of this study was to assess associations between patient characteristics, intensification of blood glucose-lowering treatment through oral glucose-lowering therapy and/or insulin and effective glycaemic control in type 2 diabetes. METHODS: 11 140 patients from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial who were randomized to intensive glucose control or standard glucose control and followed up for a median of 5 years were categorized into two groups: effective glycaemic control [haemoglobin A1c (HbA1c) ≤ 7.0% or a proportionate reduction in HbA1c over 10%] or ineffective glycaemic control (HbA1c > 7.0% and a proportionate reduction in HbA1c less than or equal to 10%). Therapeutic intensification was defined as addition of an oral glucose-lowering agent or commencement of insulin. Pooled logistic regression models examined the associations between patient factors, intensification and effective glycaemic control. RESULTS: A total of 7768 patients (69.7%), including 3198 in the standard treatment group achieved effective glycaemic control. Compared to patients with ineffective control, patients with effective glycaemic control had shorter duration of diabetes and lower HbA1c at baseline and at the time of treatment intensification. Treatment intensification with addition of an oral agent or commencement of insulin was associated with a 107% [odds ratio, OR: 2.07 (95% confidence interval, CI: 1.95-2.20)] and 152% [OR: 2.52 (95% CI: 2.30-2.77)] greater chance of achieving effective glycaemic control, respectively. These associations were robust after adjustment for several baseline characteristics and not modified by the number of oral medications taken at the time of treatment intensification. CONCLUSIONS: Effective glycaemic control was associated with treatment intensification at lower HbA1c levels at all stages of the disease course and in both arms of the ADVANCE trial.

Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83).

AIMS: Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. METHODS: In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. RESULTS: During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. CONCLUSIONS: Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism.

Incidence and predictors of hospitalization for tendon rupture in type 2 diabetes: the Fremantle diabetes study.

AIMS: To determine the incidence and predictors of tendon ruptures requiring hospitalization of representative patients with type 2 diabetes. METHODS: A total of 1296 patients from the longitudinal observational Fremantle Diabetes Study, Phase I, and 5159 de-identified age- and sex-matched control subjects without diabetes from the same urban area were studied. The patients' mean (sd) age was 64.0 (11.3) years and 48.6% of them were male. Their median (interquartile range) diabetes duration was 4.0 (1.0-9.0) years. The main outcome assessed was any tendon rupture requiring hospitalization in the Fremantle Diabetes Study subjects and the matched control subjects. Independent predictors of spontaneous ruptures in the patients from the Fremantle Diabetes Study were assessed using Cox proportional hazards modelling. RESULTS: The incidence rate ratio for any tendon rupture requiring hospitalization in patients vs control subjects was 1.44 (95% CI 1.10-1.87; P = 0.005). Independent predictors of spontaneous ruptures in patients were BMI [hazard ratio 1.05 (95% CI 1.002-1.10] for 1 kg/m2 increase; P = 0.010] and alcohol consumption [hazard ratio 1.52 (95% CI 1.11-2.09) for √1 standard drink/day increase; P = 0.010]. Adjustment of the incidence rate ratio for overall rupture requiring hospitalization for these variables using the BMI and alcohol consumption data from the contemporary Australian general population suggested it could be as high as 1.84. CONCLUSIONS: There is a greater risk of tendon rupture requiring hospitalization in people with type 2 diabetes. Alcohol consumption and adiposity are potentially modifiable risk factors of spontaneous ruptures in patients with diabetes.